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UBC Theses and Dissertations

An evaluation of the usp dissolution apparatus Desta, Belachew 1972

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AN EVALUATION OF THE USP DISSOLUTION APPARATUS by BELACHEW DESTA B.PHARM., HAILE SELLASSIE I UNIVERSITY ADDIS ABABA, ETHIOPIA, 19 64 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN PHARMACY i n the D i v i s i o n of Pharmaceutical Chemistry of the Fa c u l t y of Pharmaceutical Sciences We accept t h i s t h e s i s as conforming to the re q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA JULY, 1972 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the requirements f o r an advanced degree at the U n i v e r s i t y o f B r i t i s h Columbia, I agree tha t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and s tudy. I f u r t h e r agree t h a t permiss ion f o r ex tens ive copying o f t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . I t i s understood tha t copying o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l ga in sha l l not be al lowed w i thou t my w r i t t e n pe rm iss ion . Department o f The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada Date • , t ^ ^ -- i -ABSTRACT The o b j e c t i v e of t h i s i n v e s t i g a t i o n was to evaluate the USP d i s s o l u t i o n apparatus. The t e s t drug products used were two brands of chlorpromazine HC1 t a b l e t s which had been pre-v i o u s l y evaluated c l i n i c a l l y . On the ba s i s of the d i s s o l u t i o n c h a r a c t e r i s t i c s obtained with these and s e v e r a l other products, i t was concluded that (a) simulated g a s t r i c f l u i d was the media of choice f o r t a b l e t s c o n t a i n i n g chlorpromazine HC1, (b) the geometry of the d i s s o l u t i o n v e s s e l had no s i g n i f i c a n t e f f e c t on d i s s o l u t i o n c h a r a c t e r i s t i c s , (c) a ten mesh basket be s u b s t i t u t e d f o r the 40 mesh basket now s p e c i f i e d by the USP, (d) the depth of the basket i n the media should be 3 cm. r a t h e r than the 2 cm. now s p e c i f i e d , (e) the pH e f f e c t of the media should be studied care-f u l l y before s e t t i n g s p e c i f i c a t i o n s f o r a drug product, ( f ) t h a t the basket should be i n s e r t e d i n t o the media while r o t a t i n g i n order to prevent v a r i a t i o n s i n d i s s o l u t i o n c h a r a c t e r i s t i c s , (g) the method i s re p r o d u c i b l e under standardized c o n d i t i o n s , and (h) the method i s as good or b e t t e r than three other . d i s s o l u t i o n methods described i n the l i t e r a t u r e . This a b s t r a c t represents the true contents of the t h e s i s submitted. Supervisor - i i -TABLE OF CONTENTS Page I. INTRODUCTION 1 II. LITERATURE SURVEY 4 1. Theory of Dissolution 4 2. Development of Dissolution Methodology 15 3. Classification of Dissolution Test Methods 25 (A) Stirred Vessel Methods 25 (B) Modified USP Disintegration Methods 34 (C) Continuous Flow and Automated Procedures .. 39 (D) Miscellaneous Methods 49 (a) Forced Convection, Non-Sink Methods .. 53 (b) Forced Convection, Sink Methods 58 (c) Natural Convection, Non-Sink Methods . 64 4. Correlation of In-vitro Dissolution Tests with In-vivo Data 66 5. Development of Standard Dissolution Procedures . 69 III. THE TEST DRUG - CHLORPROMAZINE HYDROCHLORIDE (CPZ-HC1) 73 IV. EXPERIMENTAL 8 6 1. Apparatus .. 8 6 2. Chemicals and Reagents 88 3. Analysis of Chlorpromazine Hydrochloride 89 (a) Infrared Spectrum of Chlorpromazine Hydrochloride 89 (b) UV-Spectral Characteristics of Chlorpromazine 89 - i i i -Page (c) Preparation of a Calibration Curve 90 (d) Determination of the Absorptivity Value in Water 9 3 4. Determination of Content Uniformity of Chlorpromazine Hydrochloride Tablets 9 7 5. Determination of Chlorpromazine Hydrochloride in Dissolution Media 101 V. RESULTS AND DISCUSSION 10 3 1. Effect of Dissolution Media 103 2. Effect of Geometry of the Dissolution Vessel ... 108 3. Effect of Mesh Size 114 4. Effect of Stirring Rate 122 5. Effect of Basket-Stirrer Depth 131 6. Effect of pH of Dissolution Fluid 134 7. Effect of Immersion of the Basket while Rotating 139 8. Disintegration Data Versus Dissolution Data .... 142 9. Reproducibility of Dissolution Values as obtained by using the USP Method 144 10. Comparison of the Dissolution Characteristics of Different Brands of CPZ-HC1 Tablets 146 11. Comparison of the USP Dissolution Method with Three Other Methods 15 3 1.2.. Comments on and Criticisms of the USP Dissolution Apparatus 156 VI. SUMMARY AND CONCLUSIONS 159 VII. REFERENCES 161 - Iv -LIST OF TABLES Table Page 1. Nurses' Observational Scale f o r I n p a t i e n t E v a l u a t i o n 84 2. Data f o r the determination of the a b s o r p t i v i t y value of CPZ-HC1 96 3. Results of the content u n i f o r m i t y t e s t of CPZ-HC1 t a b l e t s (Brand A) 98 4. Results of the content u n i f o r m i t y t e s t of CPZ-HC1 t a b l e t s (Brand B) 99 5. Results of the content u n i f o r m i t y t e s t of CPZ-HC1 t a b l e t s (Brand C) 190 6. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s of chloropromazine hydrochloride t a b l e t s (Brands A, B and C) i n d i s t i l l e d water and simulated g a s t r i c f l u i d using the USP apparatus 105 7. Comparison of d i s s o l u t i o n values of CPZ-HC1 t a b l e t s (Brands A, B and C) i n USP v e s s e l and 1L., 2 L., and 3 L. round bottom f l a s k s . Simulated g a s t r i c f l u i d was used as the d i s s o l u t i o n medium and the 40 mesh basket was r o t a t e d at 50 r.p.m 112 8. Comparison of d i s s o l u t i o n values of CPZ-HC1 t a b l e t s (Brands A, B and C) i n USP v e s s e l and 1 L., 2 L., and 3 L. round bottom f l a s k s using d i s t i l l e d water as the d i s s o l u t i o n medium. The basket was r o t a t e d at 50 r.p.m 113 9. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s (Brands A, B and C) i n simulated g a s t r i c f l u i d using 40 mesh and 10 mesh baskets i n the USP apparatus ' 118 10. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s (Brands A, B and C) i n d i s t i l l e d water, using 40 mesh and 10 mesh baskets i n the USP apparatus .... 118 11. D i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s (Brands A, B and C) as obtained using a 10 mesh basket and a d i s s o l u t i o n medium of simulated g a s t r i c f l u i d 120 - V -Table Page 12. D i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s (Brands A, B and C) as obtained using a 10 mesh basket and a d i s s o l u t i o n medium of d i s t i l l e d water 121 13. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s (Brands A, B and C) as obtained wi t h the USP procedure at d i f f e r e n t s t i r r i n g speeds 123 14. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s (Brands A, B and C) as obtained using the USP procedure at d i f f e r e n t speeds 127 15. E f f e c t of s t i r r e r depth on the d i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s as obtained by using simulated g a s t r i c f l u i d i n the USP apparatus 132 16. E f f e c t of s t i r r e r depth on the d i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s as obtained by using simulated g a s t r i c f l u i d i n a 1 L. round bottom f l a s k I 3 5 17. E f f e c t of s t i r r e r depth on the d i s s o l u t i o n c h a r a c t e r i s t i c s o f CPZ-HC1 t a b l e t s as obtained by using simulated g a s t r i c f l u i d i n a 2 L. round bottom f l a s k 136 18. E f f e c t of s t i r r e r depth on the d i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s as obtained by using simulated g a s t r i c f l u i d i n a 3 L. round bottom f l a s k * 137 19. Comparison of d i s s o l u t i o n values of CPZ-HC1 t a b l e t s as obtained with the procedure i n which the basket i s not r o t a t e d when immersed i n t o the d i s s o l u t i o n medium (USP method) and the modified procedure i n which the basket i s immersed while r o t a t i n g 141 20. D i s i n t e g r a t i o n values of CPZ-HC1 t a b l e t s (Brands A, B and C) i n d i s t i l l e d water and i n simulated g a s t r i c f l u i d , using the USP D i s i n t e g r a t i o n Method and a modified method (USP method without d i s c s ) 143 21. Data f o r d i s s o l u t i o n values of ten t a b l e t s of each of Brands A, B and C as obtained by using simulated g a s t r i c f l u i d i n the USP apparatus I 4 5 - v i -Table Page 22. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s (T50 value) of seven brands of CPZ-HC1 t a b l e t s as obtained using 40 mesh and 10 mesh baskets. D i s t i l l e d water and simulated g a s t r i c f l u i d were used as the d i s s o l u t i o n media and the s t i r r i n g speed was 50 r.p.m 149 23. Comparison of the d i s s o l u t i o n c h a r a c t e r i s t i c s of CPZ-HC1 t a b l e t s as obtained by using simulated g a s t r i c f l u i d and water as the d i s s o l u t i o n media .... 157 - v i i -LIST OF FIGURES Figure Page 1. Schematic Diagram of D i s s o l u t i o n R a t e - l i m i t e d Absorption 14 2. Schematic Diagram of D i s s o l u t i o n from a Plane S o l i d Surface 14 3. Diagramatic Representation of S t i r r e d Vessel Types of D i s s o l u t i o n Apparatus. (A) Beaker Method 26 (B) Magnetic S t i r r e r Method 26 (C) Tape-frame Method 28 (D) S t i r r e d Water-jacketed-vessel Method 28 (E) S t i r r e r Capsule Holder Method 29 (F) Basket S t i r r e r Method 29 (G) The Case of S t a i n l e s s - s t e e l Gauze 31 (H) Wire S p i r a l Method 31 (I) Bead and P l a t e Method 3 3 (J) Blade Method 3 3 ; . (K) Method of Thomas and McCarthy 35 4. Diagramatic Representation of Modified USP D i s i n t e g r a t i o n Types of D i s s o l u t i o n Apparatus. (A) V l i e t ' s Method 37 (B) Levy's Modified Apparatus 37 (C) Apparatus of Goldberg et a l 38 (D) Apparatus of Katchen et a l 38 5. Diagramatic Representation of Continuous Flow Types of D i s s o l u t i o n Apparatus. (A) Apparatus of Schroeter and Wagner 40 (B) Apparatus of Sjogren et a l 42 (C) Apparatus of McClintock et a l 4 3 (D) Apparatus of Lapidus and L o r d i 44 (E) Apparatus of Ganderton et a l 46 (F) B a s k e t - S t i r r e r Apparatus of Pernarowski et a l 4 7 (G) Apparatus of Rippie and Johnson 48 (H) Apparatus of Baun and Walker 50 ( I ) Sample Bulb of the Apparatus of C a s t e l l o et a l 51 (J) Apparatus of Tingstad and Riegelman 52 (£) Apparatus of Burger and Nash ,5:2 6. Diagramatic Representation of Miscellaneous D i s s o l u t i o n Methods. (A) Wruble Apparatus 54 (B) Souder and Ellenbogen Apparatus 54 (C) Rotating Flask Method of G i b a l d i and Weintraub 56 . (D) P a r t i c l e Size Method of Edmundson and Lees 56 - v i i i -Figure Page (E) Shaker Method of Singh et a l 57 (F) Shaker Method of Schwartz et a l 57 (G) R o t a t i n g Disc Method of Levy and S a h l i 59 (H) Adsorption Method of Wurster and P o l l i 59 (I) P a r t i t i o n Method of G i b a l d i and Feldman 60 (J) P a r t i t i o n Method of N i e b e r g a l l et a l . . 60 (K) P a r t i t i o n Method of U l l a h and Cadwallader 62 (L) D i a l y s i s Method of P a t e l and Foss .... 63 (M) D i a l y s i s Method of F e r r a r i and Khoury. 6 3 (N) O s c i l l a t i n g D i a l y s i s C e l l of Krogerus et a l 65 (Q) Solvometer 6 5 (P) Hanging P e l l e t Method 67 (Q) S t a t i c Disc'Method 67 7. Chemical Structure of CPZ-HC1 7 3 8. F a c s i m i l e of the B r i e f P s y c h i a t r i c Rating Scale 81 9. Diagram of USP Apparatus 87 10. A Spectral-Absorbance Curve f o r CPZ-HC1 i n D i s t i l l e d Water and Simulated G a s t r i c F l u i d .. 91 11. A Spectral-Absorbance Curve f o r CPZ-HC1 i n D i s t i l l e d Water as obtained by using the Beckman DU-2 Spectrophotometer 9 2 12. A C a l i b r a t i o n Curve f o r CPZ-HC1 i n D i s t i l l e d Water 94 13. D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using D i s t i l l e d Water i n the USP Apparatus. The basket was r o t a t e d at 50 r.p.m. 104 14. D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using Simulated G a s t r i c F l u i d i n the USP Apparatus. The basket was r o t a t e d at 50 r.p.m 107 15. D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using the USP D i s s o l u t i o n V e s s e l , 1 L., 2 L. and 3 L. Round Bottom Flask. Simulated G a s t r i c F l u i d was used as the t e s t medium and the 40 mesh basket was r o t a t e d at 50 r.p.m 109 - i x -Figure Page 16. D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using a 1 L i t e r Round Bottom Flask as the D i s s o l u t i o n V e s s e l . Simulated G a s t r i c F l u i d was used as the D i s s o l u t i o n Medium, and the 40 mesh basket was r o t a t e d at 50 r.p.m I l l 17. D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using a 10 mesh basket and D i s t i l l e d Water and Simulated G a s t r i c F l u i d as the D i s s o l u t i o n Media i n the USP Apparatus. The basket was r o t a t e d at 50 r.p.m 116 18. Comparison of D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using 40 mesh and 10 mesh baskets (r o t a t e d at 50 r.p.m.) i n the USP Apparatus. Simulated G a s t r i c F l u i d was used as the t e s t medium .... 117 19. D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using the USP Apparatus, i n which the Basket i s r o t a t i n g at 25, 50, 100, and 150 r.p.m. D i s t i l l e d Water was used as the D i s s o l u t i o n Medium 124 20. D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using the USP Apparatus i n which the Basket was r o t a t e d at 25, 50, 75, and 100 r.p.m. Simulated G a s t r i c F l u i d was used as the D i s s o l u t i o n Medium 125 21. Comparison of the D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using the USP Apparatus i n which the 40 mesh Basket was r o t a t e d at 25, 75, and 100 r.p.m. Simulated G a s t r i c F l u i d was used as the D i s s o l u t i o n Medium 128 22. Comparison of the D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using the USP Apparatus i n which the 10 mesh Basket was r o t a t e d at 25, 75, and 100 r.p.m. Simulated G a s t r i c F l u i d was used as the D i s s o l u t i o n Medium 130 - X -Figure Page 23. E f f e c t of Distance of B a s k e t - S t i r r e r from the bottom of the D i s s o l u t i o n Vessel (USP Flask and 1 L i t e r Round Bottom Flask) on the T60 Values of CPZ-HC1 Tablets (Brands A, B and C) i n Simulated G a s t r i c F l u i d . The 40 mesh basket was r o t a t e d at 50 r.p.m 133 24. E f f e c t of Distance of B a s k e t - S t i r r e r from the bottom of the D i s s o l u t i o n Vessel (2 L. and 3 L. Round Bottom Flask) on the Tgo Value of CPZ-HC1 Tablets (Brands A, B and C) i n Simulated G a s t r i c F l u i d . The 40 mesh basket was r o t a t e d at 50 r.p.m 138 25. E f f e c t of pH on the D i s s o l u t i o n C h a r a c t e r i s -t i c s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using Simulated G a s t r i c F l u i d i n the USP Apparatus. The 4 0 mesh basket was r o t a t e d at 50 r.p.m 140 26. Comparison of the D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B, C, D, E, F and G) as obtained by using D i s t i l l e d Water i n the USP Apparatus. The 40 mesh basket was r o t a t e d at 50 r.p.m 147 27. Comparison of the D i s s o l u t i o n P r o f i l e s o f CPZ-HC1 Tablets (Brands A, B, C, D, E, F and G) as obtained by using D i s t i l l e d Water i n the USP Apparatus. The 10 mesh basket was r o t a t e d at 50 r.p.m 148 28. Comparison of the D i s s o l u t i o n P r o f i l e s o f CPZ-HC1 Tablets (Brands A, B, C, D, E, F and G) as obtained by using Simulated G a s t r i c F l u i d i n the USP Apparatus. The 4 0 mesh basket was r o t a t e d at 50 r.p.m 150 29. Comparison of the D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B, C, D, E, F and G) as obtained by using Simulated G a s t r i c F l u i d i n the USP Apparatus. The 10 mesh basket was r o t a t e d at 50 r.p.m 151 30. A diagramatic Representation of the P r o p e l l e r used i n the St a t i o n a r y Basket Method 153 Comparison of the D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brands A, B and C) as obtained by using the USP Method, D i s s o l u t i o n Method I I of the NF, St a t i o n a r y Basket Method, and S t a i n l e s s S t e e l C y l i n d e r Method. Simulated G a s t r i c F l u i d was used as the D i s s o l u t i o n Medium and the basket was r o t a t e d at 50 r.p.m. . - x i i ACKNOWLEDGEMENTS The author wishes to express h i s g r a t i t u d e to h i s s u p e r v i s o r , Dr. M. Pernarowski, f o r h i s guidance and encouragement during the course of t h i s study. The author would l i k e to thank Dr. F. Morrison f o r h i s h e l p f u l suggestions and c r i t i c i s m s of the o r i g i n a l manuscript. F i n a l l y , the author would l i k e to thank h i s w i f e , Ayalnesh, f o r her help i n the prepar a t i o n of the manuscript and f o r her patience and encouragement. F i n a n c i a l a s s i s t a n c e i n the form of a s c h o l a r s h i p from the Canadian I n t e r n a t i o n a l Development Agency i s g r a t e f u l l y acknowledged. I . INTRODUCTION S o l i d dosage forms are the most frequent means of a d m i n i s t e r i n g drugs i n t o the body. The compressed t a b l e t and the g e l a t i n capsule have been i n common use since the l a t t e r part of the nineteenth century. U n t i l a few decades ago, however, a l l t h a t was thought necessary f o r c l i n i c a l e f f e c t i v e n e s s of the above dosage forms was the presence of the c o r r e c t amount of the a c t i v e i n g r e d i e n t ( s ) . In more recent a d d i t i o n s of the compendia, s p e c i f i c a t i o n s f o r d i s i n t e g r a t i o n time, weight v a r i a t i o n , content u n i f o r m i t y , and d i s s o l u t i o n r a t e t e s t i n g have been included as a means of ensuring b e t t e r drug product q u a l i t y . The f a c t that d i f f e r e n t brands of the same drug have been observed to have d i f f e r e n t c l i n i c a l e f f e c t s l e d to a study of the d i s s o l u t i o n phenomenon and r e s u l t e d i n the development of a wide v a r i e t y of t e s t methods. The United States Pharmacopoeia-National Formulary (USP-NF) J o i n t Panel on P h y s i o l o g i c a l A v a i l a b i l i t y recommended to the Compendia two d i s s o l u t i o n t e s t procedures, a f t e r a study of a considerable v a r i e t y of d i s s o l u t i o n methods reported i n the l i t e r a t u r e . The USP, i n i t s eighteenth e d i t i o n , adopted the basket s t i r r e r method. The NF, i n i t s t h i r t e e n t h e d i t i o n , adopted both the basket s t i r r e r method and a m o d i f i c a t i o n of the G e r s h b e r g - S t o l l apparatus. The choice of the USP apparatus by the USP-NF J o i n t Panel was based on the r e s u l t s of c o l l a b o r a t i v e s t u d i e s c a r r i e d out - 2 -using s a l i c y l i c a c i d d i s c s and f l e x i b i l i t y of the apparatus as to the degree of a g i t a t i o n and choice of d i s s o l u t i o n media. However, various shortcomings of the o f f i c i a l apparatus have been reported i n the l i t e r a t u r e . I t a l s o appears t h a t no c o r r e l a t i o n of data obtained from d i s s o l u t i o n t e s t s using the USP d i s s o l u t i o n apparatus with c l i n i c a l s t u d i e s have been reported to t h i s date. The purpose of t h i s study i s to assess the USP apparatus and i t s merits i n d i f f e r e n t i a t i n g between two c l i n i c a l l y d i f f e r e n t brands of chlorpromazine hydrochloride t a b l e t s . This drug i n i t s dosage form was chosen f o r the i n v e s t i g a t i o n because (1) t h i s l a b o r a t o r y was requested to evaluate purportedly c l i n i c a l l y i n a c t i v e c h l o r -promazine hydrochloride t a b l e t s obtained from Riverview Mental H o s p i t a l i n Essondale, B.C.; (2) data was a v a i l a b l e f o r two c l i n i c a l l y d i f f e r e n t brands of commercial chlorpromazine hydrochloride t a b l e t s — s t u d i e s had been c a r r i e d out on these brands at the H o s p i t a l f o r Mental Diseases, i n S e l k i r k , Manitoba; and (3) there i s no d i s s o l u t i o n time l i m i t f o r chlorpromazine hydrochloride t a b l e t s l i s t e d i n the USP. The USP-NF J o i n t Panel recommended tha t the D i r e c t o r s of the R e v i s i o n of the USP and NF continue a j o i n t program t o : (1) e s t a b l i s h which a d d i t i o n a l compendial items need d i s s o l u t i o n standards, (2) s t i m u l a t e the generation of i n - v i v o data that w i l l make i t p o s s i b l e to develop more o b j e c t i v e i n - v i t r o d i s s o l u t i o n s p e c i f i c a t i o n s , and - 3 -(3) determine i f m o d i f i c a t i o n s are needed i n the methods o f f i c i a l l y adopted. This i n v e s t i g a t i o n , t h e r e f o r e , w i l l attempt to provide some data which may help to answer some of the questions r a i s e d by the USP-NF J o i n t Panel and to transmit t h i s i n f o r m a t i o n to the newly appointed USP-NF J o i n t Panel on D i s i n t e g r a t i o n and D i s s o l u t i o n . I I . LITERATURE SURVEY The s i g n i f i c a n c e of d i s s o l u t i o n r a t e as a major f a c t o r i n the e v a l u a t i o n of dosage forms was not f u l l y appreciated p r i o r to the p u b l i c a t i o n of the e a r l y papers by Wagner, Levy, Nelson, and others who f i r s t proposed the concept of 'bio-pharmaceutics' as a separate d i s c i p l i n e w i t h i n the pharma-c e u t i c a l s c i e n c e s . The r e l a t i o n s h i p of some of the p h y s i c a l and chemical p r o p e r t i e s of the drug and i t s dosage forms and i t s b i o l o g i c a l e f f e c t upon a d m i n i s t r a t i o n was demonstrated i n a number of ways and q u a n t i t a t e d by a p p l i c a t i o n of e x i s t i n g and newly derived mathematical p r i n c i p l e s . F i c k (1855) expressed d i f f u s i o n q u a n t i t a t i v e l y by adopting F o u r i e r ' s mathematical equation f o r heat conduction. According to F i c k ' s Law, the qu a n t i t y of s o l u t e (dw) which d i f f u s e s at constant temperature through an area A, i n time ( d t ) , when the concentr a t i o n changed by an amount (dc) through a distance (dx), at r i g h t angles to the plane A, i s expressed as: 1. Theory of D i s s o l u t i o n dw 3 t = - DA dc dt (Eq. 1) where D i s the d i f f u s i o n constant and the only motion involved i s due to molecular a g i t a t i o n . - 5 -The f i r s t q u a n t i t a t i v e study of the d i s s o l u t i o n process i s a c c r e d i t e d to Noyes and VJhitney (1897) and the expression g e n e r a l l y accepted to describe the r a t e of s o l u t i o n process, when the change i n surface area of the exposed s o l i d i s n e g l i g i b l e , i s known as the Noyes-Whitney Law. This law stat e s t h a t the r a t e of concent r a t i o n change at any i n s t a n t d i r e c t l y p r o p o r t i o n a l to the d i f f e r e n c e between the con c e n t r a t i o n of a saturated s o l u t i o n C s, and the concentra-t i o n C i n the bulk of the s o l u t i o n at t h i s i n s t a n t . where K = a constant w i t h a dimension of 1/time. On i n t e g r a t i o n (with c = 0 at t = 0 ) , the above equation y i e l d s : According to Noyes-Whitney, the d i s s o l u t i o n process was explained on the assumption that a very t h i n l a y e r of saturated s o l u t i o n ( f i l m t hickness or d i f f u s i o n l a y e r ) was formed at the surface of the s o l i d and that the d i s s o l u t i o n r a t e was dependent on the r a t e of d i f f u s i o n from the saturated l a y e r i n t o the bulk of the s o l u t i o n . dc 3 t = k (C s - C) (Eq. 2) In (C s - C) = In C s - kt (Eq. 3) - 6 -Nernst and Brunner (1904) advanced a t h e o r e t i c a l g e n e r a l i z a t i o n of the above law i n terms of a l l kinds of heterogenous r e a c t i o n s . They assumed the e x i s t e n c e of a s t a t i o n a r y l i q u i d f i l m through which d i f f u s i o n i n t o the main body of the s t i r r e d l i q u i d takes place. The r e a c t i o n at the l i q u i d - s o l i d i n t e r f a c e i s supposed to be i n f i n i t e l y r a p i d , hence maintaining a saturated l a y e r at t h e i r i n t e r f a c e . A few years l a t e r , Brunner and T o l l o c z k o (19 35) showed the dependence of the value of the constant k i n equations 2 and 3 upon the surface area (S) of s o l i d exposed, the i n t e n s i t y of a g i t a t i o n or v e l o c i t y of f l u i d across the s o l i d , the temperature, the s t r u c t u r e of the s u r f a c e , and the experimental apparatus. Wilderman (19 09) questioned the v a l i d i t y of the Nernst- . Brunner d i f f u s i o n theory i n e x p l a i n i n g the d i s s o l u t i o n process. Zdanovski (1946), a f t e r experimentation w i t h the d i s s o l u t i o n of i n o r g a n i c s a l t s , claimed the d e r i v a t i o n of the f o l l o w i n g g e n e r a l i z e d equation. When the d i s s o l u t i o n r a t e i s c o n t r o l l e d by the surface or i n t e r f a c e process, i t i s expressed as: -^ pp- = <S (C s - C y) (Eq. 4) when the process i s d i f f u s i o n c o n t r o l l e d , the r a t e of d i s s o l u t i o n i s expressed as: - 7 --g- = S ( C y - C x) (Eq. 5) and the g e n e r a l i z e d equation i s : d w - D S (C s - C x) (Eq. 6) dt D + o< h where, «K = r a t e constant f o r the i n t e r f a c e process C s = the concen t r a t i o n at s a t u r a t i o n C x = the concen t r a t i o n i n the bulk s o l u t i o n Cy = the con c e n t r a t i o n i n the boundary d i f f u s i o n l a y e r h = the thickness of the d i f f u s i o n l a y e r The other symbols have been p r e v i o u s l y d e f i n e d . The r a t e constant K i n the l a s t equation i s given as: 4 TT + "IT" ( E 1 - 7 ) Davion (1953) described the d i s s o l u t i o n of a s o l i d by a d i f f u s i o n c o n t r o l l e d process: = ^ _ S (C s - C) (Eq. 8) (The symbols have the same meanings as above). The v a r i a t i o n of the constant K with i n t e n s i t y of a g i t a t i o n i s shown i n the sense t h a t , as the a g i t a t i o n i n t e n s i t y i n c r e a s e s , the d i f f u s i o n l a y e r becomes t h i n n e r , and hence, the d i s s o l u t i o n r a t e value (dw/dt) i s increased. - 8 -Hixon and Crowell (19 31). d erived the r e l a t i o n s h i p shown below. = K S (C s - C) (Eq. 9) where, S = Surface area of the d i s s o l v i n g s o l i d K = A constant with dimensions of l e n g t h " /time (The other symbols are s i m i l a r to those used above). The value of the constant K has been shown to be dependent upon the temperature, the s t r u c t u r e of the surface of the d i s s o l v i n g s o l i d , the geometry of the apparatus, and the r a t e of s t i r r i n g or a g i t a t i o n or v e l o c i t y of the medium across the surface of the d i s s o l v i n g substance. They a l s o derived a new law (the cube root law) i n which the v e l o c i t y of s o l u t i o n of a s o l i d i n a l i q u i d i s expressed as a f u n c t i o n of the surface area and the c o n c e n t r a t i o n . Provided that C i s alxvays n e g l i g i b l e i n comparison to C s, Nelson (19 57) showed that Equation 9 reduces t o : ) d W = K S C s (Eq. 10) dt I n t e g r a t i n g Eq. 10 (assuming S to be a constant) g i v e s : W = K S C s t (Eq. 11) Nelson a l s o pointed out that the r a t e of d i s s o l u t i o n can be i n f l u e n c e d by f a c t o r s other than s o l u b i l i t y when he observed - 9 -the poor c o r r e l a t i o n between the water s o l u b i l i t i e s and the s o l u t i o n r a t e s of a s e r i e s of t h e o p h y l l i n e s a l t s . Nelson was the f i r s t t o show t h a t , with the other f a c t o r s being constant, the d i s s o l u t i o n rates of a s e r i e s of s a l t s of a given weak a c i d determines the r a t e of build-up of blood l e v e l with time and the maximum blood l e v e l a t t a i n e d . In a l a t e r p u b l i c a t i o n , Nelson (1959) a l s o showed tha t (a) d i s s o l u t i o n r a t e was the r a t e determining step i n a b sorption of various t e t r a c y c l i n e p r e p a r a t i o n s , (b) the a bsorption of a s p i r i n appeared to be r a t e l i m i t e d by the time necessary f o r the drug to d i s s o l v e a f t e r i n g e s t i o n , and (c) the a bsorption of benzyl p e n i c i l l i n was r a t e l i m i t e d by the i n t r i n -s i c d i s s o l u t i o n r a t e p r o p e r t i e s of the potassium and procaine s a l t s used. According to Wurster and Taylor's review (1965) of the l i t e r a t u r e concerning the e f f e c t of a g i t a t i o n speed on the v e l o c i t y of heterogenous r e a c t i o n s , i n v e s t i g a t o r s have u s u a l l y reported the f o l l o w i n g r e l a t i o n s h i p : K = a Vb (Eq. 12) where, K a constant s i m i l a r to K i n Equation 9 V v e l o c i t y of a g i t a t i o n a and b = constants - 10 -When the r e a c t i o n t a k i n g place i s d i f f u s i o n c o n t r o l l e d (Nernst-Brunner Theory), the value of the exponent b, has been found to be 1 or approximately 1. On the other hand, f o r r e a c t i o n s c o n t r o l l e d by the r a t e of the i n t e r f a c i a l r e a c t i o n , values f o r b were found to approximate zero. A f t e r studying the d i s s o l u t i o n of inorganic s a l t s , Davion (1953) reported t h a t the value f o r constant b was 0.5. Therefore Equation 12 may be r e w r i t t e n as f o l l o w s : Wurster et a l . (1965) showed, by adding complexing agents i n order to increase the s a t u r a t i o n s o l u b i l i t y , that the d i s s o l u t i o n r a t e of m-aminobenzoic a c i d was apparently con-t r o l l e d by i n t e r f a c i a l r e a c t i o n . These workers contend th a t i n the r e a c t i o n between two phases two f a c t o r s determine the o v e r - a l l measured r a t e of r e a c t i o n : (a) the r a t e of r e a c t i o n at the i n t e r f a c e and (b) ihe r a t e of t r a n s p o r t of reactant or product of r e a c t i o n to or from the i n t e r f a c e . They proposed that e i t h e r of these may be r a t e determining or the o v e r - a l l r a t e may be a f u n c t i o n of both processes, i f both are of the same order of magnitude. In l i n e with t h e i r s u p p o s i t i o n s , Wurster et a l . derived the f o l l o w i n g equations to express the d i s s o l u t i o n r a t e : K = a 4 V (Eq. 13) dw eft = (C s - C i ) (Eq. 14) - 11 -where, KR = the r a t e constant f o r the i n t e r f a c i a l r e a c t i o n Cs = s a t u r a t i o n c o n c e n t r a t i o n C i = e f f e c t i v e c o n c e n t r a t i o n ( l e s s than s a t u r a t i o n ) e x i s t i n g at the i n t e r f a c e The o v e r - a l l r a t e i s a l s o a f u n c t i o n of d i f f u s i o n away from the i n t e r f a c e as shown below: = K D ( C i - C) (Eq. 15) where, = d i f f u s i o n r a t e constant C = the con c e n t r a t i o n i n the bulk s o l u t i o n In a steady-state c o n d i t i o n of C i , assuming th a t the i n t e r f a c i a l r e a c t i o n i s i n i t i a l l y the slower r e a c t i o n , Equation 14 and Equation 15 may be equated provided t h a t K i s constant and the i n t e r f a c i a l r a t e increases u n t i l these two are equal. KR ( C s - C i ) = K D ( C i - C) (Eq. 16) Rearrange, K R + K C S u b s t i t u t e the r i g h t hand side of Equation 17 f o r C i i n Equation 14 and Equation 15: - 12 -dw _ KR K p (Cg - C) (Eq. 18) KR + K D Higuchi (1967) r a t h e r than using e m p i r i c a l or a r b i t r a r y mathematical k i n e t i c models, has derived equations based on p h y s i c a l models i n v o l v i n g drug t r a n s p o r t . S i g n i f i c a n t a p p l i c a t i o n s of t h i s approach to the study of drug r e l e a s e from matrix systems have been reported i n the l i t e r a t u r e ( H i g u c h i , 1960; 1961; 1963). This model approach i s a l s o evident i n much of the t h i n k i n g and research being done today on d i f f u s i o n c o n t r o l l e d r e l e a s e of drugs. I f the matrix i s a homogenous l i q u i d , the one dimensional theory (planar r e l e a s e ) , according to H i g u c h i , g i v e s : where, D = the drug molecule d i f f u s i o n c o e f f i c i e n t i n the matrix A = the drug ( t o t a l amount) present i n the matrix per u n i t volume Cs = the s o l u b i l i t y of the drug i n the matrix substance t = time Q = D i s s o l u t i o n r a t e I f the matrix i s heterogenous and d i f f u s i o n takes place i n the i n t r a g r a n u l a r pores, Higuchi assumes t h a t : (Eq. 19) (2A (Eq. 20) - 13 -where Y = t o r t u o s i t y of the matrix (accounts f o r the a d d i t i o n a l distance a molecule must t r a v e l due t o i t s c i r -c u itous path w i t h i n the t a b l e t ) . ^ = the p o r o s i t y of the matrix The above r e l a t i o n s h i p s hold as long as 2A i s more than about three times greater than £ C s ( i . e . , f o r Equation 20) and as long as 2A >^ > C s ( f o r Equation 19). Wagner (19 71) depicted the sequence of events before a drug i n a s o l i d dosage form can be absorbed i n the manner i n d i c a t e d i n F i g . 1. Wagner's (1964) schematic diagram of the d i s s o l u t i o n process i s shown i n F i g . 2. Wurster and Taylor (1965) st a t e d that the f i l m theory appears to be acceptable with c e r t a i n m o d i f i c a t i o n s , on the b a s i s of the s i m i l a r i t y of c a l c u l a t e d values f o r f i l m t h i c k n e s s . They a l s o pointed out t h a t though the " i d e a l i z e d f i l m l a y e r " i s not w e l l d e f i n e d , i t allows the c o r r e l a t i o n o f experimental data w i t h the p h y s i c a l p r o p e r t i e s of both the s o l u t e and the s o l v e n t . According to these workers d i s s o l u t i o n r a t e i s i n f l u e n c e d by the f o l l o w i n g f a c t o r s : (a) Temperature and a g i t a t i o n (b) Changes i n d i s s o l u t i o n medium: ( i ) v i s c o s i t y ( i i ) s o l u b i l i z a t i o n and surface a c t i v i t y ( i i i ) u n-reactive and r e a c t i v e a d d i t i v e s ( i v ) adsorption - 14 -T A B L E T GRANULES FINF or DISINTEGRATION, or OEAGCREGATION CAPSULE AGGREGATES o a o CO I 3» C3 CO o 3 3 —I o z (2) PARTICLES DRUG IN SOLUTION K V (in vitro or in vivo) 5>* DRUG IN BLOOD,OTHER FLUIDS & TISSUES Figure .1. .Schematic Diagram.of Dissolution Rate-limited Absorption. INTESTINAL WALL (LIPOID-SIEVE BARRIER) ^DIFFUSION LATER DIFFUSING MOLECULES MOVING BULK SOLUTION OR GASTROINTESTINAL CONTENTS DIFFUSING MOLECULES BLOOD SIDE OF INTESTINAL WALL Figure 2. Schematic Diagram of Dissolution from a Plane Solid Surface. - 15 -(c) Changes i n so l u t e p a r t i c l e c h a r a c t e r i s t i c s ( i ) polymorphism ( i i ) e f f e c t i v e surface Wagner c l a s s i f i e s the f a c t o r s a f f e c t i n g d i s s o l u t i o n r a t e i n the f o l l o w i n g manner: (a) Geometry of the system (b) Rate of flow of f l u i d s ; presence or.absence of turbulence. (c) Composition of t e s t media or f l u i d s : pH, i o n i c s t r e n g t h , v i s c o s i t y , surface t e n s i o n . Although some of the p h y s i c a l and chemical f a c t o r s i n v o l v e d are recognised, many as yet are not w e l l defined or understood. The a b i l i t y t o p r e d i c t the complete p h y s i o l o g i c a l c h a r a c t e r i s t i c s of a new drug on the ba s i s of i t s chemical p r o p e r t i e s i s , f o r the present, an u n r e a l i z e d o b j e c t i v e . 2. Development of D i s s o l u t i o n Methodology The f i r s t d i s s o l u t i o n procedure was probably t h a t used by K l e i n (19 32) i n which he determined the r a t e of s o l u t i o n of s o l i d l y s o l t a b l e t s . In 19 33, E l l i o t t (19 33) may have r e a l i z e d the importance of d i s s o l u t i o n when he demonstrated the use of the solvometer i n determining the r a t e of s o l u t i o n of t a b l e t s . Wruble (19 30) developed a d i s s o l u t i o n t e s t procedure. His purpose was to evaluate the pe r m e a b i l i t y o f t a b l e t coatings but not the d i s s o l u t i o n of the t a b l e t s as such. - 16 -Many of the e a r l i e r studies (e.g., Souder and Ellenbogen) on d i s s o l u t i o n methodology involved the e v a l u a t i o n of o r a l prolonged r e l e a s e dosage forms. Methods developed i n l a t e r years drew on experiences gained w i t h such dosage forms or were m o d i f i c a t i o n s of the USP XV method f o r the measurement of d i s i n t e g r a t i o n time of e n t e r i c coated t a b l e t s . The e a r l y procedures have the same b a s i c p r i n c i p l e s , w i t h the f o l l o w i n g c o n d i t i o n s i n common—the use of simulated g a s t r i c and i n t e s t i n a l f l u i d s at 37° C., the use of an a g i t a t i n g device, and the use of a screen f o r separating d i s i n t e g r a t e d p a r t i c l e s from the bulk of the product. The time i n t e r v a l s , the composition of f l u i d s , the a g i t a t i o n , and the mesh s i z e of the screen are the v a r i a n t s i n the methods. The medium or the residue i s assayed f o r drug content. Micciche (19 55) determined the r e l e a s e of drug from coated granules. In h i s procedure, the granules were immersed f o r four hours i n simulated g a s t r i c f l u i d and f o r s i x hours i n simulated i n t e s t i n a l f l u i d . Chaudhry and Saunders (19 56) evaluated three d i f f e r e n t types of e x t r a c t i o n processes f o r measuring the r e l e a s e r a t e of ephedrine or d-amphetamine from s u l f o n i c a c i d r e s i n s . They found that i t was necessary t o expose the r e s i n repeatedly or continuously to f r e s h p o r t i o n s of the eluant to get complete e x t r a c t i o n . In t h e i r "closed tube" method, they used only one p o r t i o n of eluant; i n t h e i r "replacement c l o s e d tube" method, they used f r e s h p o r t i o n s of eluant repeatedly; and i n t h e i r - 17 -" i n f i n i t e bath" method they e x t r a c t e d w i t h a slow continuous flow of eluant. F l u i d s were maintained at 25° C. Cooper (19 57) described an i n - v l t r o r e l e a s e t e s t procedure i n which triplennamine prolonged a c t i o n t a b l e t s were placed i n a Stoll-Gershberg apparatus (the USP XV d i s i n t e g r a t i o n apparatus) with basket f i t t e d w ith a No. 40 mesh screen. The apparatus was f i l l e d w i t h simulated g a s t r i c f l u i d which was replaced a f t e r the f i r s t hour with an equal volume of f r e s h f l u i d . At the end of the second hour, simulated i n t e s t i n a l f l u i d was placed i n the beaker and the process repeated with a fr e s h volume of the l a t t e r f l u i d f o r an a d d i t i o n a l nine hours. A sample of each p o r t i o n of the eluant was assayed to ob t a i n a r e l e a s e p a t t e r n . Nelson (1957) used a d i s s o l u t i o n procedure i n which t h e o p h y l l i n e p e l l e t s compressed at 100,000 p s i were placed i n the bottom of a 600 ml. beaker and s t i r r e d . Sampling was c a r r i e d out by use of a sigmamotor pump. Souder and Ellenbogen (19 58) reported a t e s t method f o r sustained r e l e a s e capsules c o n t a i n i n g dexamphetamine sulphate i n which the dosage form was put i n t o 90 ml. b o t t l e s c o n t a i n i n g 60 ml. of simulated g a s t r i c f l u i d at 37° C. The b o t t l e s were ro t a t e d at 40 r.p.m. and were withdrawn at s p e c i f i e d time i n t e r v a l s . The residues were assayed a f t e r the contents were f i l t e r e d through a 40 mesh screen. In an e f f o r t to set up standards, Wiley (1957) developed a procedure to measure the r e l e a s e of a drug from i t s dosage - 18 -form. His apparatus c o n s i s t e d of a stoppered c y l i n d r i c a l tube wi t h a coarse p o r o s i t y f r i t t e d glass f i l t e r above the bottom o u t l e t and having a side arm o u t l e t f o r the r e t u r n of the e l u t i n g f l u i d to a r e s e r v o i r . The eluant at 37° C. was c i r c u -l a t e d through c y l i n d r i c a l tube by a pump. One hundred ml. of simulated g a s t r i c f l u i d was used f o r the f i r s t hour; 50 ml. of the s o l u t i o n was removed each hour f o r a n a l y s i s and replaced with 50"ml. of simulated i n t e s t i n a l f l u i d . The process was repeated f o r the maximum period i n d i c a t e d . This method was l a t e r c r i t i c i z e d as being long and cumbersome. Blythe (1'958 ) described the use of three b a s i c methods f o r t e s t i n g sustained r e l e a s e products. In the method f o r l i q u i d s and capsules, samples were placed i n separate 91 ml. b o t t l e s and r o t a t e d at 44 r.p.m. i n a medium maintained at 37° C. Water and a s p e c i a l medium buffered at pH 6.4 was used f o r capsules and l i q u i d s r e s p e c t i v e l y . The USP d i s -i n t e g r a t i o n method was used f o r t a b l e t s with the basket modified to hold more tubes. Parrot et a l . (1955) reported the r e s u l t s of t h e i r i n v e s t i g a t i o n of drug r e l e a s e from s o l i d s . T h e i r d i s s o l u t i o n methodology c o n s i s t e d of p u t t i n g the t a b l e t i n an a g i t a t e d aqueous medium, kept at constant temperature. The solvent phase was f r e q u e n t l y renewed to maintain a low s o l u t e con-c e n t r a t i o n . Measurements of the weight and r a d i u s , i n the case of s p h e r i c a l t a b l e t s (using an o p t i c micrometer) were taken i n i t i a l l y and at various time i n t e r v a l s . Samples of - 19 -the solvent phase were a l s o t i t r a t e d at corresponding time i n t e r v a l s and i t was shown t h a t there was no v a r i a t i o n between the t i t r a t i o n and weighing methods. Nelson (19 59) reported that d i s s o l u t i o n was a r a t e l i m i t i n g f a c t o r i n p h y s i o l o g i c a l a v a i l a b i l i t y and discussed the i n f l u e n c e of d i s s o l u t i o n r a t e and surface on t e t r a c y c l i n e a b s o r p t i o n . He used h i s hanging p e l l e t method f o r d i s s o l u t i o n t e s t i n g of t a b l e t s of weak acids and t h e i r sodium s a l t s . V l i e t (1959) suggested an i n - v i t r o procedure f o r measuring the r a t e of drug r e l e a s e from timed r e l e a s e t a b l e t s and capsules. His apparatus c o n s i s t e d of a s t a i n l e s s s t e e l c a r t r i d g e covered at both ends wi t h a 40 mesh wire screen, and f i t t e d i n a c a r t r i d g e holder i n a modified USP basket rack assembly. Levy and Hayes (1960) described a method i n which a d i s s o l u t i o n medium of 250 ml. of 0.1 N Hcl was placed i n a 4-00 ml. pyrex G r i f f i n beaker and e q u i l i b r i a t e d to 37 +_ 0.1° C. A 3-blade, 5 cm. diameter polyethylene s t i r r e r attached to an e l e c t r o n i c c o n t r o l l e d s t i r r i n g motor (with p r e c i s i o n speed c o n t r o l ) was immersed to a depth of 27 mm. and a c c u r a t e l y centered by means of a guide. S t i r r i n g was maintained at 59 r.p.m. and the t a b l e t ( a s p i r i n ) was dropped i n t o the medium along the side of the beaker. Seven ml. samples were taken at s p e c i f i e d i n t e r v a l s of time by means of a f r i t t e d g l a s s immersion f i l t e r tube of medium p o r o s i t y . The p o p u l a r i t y of t h i s method i s evident on the ba s i s of the many m o d i f i c a t i o n s now described i n the l i t e r a t u r e . - 20 -Nash and Marcus (1960) reported a modified v e r s i o n c o n s i s t i n g of a 600 ml. buchner type funnel w i t h a medium p o r o s i t y f r i t t e d d i s c which was f i t t e d i n t o a 500 ml. s u c t i o n f l a s k with a stopcock at the bottom. The sample was placed i n a 400 ml. of simulated g a s t r i c f l u i d and g e n t l y a g i t a t e d by a s t i r r e r . Two hundred ml. po r t i o n s of a f l u i d were drawn o f f f o r a n a l y s i s . Fresh f l u i d (200 ml.) was added to the apparatus and the process was repeated f o r the s p e c i f i e d time i n t e r v a l . During the same year, V l i e t (1960) compared three procedures - (a) the modified USP d i s i n t e g r a t i o n method, (b) the procedure described by Blythe (Smith K l i n e and French method), and (c) Wiley's method. He found that preparations c o n t a i n i n g f r e e l y s o l u b l e drugs produced the same r e l e a s e p a t t e r n by a l l the three methods and drug r e l e a s e was complete i n 8 hours. On the other hand, t a b l e t s c o n t a i n i n g s p a r i n g l y s o l u b l e drugs showed d i f f e r e n t r e l e a s e p a t t e r n s . In 1961-62, an attempt to standardize d i s s o l u t i o n techniques was made by Simoons (1962) who considered the advantages and disadvantages of the e x i s t i n g method and developed the r i n g apparatus. He derived i n - v i t r o r a t e con-stants (k v i t r o ) f o r t a b l e t s , obtained corresponding i n - v i v o r a t e constants (k viv o ) from u r i n a r y e x c r e t i o n data, c o r r e l a t e d the two values, and obtained a r i n g constant (R) f o r a p a r t i c u l a r drug. R = ,k v i v o (Eq. 21) k v i t r o - 21 -He concluded that the i n - v i v o c h a r a c t e r i s t i c s of a drug could be p r e d i c t e d from i n - v i t r o determinations provided that the r i n g constant (R) was determined. However, Wagner (1961) claimed that t h i s approach was erroneous and a r t i f i c i a l and suggested i t should not be used.. In a study e n t i t l e d "Loss of S e n s i t i v i t y i n D i s t i n g u i s h i n g Real D i f f e r e n c e s i n D i s s o l u t i o n Rates Due to Increasing I n t e n s i t y of A g i t a t i o n " , Hamlin et a l . (1962) used three d i f f e r e n t methods: (a) the Hanging P e l l e t method described by Nelson, (b) the P e l l e t Holder method i n a Wruble machine, and (c) the P e l l e t Holder method i n the Souder and Ellenbogen apparatus. At about the same time, Schroeter et a l . (1962) described an automated d i s s o l u t i o n apparatus i n which the USP basket rack assembly i n a one l i t e r beaker was used as the d i s s o l u t i o n v e s s e l and the d i s s o l u t i o n medium was c i r c u l a t e d through a flow c e l l i n a UV-Spectrophotometer. Levy (1963) used the o s c i l l a t i n g tube method ( i n which a p l e x i g l a s s c y l i n d e r w i t h a 100 mesh s t a i n l e s s s t e e l wire screen on the bottom i s attached to the bas i c u n i t of the USP t a b l e t d i s i n t e g r a t i o n apparatus w i t h no basket r a c k ) , the r o t a t i n g d i s c method (developed by Levy and S a h l i (1962), and the S t a t i c Disc method. The f o l l o w i n g year, P a t e l et a l . (1964) described a sink method i n which a d i a l y s i s membrane was placed between two p l e x i g l a s s blocks having a 20 ml. c a v i t y one of which contains - 2 2 -the d i s s o l u t i o n medium and the sample. Middleton et a l . (1964) and Yen (19 64) used the apparatus and f l u i d s of the USP XVI d i s i n t e g r a t i o n procedure. Sjflgren et a l . (1964) described a continuous flow method (automated procedure) i n which the d i s s o l u t i o n v e s s e l was s t i r r e d w hile the d i s s o l u t i o n medium was c i r c u l a t e d through a flow c e l l i n a r e c o r d i n g spectrophotometer. Montgomery et a l . (1964) used the r o t a t i n g b o t t l e apparatus of Souder and Ellenbogen and the samples of d i s s o l u t i o n medium were p e r i o d i c a l l y analysed by s c i n t i l l a t i o n counting. Barlow's (19 65) modified B P ^ d i s i n t e g r a t i o n method wi t h r e l e a s e r a t e determined by an immersion c o n d u c t i v i t y c e l l ; the magnetic s t i r r e r method f o r i n t r i n s i c d i s s o l u t i o n determination described by Desai et a l . (1965); the tape frame method f o r d i s s o l u t i o n studies of m u l t i p a r t i c u l a t e systems described by Goldberg et a l . (1965); the nuclear r e l e a s e apparatus of McClintock et a l . (1965); P a i k o f f and Drumm's (1965) s t i r r e r capsule holder method; S t r i v a s t a v a and Maney's (1965) r a d i o -isotope technique w i t h the Souder and Ellenbogen apparatus; a m o d i f i c a t i o n of the beaker method of Levy et a l . (1965); the non-turbulent continuous flow method of Lapidus et a l . (1966); the modified USP method of Huber and Dale (1966); the modified beaker method of F i n h o l t et a l . (1966) and the modified BP d i s i n t e g r a t i o n method of Broadbent et a l . (1966) were reported i n the l i t e r a t u r e . The f o l l o w i n g d i s s o l u t i o n methods were reported i n 1967: the s t i r r e d , water jacketed v e s s e l method of Bates et a l . (1967); - 23 -Se a r l and Pernarowski's (19 67) basket s t i r r e r method w i t h the basket suspended below the i m p e l l e r of a s t i r r i n g s h a f t ; Marlowe and Shangraw's (1967) r o t a t i n g d i a l y s i s c e l l ; the Cube of gauze method of Ganderton et a l . (1967); the p a r t i t i o n methods of G i b a l d i and Feldman (1967) and Niebergal et a l . (1967) and the o s c i l l a t i n g s t a i n l e s s s t e e l c y l i n d e r method of Katchen and Synchowicz (1967). In 19 68, methods described i n the l i t e r a t u r e were - the m u l t i p l e t e s t i n g s t a t i o n apparatus of C a s t e l l o et a l . (1968); the continuous flow and r o t a t i n g basket assembly of Pernarowski et a l . (1968 ) the shaker method of Schwartz et a l . (1968 ); and the wire s p i r a l method of Poole et a l . (1968). Rippie and Johnson's (1969) continuous flow d i s s o l u t i o n chamber method and the constant c i r c u l a t i o n glass d i s s o l u t i o n c e l l apparatus of Baun and Walker (1969), both of which have the same b a s i c p r i n c i p l e of smooth continuous flow of the medium past the t e s t sample were described i n the l i t e r a t u r e . Florence (1970) determined d i s s o l u t i o n r a t e and b i o l o g i c a l a c t i v i t y simultaneously by using the beaker method and gold f i s h (Carassius Auratus). Shah and More (1970) used a s t i r r i n g loop and the beaker method. Bead, blade, holder and p l a t e methods were used by L i n et a l . (19 70) i n a com-pa r a t i v e study of various d i s s o l u t i o n apparatus f o r capsule dosage forms. The glass bowel sink method of U l l a h and Cadwallader (1970) and the magnetic s t i r r e r m o d i f i c a t i o n of S e a r l and Pernarowski's method, developed by Thomas and McCarthy (19 70) were published. - 24 -Tingstad and Riegelman (1970) devised a continuous flow apparatus which they claimed to be the best of the methods so f a r described i n the l i t e r a t u r e . Burger and Nash (1971) described an automatic d i s s o l u t i o n apparatus which used an o s c i l l a t i n g p l a s t i c d i s s o l u t i o n chamber. Shah (1971) developed a continuous t i t r a t i o n technique f o r the automated d i s s o l u t i o n - r a t e e v a l u a t i o n o f a weak ba s i c drug. According to t h i s technique, the drug, as i t d i s s o l v e s , i s r a p i d l y t i t r a t e d by the a d d i t i o n of the r e q u i r e d amount of t i t r a n t l i q u i d to maintain a set constant pH of the d i s s o l u t i o n media. This i s monitored by a pH-stat t i t r a t o r instrument. From the amount of t i t r a n t added as a f u n c t i o n of time, which i s recorded on a c h a r t , the d i s s o l u t i o n r a t e of the drug i s estimated. The author claims t h a t t h i s technique can be g e n e r a l l y a p p l i e d as an automated d i s s o l u t i o n method f o r the t a b l e t f o r m u l a t i o n of a c i d i c or b a s i c drugs. Beyer and Smith (19 71) reported an automated d i s s o l u t i o n t e s t method which incorporates the NF X I I I method I -USP XVIII d i s s o l u t i o n apparatus, using s t i r r i n g basket assemblies and 1,000 ml. r e s i n f l a s k s . Six t e s t s are conducted simultan-eously using a commercially a v a i l a b l e spectrophotometer capable of monitoring seven separate c e l l s at programmed i n t e r v a l s and a six-channel pump. The authors present data demonstrating the a p p l i c a t i o n of the system f o r capsules and t a b l e t s . - 25 -3. C l a s s i f i c a t i o n of D i s s o l u t i o n Test Methods D i s s o l u t i o n procedures can be c l a s s i f i e d i n a v a r i e t y of ways. The c l a s s i f i c a t i o n given below was based on the r e l a t i v e p o p u l a r i t y or frequency of use of the various methods and t h e i r m o d i f i c a t i o n s . According t o the l i t e r a t u r e , the s t i r r e d v e s s e l methods, the modified USP d i s i n t e g r a t i o n methods, and the continuous flow methods are most commonly used, and so are put i n t o separate d i v i s i o n s , i n decreasing order of p o p u l a r i t y . The miscellaneous methods in c l u d e - forced convection, non-sink methods; forced convection, sink methods; and n a t u r a l convection, non-sink methods (Hersey, 1969). I n t r i n s i c and n o n - i n t r i n s i c d i s s o l u t i o n methods can a l s o be c l a s s i f i e d but, f o r the purposes of t h i s t h e s i s , only a d e f i n i t i o n of the words w i l l be given. An i n t r i n s i c d i s s o l u t i o n method i s a procedure whereby the surface area of the pure drug i s kept constant and r e l e a s e r a t e i s measured under s t a t i c c o n d i t i o n s . This method uses t a b l e t s t h a t have been compressed at very high pressures. N o n - i n t r i n s i c methods, however, deal w i t h samples that undergo d i s i n t e g r a t i o n and so present v a r i a b l e surface area to the d i s s o l u t i o n medium. (A) S t i r r e d Vessel Methods The methods i n t h i s group are m o d i f i c a t i o n s of the Levy-Hayes (1960) s t i r r e d beaker method. See F i g . 3(A). The m o d i f i c a t i o n s i n v o l v e d i f f e r e n t v e s s e l s , s o l v e n t s , s t i r r i n g - 26 -c="o -STIRRING MOTOR -BEAKER WATER BATH -TABLET (A) Beaker Method o > . ^ < ( ,."""> • GLASS TUBE REMOVABLE CORK • CONTAINER COVER SOLVENT LEVEL WAX TABLET IMBEDBED IN WAX WATER JACKET MAGNETIC STIRRING BAR -STIRRING MOTOR (B) Mognetic Stirrer Method Figure 3. Dissolution Diagramatic Apparatus, Representation! See text for of Siirred Vessel Types of a description of each apparatus. - 27 -devices. The versatility of the general method is reflected in the many modifications shown in Fig. 3. The magnetic stirrer method of Desai et a l . (1965) for the determination of intrinsic dissolution uses 500 ml. of solvent maintained at 30° C. by circulating water through the jacket enclosing the beaker. See Fig. 3(B). The tape-frame method (Goldberg et a l . , 1965) was used to determine rates of dissolution of multiparticulate systems and consisted of (a) a pressure sensitive tape 3/4 inch wide that holds the particles of the drug; (b) a frame for mounting the tape; (c) a beaker with modifications to contain runners to position the frame in contact with the dissolution medium; and (d) a sti r r e r with i t s controls. See Fig. 3(C). Four hundred ml. of dissolution medium at 37 + 1° C. is stirred at 5 3.5 r.p.m., and at time zero the tape frame is dropped down the runners below the surface of the medium. Ten ml. samples are withdrawn at definite intervals of time and 10 ml. of pre-heated (37° C.) medium is added to the vessel after every sampling. The stirred water-jacketed vessel method is another variation in which agitation is carried out by means of an overhead s t i r r e r (2.5 cm. blade) rotating at 800 r.p.m. See Fig. 3(D). In the sti r r e r capsule holder method (Paikoff and Drumm, 1965) the capsule after being inserted into the holder, is placed half-way down into the dissolution medium and rotated. See Fig. 3(E). - 28 -BEAKER-S0LVENT-PADDLE — B -STIRRING MOTOR -WATER BATH -RUNNERS TO POSITION THE FRAME TAPE FRAME (C) T a p e - f r a m e Method STIRRING MOTOR DISSOLUTION FLUID WATER JACKET TABLET ( D ) S t i r red Water- jacketed« vessel Method F igure 3 , cont inued - 29 -STIRRING MOTOR WATER BATH BEAKER CONTAINING DISSOLUTION FLUID •STIRRER CAPSULE HOLDER (E) S t i r r e r Capsu le Ho lde r Method STIRRING MOTOR IMPELLER 10 MESH BASKET STIRRER ROUND BOTTOM FLASK HAVING EXTRA NECKS FOR SAMPLING AND FLUID REPLACEMENT WATER BATH (F ) Basket St i r rer Method Figure 3, continued - 30 -The b a s k e t - s t i r r e r method of S e a r l and Pernarowski (1967) c o n s i s t s of 2.5 L i t r e s of simulated i n t e s t i n a l f l u i d (without enzymes) maintained at 37 + 1° C , i n a 3 - L i t r e glass j a r . One t a b l e t i s placed i n a c y l i n d r i c a l wire basket (2.2 cm. i n diameter and 2.8 cm. i n length) suspended below the i m p e l l e r of a s t i r r i n g shaft (3 blade, t e f l o n - c o a t e d p r o p e l l e r , 0.5 cm. i n diameter) connected to a F i s h e r stedi-speed s t i r r e r . The shaft i s submerged to a depth of 10 cm. below the surface of the medium and r o t a t e d clockwise at e x a c t l y 100 r.p.m. Samples of 10 ml. are taken out at 15 minute i n t e r v a l s during the f i r s t hour and at 30 minute and hourly i n t e r v a l s during the second and t h i r d hours r e s p e c t i v e l y . Samples were analysed s p e c t r o p h o t o m e t r i c a l l y . See F i g . 3(F). The Cube of s t a i n l e s s s t e e l gauze apparatus (Ganderton et a l . , 1967) c o n s i s t s of a 2 - L i t r e beaker c o n t a i n i n g 1.5 L i t r e s of d i s s o l u t i o n medium s t i r r e d by a perspex paddle 11 cm. i n diameter held 0.5 cm. above the bottom of the bath and r o t a t i n g at 50 r.p.m. The two blades of the paddle were 2.5 cm. deep and blade pitch'n was 45°. Two d i a m e t r i c a l l y opposed b a f f l e s , 1.3 cm. wide, were f i x e d i n the bath. The t a b l e t was placed i n a cube of 100 mesh s t a i n l e s s s t e e l gauze of side 1.5 cm. which was r i g i d l y suspended i n the bath 4 cm. from the paddle a x i s 2 cm. below the surface of the l i q u i d . See F i g . 3(G). In the wire s p i r a l method (Poole et a l . , 1968) the dosage form i s placed i n a wire s p i r a l and suspended i n a 1 - L i t r e round bottom f l a s k c o n t a i n i n g 500 ml. of d i s t i l l e d water - 31 -VZ777\'V7777* Y777A a -STIRRING MOTOR -SAMPLING POSITION BAFFLE CUBE OF STAINLESS- STEEL GAUZE -PADDLE (G) The Case of Stain less - steel Gauze ] STIRRING MOTOR SAMPLING DEVICE WATER BATH FLASK (CONTAINING DISSOLUTION FLUID) WIRE SPIRAL PADDLE H Wire Spiral Method Figure 3, continued. - 32 -maintained at 37 ^0.5° C. The medium i s a g i t a t e d by a t e f l o n paddle r o t a t e d at 50 r.p.m. See F i g . 3(H). M o d i f i c a t i o n s ( U l l a h and Cadwallader, 1969) of t h i s method have been described i n the l i t e r a t u r e . L i n et a l . (1970) used the bead, p l a t e , blade, and holder methods i n order to compare them with the USP d i s i n t e g r a t i o n method and the then proposed USP d i s s o l u t i o n method. They used an 80 0 ml. pyrex beaker with a convex bottom face. A g i t a t i o n (at 60 r.p.m.) was e f f e c t e d by an overhead s t i r r e r (depending upon the p a r t i c u l a r method used) placed at the centre of the beaker. The d i s s o l u t i o n medium (the yolume of which v a r i e d w i t h the d i f f e r e n t methodology) was kept at 37° C. A l i q u o t s of samples were immediately f i l t e r e d through a O.M-5 micron pore s i z e m i l l i p o r e f i l t e r paper, d i l u t e d , and analysed s p e c t r o p h o t o m e t r i c a l l y . In the bead method, the capsule i s weighted down to the bottom of the beaker by i n s e r t i n g two glass beads at both ends of the capsule,.before the capsule i s f i l l e d w i t h drug. See F i g . 3(1,a). In the p l a t e method, the capsule i s f i x e d to a 2 x 2 cm. s t a i n l e s s s t e e l p l a t e by means of water r e p e l l a n t glue (See F i g . 3 ( I , b ) ) ; i n the blade method the capsule i s attached to one of the three blades of the s t i r r e r w ith the same type of glue. See F i g . 3 ( J ) . The holder method i n v o l v e s the placement of the capsule i n t o the o r i f i c e of a p l a s t i c capsule holder designed f o r a No. 1 g e l a t i n capsule. The authors reported that they p r e f e r r e d - 33 -(a) (b ) (><> - O r • STIRRING MOTOR •WATER BATH -CONVEX BOTTOM BEAKER (CONTAINING DISSOLUTION FLUID) •CAPSULE HOLDER ( I ) , Bead and Plate Method STIRRING MOTOR WATER BATH CONVEX BOTTOM BEAKER (CONTAININC DISSOLUTION FLUID) CAPSULE ATTACHED TO ONE OF THE BLADES (J) Blade Method F ig ur e 3, con t inued . - 34 -the s i m p l i c i t y , convenience, and v e r s a t i l i t y of the basket-s t i r r i n g method to a l l the other methods but c r i t i c i z e d the use of 40 mesh wire screen i n the proposed USP d i s s o l u t i o n method (now o f f i c i a l i n USP X V I I I ) . In order to provide a convenient v i s u a l observation of the dosage form i n the basket and to prevent the f a l l and accumulation of l a r g e drug p a r t i c l e s and t h e i r aggregates to the bottom of the f l a s k , they suggested the design of baskets w i t h screen c l o t h s of somewhere between 8 and 40 mesh s i z e . Another m o d i f i c a t i o n of the Sea r l and Pernarowski method (1967) was that of Thomas et a l . (1970) who used a c y l i n d r i c a l wire basket (4 cm. diameter and 2 cm. deep) suspended i n the f l u i d at a depth of 4 cm. from the base of the v e s s e l . The system i s s t i r r e d w ith a magnetic s t i r r e r at a constant r a t e of 800 r.p.m. F i l t e r e d a l i q u o t s are taken every 10, 20, and 30 minutes during the f i r s t , second, and t h i r d hours r e s p e c t -i v e l y . See F i g . 3(K). (B) Modified USP D i s i n t e g r a t i o n Methods A modified USP d i s i n t e g r a t i o n method was used by V l i e t (19 59) to determine d i s s o l u t i o n r a t e . This was perhaps a l o g i c a l step i n t h a t a r e a d i l y a v a i l a b l e standardized apparatus was being used f o r d i s s o l u t i o n t e s t i n g . His apparatus c o n s i s t e d of a s t a i n l e s s s t e e l c a r t r i d g e covered at both ends with a 40 mesh wire screen f i t t e d i n a c a r t r i d g e - 35 -SYRINGE SINTERED GLASS FILTER WATER JACKET THERMOMETER SIMULATED INTESTINAL (FLUID USP MINUS ENZYME ) WIRE BASKET MAGNETIC STIRRER (K) Method of Thomas and McCarthy F igu re 3, con t inued. - 36 -holder and set up i n a modified USP basket rack assembly. See F i g . 4(A). Levy (1963) used a p l e x i g l a s s c y l i n d e r (2.5 cm. x 19.5 cm.) with a 10 0 mesh s t a i n l e s s s t e e l wire screen on the bottom which was attached to the ba s i c u n i t of the USP t a b l e t d i s i n t e g r a t i o n apparatus ( r e p l a c i n g the basket rack assembly). The c y l i n d e r o i s immersed i n a beaker c o n t a i n i n g 800 ml. of 0.1 N Hcl at 37° C. The apparatus i s set i n motion and a t a b l e t i s dropped i n t o the c y l i n d e r . The medium i s sampled at r e q u i r e d i n t e r v a l s o f time by use of a f r i t t e d glass immersion f i l t e r tube. See F i g . 4(B). Middleton et a l . (1964) used the apparatus and f l u i d s of the USP XVI and i n Yen's (1964) method, the basket rack bottom was adjusted so that 1/4 inch remained above the bottom at the end of the downward st r o k e . Barlow (196 5) used the BP d i s i n t e g r a t i o n method and measured r e l e a s e r a t e by immersion c o n d u c t i v i t y . The o s c i l l a t i n g b o t t l e apparatus described by Goldberg et a l . (1965) c o n s i s t s of 10 ml. m u l t i p l e dose v i a l s sealed with an elastomer stopper and capped with a metal f e r r u l e having a hole i n the center and thus exposing a p o r t i o n of the top of the elastomer. Ten ml. of water at 3 7° C. are i n j e c t e d by a syringe at time zero and the v i a l i s immediately put on the o s c i l l a t i n g p l a t f o r m assembly i n the water bath. The p l a t f o r m i n motion describes a 15° arc 14 times per minute. Two ml. samples are withdrawn f o r spectrophotometric a n a l y s i s . See F i g . 4(C). - 37 -40 MESH WIRE SCREEN STAINLESS STEEL CARTRIDGE DISSOLUTION MEDIUM TABLET (RESTING ON A 40 MESH SCREEN) (A) Vliet's Method <S5 PLEXIGLASS CYLINDER -BEAKER (CONTAINING DISSOLUTION MEDIUM) TABLET 100 MESH WIRE SCREEN (B) Levy's Modi f ied Apparo tus Figure 4-. Diogromotlc Representation of Modified USP Disintegration Types of Dissolution Apparatus. See text for a description of each apparatus. - 38 -WATER BATH DISSOLUTION MEDIUM 10 ML. VIAL TABLET ( C ) A p p a r a t u s of Goldberg et al r -STIRRING MOTOR -DISSOLUTION MEDIUM • STAINLESS STEEL CYLINDER (WITH 40 MESH SCREEN AT EACH END) -STIRRER (D) Apparatus of Katchen et al . Figure 4, continued - 39 -Katchen et a l . (1967) used the Ger s h b e r g - S t o l l apparatus i n a 2 0 - L i t e r c o n t a i n e r i n which a 25 x 64 mm. s t a i n l e s s s t e e l c y l i n d e r w i t h 40 mesh screen at each end was immersed i n a d i s s o l u t i o n medium contained i n a 10 x 18 mm. pyrex c y l i n d e r maintained at 37 +_ 1° C. The c y l i n d e r was moved i n a v e r t i c a l plane beneath the surface of the d i s s o l u t i o n medium. The d i s s o l u t i o n medium was s t i r r e d continuously with a four-blade t u r b i n e type p r o p e l l e r at 240 - 260 r.p.m. See F i g . 4(D). The methods i n t h i s group have been c r i t i c i z e d f o r t h e i r lack of r e p r o d u c i b i l i t y , non-constancy of o s c i l l a t i o n , and extreme a g i t a t i o n . Abrasion on the t e s t dosage form has been observed to mask d i s s o l u t i o n d i f f e r e n c e s between batches. (C) Continuous Flow and Automated Procedures The methods i n t h i s group are c h a r a c t e r i z e d by the continuous flow of d i s s o l u t i o n medium past the t e s t sample. The medium i s , i n some cases, r e - c i r c u l a t e d , w h i l e i n others i t i s accumulated i n a r e s e r v o i r . The c i r c u l a t i n g f l u i d g e n e r a l l y provides the necessary a g i t a t i o n or various a d d i t i o n a l a g i t a t i o n devices may be employed. In most cases, these procedures are t o t a l l y automatic. Schroeter and Wagner (1962) used the modified USP d i s i n t e g r a t i o n method adapted f o r a continuous c y c l i n g of f i l t e r e d d i s s o l u t i o n f l u i d through a flow c e l l . See F i g . 5(A). - 40 -U.V. FLOW-CELL I I t v. PUMP --.< J 1/8 ID. LATEX TUBING USP DISINTEGRATION BASKET RACK ASSEMBLY IN ONE LITER BEAKER DISSOLUTION MEDIUM (A) Apparatus of Schroeter and Wagner. Figure'5. Diagramatic Representation of Continuous Flow Types of Dissolution Apparatus. See text for a description of each apparatus. / - 41 -Sjflgren et a l . (1964) used the same method except t h a t the d i s s o l u t i o n f l u i d was a g i t a t e d by an overhead s t i r r e r . See F i g . 5(B). McClintock et a l . (1965) used an apparatus which c o n s i s t s of a sample s e c t i o n (A), a s t i r r i n g compartment (B), and a dry c e l l f o r d e t e c t i o n (C). The s t i r r e r compartment i s s t i r r e d by means of a magnetic s t i r r e r which shunts the medium i n t o the part of the apparatus e n c l o s i n g the d e t e c t o r , from which i t enters the sample s e c t i o n , thereby completing the c y c l e . See F i g . 5(C). In t h e i r study of drug r e l e a s e from a s i n g l e face, Lapidus and L o r d i (1966) worked with a s p e c i a l l y designed flow c e l l i n which a g i t a t i o n i s e f f e c t e d only by the solvent flow. See F i g . 5(D). Genderton et a l . (1967) used a c y l i n d r i c a l perspex c e l l , 5.1 cm. i n diameter, with a 100 mesh concave s t a i n l e s s s t e e l gauze f i x e d across the c e l l . The t a b l e t i s he l d l i g h t l y i n the centre w i t h a v e r t i c a l p i n . The d i s s o l u t i o n medium i s admitted through the centre of the c e l l base and d i r e c t e d r a d i a l l y across the c e l l to avoid d i r e c t impingement on the gauze below the t a b l e t . When the t a b l e t i s wetted, the r e t a i n i n g p i n i s removed and the l i q u i d coming out from the top of the c e l l i s c o l l e c t e d and assayed. See F i g . 5(E). Pernarowski et a l • (1968) adapted the b a s k e t - s t i r r e r method (10 mesh b a s k e t ) , f o r continuous flow. The f l u i d flow or changeover i s c a r r i e d out by means of a f i l t e r i n g device and - 42 -RECORDING SPECTROPHOTOMETER STIRRING MOTOR COVER WATER BATH BEAKER (CONTAINING DISSOLUTION MEDIUM) TABLET FILTER ( B ) Apporatus of S jog ren et ol. Figure 5. Diagramatic Representation of Continuous Flow Types of Dissolution Apparatus-See tex t for a description of each apparatus. - 43 -A: Sample S e c t i o n B: S t i r r i n g Compartment C: Dry Well f o r Detec t i o n (C) Apparatus of McClintock et a l Figure 5, continued. - 44 -THERMOMETER -KEL-F CYLINDER •RUTGERS FLOW CELL TABLET (WITH ONE EXPOSEO) SURFACE) PUMP I L D. TYGON TUBING -RESERVOIR OF DISSOLUTION MEDIUM WATER BATH • BECKMAN FLOW CELL RECORDING SPECTROPHOTOMETER (D) Apparat-us of Lopidus and Lordi. Figure 5, cont inued. - 45 -short lengths of l a t e x t u b i n g . The t e s t f l u i d can be d i r e c t e d through a 1 cm. flow c e l l i n a spe c t r o n i c 505 re c o r d i n g spectrophotometer and then to the c o l l e c t i o n c o n t a i n e r . See F i g . 5(F). Rippie and Johnson's (1969) c y l i n d r i c a l glass tube (14 cm. long) w i t h a gradation of diameter from 2 cm. at the bottom to 2.5 cm. at the top, p r o v i d i n g a gradation i n flow s u f f i c i e n t to suspend the p e l l e t s and w i t h screens at both ends, was used as a d i s s o l u t i o n chamber. A mixing v e s s e l , a motor, a c o l o r i m e t e r , and a rotometer comprised the basic apparatus. The apparatus i s f i l l e d w ith 470 ml. of solvent c o n t a i n i n g a pre-determined c o n c e n t r a t i o n of d i s s o l v e d p e l l e t s . Fresh solvent i s added to maintain the c o l o r i m e t r i c reading at 76% transmittance as the sample d i s s o l v e s . Time r e q u i r e d f o r a d d i t i o n of 200 ml. i s recorded; 200 ml. of solvent i s withdrawn and the process i s repeated u n t i l 70% of the i n i t i a l volume of the p e l l e t s i s d i s s o l v e d . See F i g . 5(G). Baun and Walker (1969) used a glass d i s s o l u t i o n c e l l , the upper and the middle parts of which are equipped w i t h a s t a i n l e s s s t e e l wire screen (100 or 200 mesh) and the d i s s o l u t i o n medium i s c i r c u l a t e d past the t e s t sample at 70 +_ 2 ml. per minute by means of a continuous duty o s c i l l a t i n g pump. See F i g . 5(H). C a s t e l l o et a l • (1968) devised a d i s s o l u t i o n apparatus w i t h " m u l t i p l e t e s t i n g s t a t i o n s " . The apparatus c o n s i s t s of (a) a stand and r a i s i n g mechanism; (b) an a g i t a t o r support and d.c. motor d r i v e ; (c) e l e c t r i c c o n t r o l s ; and (d) a sampling device. - 46 -- 47 -DISCHARGE '.' ISPgCtBOPWOTOMETER I ^ ISTinngBl (F) Basket - St ir-r e r Apparatus of Pernarowski et a l . Figure 5 , cont inued-. - 48 -A: Solvent Reservoir F: - Roto-neter C: Mixing Vessel P: D i s s o l u t i o n Chamber F: C o l o r i r e t e r C e l l F: Furn (G) Apparatus of Ripnie and Johnson F i r u r e 5, continued. - 49 -Twenty d i s s o l u t i o n determinations can be made simultaneously with each d i s s o l u t i o n f l a s k c o n t a i n i n g 750 ml. of d i s s o l u t i o n medium maintained at 37° C , and a g i t a t e d at 180 r.p.m. Samples (1.5 ml.) are a u t o m a t i c a l l y withdrawn at 30 minute i n t e r v a l s f o r a t o t a l period of four hours and analysed. See F i g . 5(1). Tingstad and Riegelman's (1970) apparatus c o n s i s t s of a 17 ml. c a p a c i t y d i s s o l u t i o n c y l i n d r i c a l g l a s s c e l l (1.9 cm. x 6.1 cm.) which i s f i l l e d on each side (upper and lower) with a standard coarse p o r o s i t y s i n t e r e d glass f i l t e r . The d i s s o l u t i o n medium i s pumped through the flow meter, the d i s s o l u t i o n chamber (upwards) and v i a an a i r t r a p , to a spectrophotometer. See F i g . 5 ( J ) . Burger and Nash (1971) used d i r e c t c o n c e n t r a t i o n r e c o r d i n g i n t h e i r automatic procedure. The apparatus c o n s i s t s of a transparent, V-shaped p l a s t i c d i s s o l u t i o n chamber which o s c i l l a t e s about i t s centre; a s i l i c a flow c e l l i n the sample beam of a Beckman model DB-spectrophotometer, equipped with a Beckman model 131902 con c e n t r a t i o n converter; and a 100 mv. potentiometric s t r i p chart recorder. See F i g . 5(K). (D) Miscellaneous Methods This group includes a v a r i e t y of t e s t procedures which are c l a s s i f i e d as sink or non-sink and n a t u r a l convection or forced convection. The sink type i s the procedure i n which a - 50 -A: Glass D i s s o l u t i o n C e l l P: R e s e r v o i r f o r the Medium C: Pumr, D: V a r i a b l e Transformer E: Hater Bath F: Therrrostated C i r c u l a t i n g Fur .D (H) A c ^ r a t u s of ?aur and HalVer Figure 5, corstinuec 1. '. - 51 -TO VACUUM MANtrOuD \ 7 • TO DtSSnLUTlON FLASK (I) Sample Bulb of the Apparatus qf C a s t e l l o et a l . Figure 5, continued. - 52 -JI Air Trap 3-* To Spectrophotometer Li U c b dissolution cell "flow , meter PumP J) Apparatus of Tin ^ s t a d and RieFelman FLOW CELl A = DISSOLUTION CHAMBER B = SPECTROPHOTOMETER C = CONCENTRATION CONVERTER D = RECORDER (K) Apporotus* of Burger and Nash. F igure 5 , cont inued. - 53 -build-up of the so l u t e i s prevented by removal of the d i s s o l v e d s o l u t e . The non-sink type allows the so l u t e to stay i n the d i s s o l u t i o n medium, and the volume i s such t h a t the con c e n t r a t i o n of the so l u t e w i l l always remain below 2 5 per cent s a t u r a t i o n . Natural convection types are those procedures i n which homo-geneity of the d i s s o l u t i o n medium i s maintained by movement of the solvent surrounding the t e s t sample, due to de n s i t y d i f f e r e n c e s (or by d i f f u s i o n ) . Forced convection types i n v o l v e streamline flow or tu r b u l e n t flow of the d i s s o l u t i o n medium due to a g i t a t i o n by pumping or s t i r r i n g devices r e s p e c t i v e l y . (a) Forced Convection, Non-Sink Methods ( i ) R otating Vessel Methods. This group i s c h a r a c t e r i z e d by the methods of Wruble (19 30) and Souder and Ellenbogen (19 58). The Wruble procedure employs t e s t tubes ( c o n t a i n i n g the t a b l e t i n the d i s s o l u t i o n medium) f i x e d to a r e v o l v i n g d i s c which i s r o t a t e d at a speed of from 6 to 12 r.p.m. i n a water bath maintained at 37° C. See F i g . 6(A). Souder and Ellenbogen used b o t t l e s r o t a t e d at 40 r.p.m. See F i g . 6(B). Montgomery et a l . (1964) used the above method but analysed the withdrawn samples by s c i n t i l l a t i o n counting. S t r i v a s t a v a et a l . (1965) used the Souder and Ellenbogen apparatus to study the r e l e a s e of s u l p h u r - 3 5 - l a b e l l e d m a t e r i a l from e n t e r i c coated t a b l e t s . G i b a l d i and Weintraub (1970) used a s p h e r i c a l r o t a t i n g f l a s k supported by gl a s s rods fused to i t s sides which form - 54 -WATER BATH TEST TUBE (CONTAINING TABLET AND DISSOLUTION FLUID) REVOLVING DISC (A) W r u b l e Appara tus WATER BATH BOTTLE (CONTAINING TABLET AND DISSOLUTION FLUID) REVOLVING DISC (B) Souder and EITenbogen Apparatus Figure 6, Diagramatic Representation of Miscel laneous Dissolution Methods. See t e x t for a description of each apparatus. - 55 -the h o r i z o n t a l a x i s about which the f l a s k r o t a t e s (1.2 r.p.m.). The h o r i z o n t a l a x i s i s coupled to a constant speed motor. See F i g . 6(C). ( i i ) P a r t i c l e Size Methods. Edmundson and Lees (1965) measured changes i n p a r t i c l e s i z e using a C o u l t e r counter i n t h e i r study of the d i s s o l u t i o n of c r y s t a l l i n e hydro-cortisone acetate. They a p p l i e d vigorous s t i r r i n g i n order to suspend the p a r t i c l e s and used the beaker type apparatus. See F i g . 6(D). Though the p a r t i c l e s i z e data can be u s e f u l f o r f o l l o w i n g d i s s o l u t i o n k i n e t i c s of d i s i n t e g r a t i n g t e s t samples, the method cannot be used f o r dosage forms due to the presence of t a b l e t e x c i p i e n t s . ( i i i ) Shaker Methods. Singh et a l . (19660 used a m o d i f i c a t i o n of Nelson's technique of f i r m l y f i x i n g a t a b l e t i n t o a c y l i n d r i c a l p l e x i g l a s s c ontainer with the a i d of p a r a f f i n wax so t h a t only one surface i s exposed to the d i s s o l u t i o n medium. The p l e x i g l a s s i s placed i n a 250 ml. f l a s k c o n t a i n i n g 100 ml. of the medium maintained at 37° C. The f l a s k i s placed i n a constant temperature shaker bath operated at 120 strokes per minute. See F i g . 6(E). Schwartz et a l . (19 68 ) used a 2 50 ml. volumetric f l a s k c o n t a i n i n g a t a b l e t and 100 ml. of s o l v e n t . The f l a s k was placed i n a shaking water bath maintained at 30° C. as shown i n F i g . 6(F). ( i v ) R otating Disc Method. Levy and S a h l i (1962) pro-posed t h i s method i n which a plane faced t a b l e t (0.5 i n diameter) was mounted i n t o an a c r y l i c holder by means of p a r a f f i n wax. - 56 -MOTOR CONNECTION SAMPLING PORT SUPPORT BEARING DISSOLUTION FLUID WATER BATH (C) Ro ta t ing Flask Method of Gibaldi and Weintraub. STIRRER DISSOLUTION VESSEL CONTAINING THE ELECTRODES OF A COULTER COUNTER (D) Part ic le Size Method of Edmundson and Lees. Figure 6, continued. - 57 -< TABLET (WITH ONE SURFACE EXPOSED) DISSOLUTION FLUID CYLINDERICAL PLEXIGLASS CONTAINER -WATER BATH (E) Shaker Method of Singh et al. < > WATER BATH DISSOLUTION FLUID TABLET IF) S h a k e r Method of SchwaMz et al. F igure 6, continued - 58 -Only one surface of the t a b l e t i s exposed to the d i s s o l u t i o n medium. The holder was r o t a t e d at 555 r.p.m. i n a three neck round bottom f l a s k c o n t a i n i n g 200 ml. of d i s s o l u t i o n medium maintained at 37 +_ 0.1° C. The t a b l e t i n i t s holder was immersed to a depth of one inc h . See F i g . 6(G). (b) Forced Convection, Sink Methods . ( i ) Adsorption Method. Wurster and P o l l i (1961) employed No r i t e A charcoal or bentonite i n the d i s s o l u t i o n medium to adsorb d i s s o l v e d benzoic a c i d . See F i g . 6(H). However, i f the adsorbant modifies the v i s c o s i t y , i t can create a problem because the d i f f u s i o n c o n t r o l l e d d i s s o l u t i o n r a t e i s a f f e c t e d by v i s c o s i t y . ( i i ) P a r t i t i o n Methods. G i b a l d i and Feldman (1967) used a 500 ml. three neck round bottom f l a s k immersed i n a constant temperature bath maintained at 3 7 +_ 0.1° C. One hundred and f i f t y ml. of 0.1 N HCl was e q u i l i b r i a t e d to 37° C. and the s t i r r i n g blade immersed i n the d i s s o l u t i o n medium to a depth of 20 mm. The t a b l e t was dropped i n t o the aqueous medium and 150 ml. of organic solvent (1:1 mixture of cyclohexane and 1-octanol, f o r the benzoic a c i d study) was slowly added. S t i r r i n g was then s t a r t e d and 1 ml. samples of the organic phase were assayed. The organic phase volume was maintained by adding appropriate q u a n t i t i e s of f r e s h s o l v e n t . See F i g . 6(1). - 59 -Rota t ing Disc Method o f Levy and Sahli. STIRRING MOTOR NORITE- A CHARCOAL OR BENTONITE IN THE DISSOLUTION FLUID TABLET A d s o r p t i o n Method of Wurster and Polli. Figure 6, continued. - 60 --STIRRING MOTOR \ c= -WATER BATH ORGANIC SOLVENT AQUEOUS MEDIUM •TABLET Par t i t i on Method ' of Gibaldt and Fe ldman STIRRING MOTOR STIRRING SHAFT BEARING THREE IMPELLERS WATER BATH ORGANIC PHASE AQUEOUS PHASE P a r t i t i o n Method of Nie&ergal l et a I. F igure 6, cont inued. - 61 -Niebergal et a l . (1967) used the same p r i n c i p l e as the above except t h a t they used three p r o p e l l e r s - two i n the organic phase and one i n the aqueous phase. See F i g . 6 ( J ) . U l l a h and Cadwallader (1970) devised an apparatus which c o n s i s t s of two glass bowls; a main frame with a p a i r of t e f l o n gaskets; a screen or a f i l t e r membrane h o l d i n g frame; two con-t r o l l e d speed s t i r r e r s with s t i r r i n g s h a f t s ; p r o p e l l e r s and i m p e l l e r s ; and a sample i n j e c t o r . See F i g . 6(K). ( i i i ) D i a l y s i s Method. P a t e l and Foss (1964) used an apparatus which c o n s i s t s of two p l e x i g l a s s b l o c k s , 2 1/2 by 2 1/2 by 1 1/16 inches with a c a v i t y of 20 ml. c a p a c i t y . The d i a l y s i s membrane i s placed between the two blocks w i t h the c a v i t i e s f a c i n g each other. The t e s t sample i s placed i n one of the c a v i t i e s and the c e l l i s r o t a t e d . See F i g . 6 ( L ) . The same procedure was used by Marlowe and Shangraw (1967) who r o t a t e d the c e l l ( c o n t a i n i n g two t a b l e t s and 15 ml. of d i s t i l l e d water i n one compartment and 15 ml. of d i s t i l l e d water i n the other) at a r a t e of 15 r.p.m. They reported t h a t a s l i g h t d i s t o r t i o n of the d i s s o l u t i o n p r o f i l e could occur due to the i n t e r r u p t i o n of the r o t a t i o n during sampling. The method described by F e r r a r i and Khoury (1967) used a b a f f l e d r o t a t i n g round bottom f l a s k which gave a " s l o s h i n g " a c t i o n . The f i l t e r e d contents (maintained at 37° C.) of the f l a s k were c i r c u l a t e d continuously through the d i a l y s e r and back to the f l a s k . The r e c i p i e n t stream was continuously analysed by means of a c o l o r i m e t e r . This procedure was claimed to c l o s e l y approximate i n - v i v o c o n d i t i o n s . See F i g . 6(M). - 62 -Figure 6, continued. - 63 -STIRRING SHAFT PLEXIGLASS SLOCKS DiALYSIS MEMBRANE TEST SAMPLE ( L) D io lys is Method of Po te l ohd Foss CIRCULATING DONOR FLUID FLASK (CONTAINING TEST SAMPLE AND DISSOLUTION FLUID) TRANSFER ACROSS THE DIALYSIS MEMBRANE RECIPIENT STREAM (M) Dialysis Method of Ferrari and Khoury. Figure 6, continued. - 64 -Krogerus et a l , (1967) used an o s c i l l a t i n g d i a l y s i s c e l l . Samples f o r assay are withdrawn from the bath i n t o which the c e l l o s c i l l a t e s . See F i g . 6(N). A problem common to the d i a l y s i s methods i s the change i n d i f f u s i o n g r a d i e n t , due to v a r i a t i o n i n r e l a t i v e volume of f l u i d i n the compartments. This can d i s t o r t the i n t e r p r e t a t i o n of the data. Hersey (1969) shates t h i s d i f f i c u l t y can be overcome by continuously removing the donor f l u i d f o r subsequent a n a l y s i s i n the manner described by B a r z i l a y and Hersey (1968). (c) N a t u r a l Convection, Non-Sink Methods ( i ) The solvometer described by E l l i o t t (19 33) involved the immersion of a 'boat' i n a d i s s o l u t i o n medium. The 'boat' was surmounted by a f l o a t and a measuring bar extended from the f l o a t upwards i n t o a c a l i b r a t e d scale s i m i l a r to th a t on a hydrometer. When the t a b l e t was placed i n the 'boat', the scal e bar moved to i t s lowest p o s i t i o n and gr a d u a l l y rose as the t a b l e t d i s s o l v e d . The weight l o s s of the t a b l e t could be read from the c a l i b e r a t e d s c a l e . See F i g . 6(0). ( i i ) The Hanging P e l l e t Method. This was f i r s t devised by Nelson (1958). In t h i s technique the t e s t t a b l e t s were suspended by means of a nylon thread to the suspension hook of a Sa r a t o r i u s S e l e c t a balance, i n such a way th a t the e n t i r e mounting p l a t e w i t h specimen was immersed i n the d i s s o l u t i o n medium. The times r e q u i r e d f o r apparent l o s s e s of 4 or 5 mg. were read o f f an i l l u m i n a t e d 0 t o 100 mg. sc a l e and recordings - 65 -Q--OSC ILLATIN6 DIALYSIS CELL -TEST SAMPLE -DISSOLUTION MEDIUM (N) Osci l la t ing Dialysis Cell of Krogerus et al. MEASURING BAR DISSOLUTION MEDIUM (0) Solvometer F igu re 6, continued. - 66 -were done f o r the f i r s t 30 to 40 mg. The apparent lo s s e s of weight m u l t i p l i e d by the r a t i o s of the d e n s i t i e s of the p e l l e t s to the d i f f e r e n c e between the d e n s i t i e s of the p e l l e t s and the medium gave the amounts d i s s o l v e d . See F i g . 6(P). ( i i i ) S t a t i c Disc Method. This method was devised by Levy (1963). The t a b l e t i s mounted i n an a c r y l i c holder and placed i n a 2 5 ml. v i a l by means of a rubber stopper. The i n v e r t e d v i a l c o n t a i n i n g the d i s s o l u t i o n medium (0.1 N HC1) i s placed i n an incubator maintained at 37° C. V i a l s are removed and the s o l u t i o n analysed at s p e c i f i e d time i n t e r v a l s . See F i g . 6(0). 4. C o r r e l a t i o n of I n - v i t r o D i s s o l u t i o n Tests with In-vivo Data The magnitude of the s o l u b i l i t y of a drug i n aqueous media " i n d i c a t e s whether or not d i s s o l u t i o n i s the r a t e determining step i n a b s o r p t i o n . Many i n v e s t i g a t o r s (Levy, 19 61; Campagna et a l . , 1963; Nelson, 19 59 , Levy and Hayes, 1961; Bates et a l . , 1969) have shown that the absorption of s l i g h t l y s o l u b l e drugs i s r a t e l i m i t e d by t h e i r r a t e of d i s s o l u t i o n . Levy and Hayes (1960) stated that the r a t e of d i s s o l u t i o n of drugs i s a f u n c t i o n of the i n t r i n s i c d i s s o l u t i o n r a t e of the pure drug as w e l l as the pharmaceutical p r o p e r t i e s of the dosage form. In a l a t e r p u b l i c a t i o n , Levy (1964) enumerated the f a c t o r s t h a t can a f f e c t i n - v i t r o - i n - v i v o c o r r e l a t i o n s t u d i e s : - 67 -7S NYLON THREAD TABLET DISSOLUTION MEDIUM Hanging Pel let Method. -TABLET ACRYLIC HOLDER -RUBBER STOPPER S t a t i c Disc Method. Figure 6, continued. - 68 -(a) Drug degradation (b) pH of contents (c) F i l m formation, p a r t i c u l a r l y i n the case of r e l a t i v e l y l a r g e drug p a r t i c l e s , (d) I r r i t a t i o n of the g a s t r i c mucosa by c e r t a i n drugs; e.g., bishydroxycoumarin (e) Biotransformation i n the g a s t r o - i n t e s t i n a l mucosa during absorption ( f ) Amount of f l u i d ingested, On the b a s i s of the above, one can say th a t p h y s i o l o g i c a l a v a i l a b i l i t y of the drug i n a p a r t i c u l a r dosage form depends upon i t s d i s s o l u t i o n r a t e as w e l l as pharmaceutical and b i o -l o g i c a l f a c t o r s . Hence, an i n - v i t r o d i s s o l u t i o n t e s t would be useless unless i t i s c o r r e l a t e d with i n - v i v o data. Such c o r r e l a t i o n s have been reported with s t i r r e d v e s s e l types of methodology (Campagna et a l . , 19 63; Poole et a l . , 19 68; Bates et a l . , 1969 ; O ' R e i l l y et a l . , 1966 ; Dressman et a l . , 1962 ; Wood, 1967; Levy, 1961; 1964; Levy and Hayes, 1961; Levy et a l • , 1965; 1967) as w e l l as the modified USP d i s i n t e g r a t i o n methods of t e s t i n g (Katchen and Synchowicz, 1967; Levy, 1962; Taraszka and Delor, 1969). Some of the miscellaneous methods of t e s t i n g (see Section 2, D) have a l s o been c o r r e l a t e d w i t h various i n - v i v o parameters ( G i b a l d i and Weintraub, 1970; MacDonald et a l . , 1969). However, i n - v i t r o - i n - v i v o c o r r e l a t i o n s may only be a p p l i e d to a p a r t i c u l a r formulation of the drug and the main - 69 -use of the i n - v i t r o d i s s o l u t i o n t e s t i s to maintain repro-d u c i b i l i t y of re l e a s e between batches of a s p e c i f i c f o r m u l a t i o n . Although two c l i n i c a l l y d i f f e r e n t brands of chlorpromazine hydrochloride t a b l e t s were used i n t h i s i n v e s t i g a t i o n , the p r i n c i p a l o b j e c t i v e h e r e i n i s to study the i n - v i t r o c h a r a c t e r -i s t i c s of a s p e c i f i c d i s s o l u t i o n t e s t . In-vivo t e s t i n g of drug products i s , t h e r e f o r e , secondary but, f o r more informa t i o n on the s u b j e c t , the various chapters i n Wagner's textbook (19 71) on biopharmaceutics should be consulted. 5. Development of Standard D i s s o l u t i o n Procedures Although none of the procedures described i n the l i t e r a t u r e can be a p p l i e d to a l l drugs and t h e i r dosage forms, many can be used under c a r e f u l l y c o n t r o l l e d c o n d i t i o n s f o r s p e c i f i c purposes. Because of the p r o l i f e r a t i o n of methodology, s t a n d a r d i z a t i o n of d i s s o l u t i o n r a t e t e s t i n g became necessary. Furthermore, the r e c o g n i t i o n of the s i g n i f i c a n c e of d i s s o l u t i o n i n the b i o -a v a i l a b i l i t y of drugs made the matter even more urgent (Campagna et a l . , 1963; Levy, 1964; Bauer et a l . , 1962; L a z i n s k i , 1960; Frostad, 1961). In August 1967, the D i r e c t o r s of Revis i o n of the USP and NF appointed a J o i n t Panel on P h y s i o l o g i c a l A v a i l a b i l i t y . A f t e r a study of the l i t e r a t u r e , the Panel s e l e c t e d three d i s s o l u t i o n procedures f o r c l o s e r s c r u t i n y : (1) The r o t a t i n g basket procedure of Pernarowski et a l . (1968) - 70 -(2) The s t a t i o n a r y basket method described by Cook et a l , of the Food and Drug D i r e c t o r a t e (3) The modified USP-NF d i s s o l u t i o n method These were chosen because method (1) showed a c o r r e l a t i o n of d i s s o l u t i o n r a t e and blood l e v e l s f o r a s e r i e s of phenylbutazone t a b l e t s ; method (2) gave d i f f e r e n t d i s s o l u t i o n r a t e s as reported f o r various brands of h y d r o c h l o r o t h i a z i d e t a b l e t s ; and method (3) was used by many i n v e s t i g a t o r s who had c o l l e c t e d data comparing d i s s o l u t i o n r a t e s and b i o l o g i c a v a i l a b i l i t y . A f t e r a f u r t h e r c o n s i d e r a t i o n i n which c o l l a b o r a t i v e experimental stud i e s were done with the above three pro-cedures, the basket s t i r r e r method and the procedure using the USP-NF d i s i n t e g r a t i o n apparatus were s e l e c t e d with s l i g h t m o d i f i c a t i o n s . The USP XVIII adopted the basket s t i r r e r method and the NF adopted both the basket s t i r r e r method and the modified USP-NF d i s i n t e g r a t i o n apparatus. The Panel suggested that the l a t t e r method be used only f o r those mono-graphs where i n - v i v o c o r r e l a t i o n has been obtained. In the basket s t i r r e r method, the v a r i a b l e degree of a g i t a t i o n and the choice of s e v e r a l media, the combination of which can s u i t s p e c i f i c t e s t c o n d i t i o n s f o r i n - v i v o c o r r e l a t i o n of the p a r t i c u l a r f o r m u l a t i o n , was the main reason f o r i t s adoption. However, the f o l l o w i n g c r i t i c i s m s have been d i r e c t e d towards the basket s t i r r e r method: - 71 -( i ) P o s s i b l e c l o g g i n g of granules or t h e i r aggregates on the screen of the 40 mesh s t a i n l e s s s t e e l basket r e s u l t i n g i n a d i s t o r t e d d i s s o l u t i o n p a t t e r n (Shah and Moore, 1970; Blythe and Mader, 1969). ( i i ) Formation of a mound of the d i s i n t e g r a t e d granules at the outside perimeter of the bottom of the f l a s k (convex faced bottom) ( G i b a l d i and Weintraub, 1970). ( i i i ) N o n - v i s i b i l i t y of the t e s t sample w i t h i n the basket. ( i v ) A i r bubbles trapped i n the r o t a t i n g basket can co n t r i b u t e to v a r i a t i o n s i n d i s s o l u t i o n r a t e (Blythe and Mader, 1969). (v) The basket can be corroded by the h y d r o c h l o r i c acid, s o l u t i o n r e q u i r e d f o r t e s t i n g s u l f i s o x a z o l e and sulfameth-oxazole t a b l e t s , and so cannot be used a f t e r 40 hours of exposure to the a c i d (Mattok et a l . , 1972). The method using the USP-NF d i s i n t e g r a t i o n apparatus has al s o been c r i t i c i z e d : ( i ) The o s c i l l a t i n g set-up exposes the t e s t sample to a i r and to p o s s i b l e o x i d a t i o n i f the sample i s so l i a b l e . Spectrophotometric determinations during assay may r e s u l t i n erroneous data. ( i i ) The t e s t procedure i s c a r r i e d out i n the open and solvent l o s s e s can adversely a f f e c t the d i s s o l u t i o n p r o f i l e i f the t e s t takes a r e l a t i v e l y long pe r i o d of time. - 72 -Shortcomings of the USP-NF d i s s o l u t i o n procedures i n c l u d e : (a) Inherent l a c k of homogeneity (b) V a r i a b l e movement due to a g i t a t i o n with a wire mesh or by o s c i l l a t i o n (c) I n t e g r a l d i s s o l u t i o n procedures In the l i g h t of the above d e f i c i e n c i e s , Tingstad and Riegelman (19 70) claimed t h a t a new "Standard" d i s s o l u t i o n r a t e t e s t i n g method was needed. Such a method should -(a) have a much greater degree of f l e x i b i l i t y (b) y i e l d data i n a d i f f e r e n t i a l form which can then be converted to the i n t e g r a l form, i f d e s i r e d (c) u t i l i z e a r e l a t i v e l y homogeneous low volume system (d) prevent excessive accumulation of s o l u t e i n the system (e) provide solvent flow on a c o n t r o l l e d , p r e c i s e , measurable manner which can be mathematically r e l a t e d to fundamental d i s s o l u t i o n r a t e equations. The authors c l a i m that t h e i r method meets the above requirements. Nevertheless, since no apparatus or procedure can e x a c t l y d u p l i c a t e i n - v i v o c o n d i t i o n s , a l l d i s s o l u t i o n s t u d i e s are r e l a t i v e , the most important c o n s i d e r a t i o n s being r e p r o d u c i b i l i t y , p r a c t i c a l i t y and reasonableness. I I I . THE TEST DRUG - CHLORPROMAZINE HYDROCHLORIDE Chlorpromazine hydrochloride i s a white or s l i g h t l y creamy white, o d o r l e s s , c r y s t a l l i n e powder which darkens on prolonged exposure to l i g h t . I t i s very s o l u b l e i n water; f r e e l y s o l u b l e i n a l c o h o l and i n chloroform; but i n s o l u b l e i n ether and i n benzene. I t s chemical name i s 2-chloro-10-[3-(dimethyl-amino) Propyl]-phenothiazine Monohydrochloride and has a melting point range of 19 5-198° C. The molecular weight i s 355.33. / c i -Figure 7. Chemical s t r u c t u r e of chlorpromazine hydrochloride, The pH of a 5% aqueous s o l u t i o n i s between 4 and 5. Solut i o n s remain s t a b l e f o r more than 24 hours but d i s c o l o r i n b r i g h t l i g h t . Chlorpromazine hydrochloride can be p r e c i p i t a t e d by many substances i n c l u d i n g t h i o b a r b i t u r a t e s and a t r o p i n e . I t absorbs a maximum of electromagnetic r a d i a t i o n at a wavelength range of 254 to 25 5 nanometers. - 74 -Chlorpromazine hydrochloride i s marketed f o r o r a l use i n 10, 25, 50, 100 and 200 mg. t a b l e t s . For i n j e c t i o n i t i s a v a i l a b l e i n 1 and 2 ml. ampuls c o n t a i n i n g 2 5 mg. per ml. and i n 10 ml. m u l t i p l e dose v i a l s c o n t a i n i n g the same co n c e n t r a t i o n . I t i s a l s o marketed as a syrup c o n t a i n i n g 10 mg. per teaspoon-f u l i n a f lavoured v e h i c l e . This drug was f i r s t synthesized as the f r e e base by Charpentier i n 19 52. L a b o r i t et a l . (19 52) described the a b i l i t y of t h i s compound to p o t e n t i a t e anaesthe-t i c s and produce " a r t i f i c i a l h i b e r n a t i o n " . They noted that chlorpromazine by i t s e l f d i d not cause a l o s s of consciousness but produced only a tendency to sleep and a marked l a c k of i n t e r e s t i n what was going on. C o u r v o i s i e r et a l . (19 53) de-s c r i b e d a l a r g e number of a c t i o n s manifested by chlorpromazine. These in c l u d e d g a n g l i o l y t i c , a d r e n o l y t i c , a n t i f i b r i l l a t o r y , antiedema, a n t i p y r e t i c , antishock, a n t i c o n v u l s a n t and a n t i -emetic p r o p e r t i e s . They a l s o observed that the drug enhanced the a c t i v i t y of a number of analgesic and c e n t r a l depressant drugs. The treatment of mental i l l n e s s by chlorpromazine above was f i r s t reported by Delay and Associates (19 52). They reported that chlorpromazine achieved more than symptomatic r e l i e f of a g i t a t i o n or a n x i e t y and that i t could have an a m e l i o r a t i v e e f f e c t upon psychotic processes with q u i t e d i v e r s e symptomatology. The above workers d i s t i n g u i s h e d the e f f e c t s of chlorpromazine i n psychoses from those seen w i t h "sleep therapy" and noted that both a g i t a t i o n and confusion were reduced i n c o n t r a s t to the e f f e c t of h y p n o t i c - n a r c o t i c mixtures. Never-- 75 -t h e l e s s , these authors f e l t t h a t chlorpromazine was l e s s u s e f u l i n retarded or depressed c o n d i t i o n s than were e l e c t r o - c o n v u l s i v e therapy and other treatments. Lehman and Hanrahan (19 54) r e p o r t e d , f o r the f i r s t time i n the Western Hemisphere, the use of chlorpromazine i n the t r e a t -ment of psychomotor excitement and manic s t a t e s . Following i t s r e l e a s e f o r marketing i n the United S t a t e s , i t was f i r s t employed c l i n i c a l l y as an a n t i - e m e t i c , but i t was a l s o noted that i t produced sed a t i o n , r e l a x a t i o n and hypothermia ( J a r v i k , 1970). C l i n i c a l s t u d i e s soon revealed that the most widespread u s e f u l -ness of chlorpromazine was i n the treatment of psychotic s t a t e s , and i t has since been used p r i m a r i l y f o r psychotic purposes. During the e a r l y years of the c l i n i c a l use of t h i s drug, many p s y c h i a t r i s t s expressed s k e p t i c i s m t h a t chlorpromazine was any more e f f e c t i v e than a placebo and f e l t t hat i t would not l a s t long i n the treatment of mental diseases. Yet, now, the accumulated evidence (10,000 p u b l i c a t i o n s have d e a l t with chlorpromazine from 1955 to 1965) shows t h a t i t i s q u i t e a c t i v e i n d i m i n i s h i n g psychotic signs and i t w i l l most l i k e l y be used i n one form or another f o r many years to come. Chlorpromazine hydrochloride i s c a t e g o r i s e d i n the USP as a major t r a n q u i l l i z e r . The t h e r a p e u t i c a p p l i c a t i o n s of chlorpromazine hydrochloride may be c l a s s i f i e d as f o l l o w s : (a) Anti-emetic e f f e c t s (b) P o t e n t i a t i o n of the e f f e c t s of a n a e s t h e t i c s , a n a l g e s i c s and sedatives - 76 -(c) Treatment of moderate and severe mental and emotional s t a t e s . I t i s used most widely i n the treatment of a n x i e t y , t e n s i o n , a g i t a t i o n , and i n l e s s e n i n g motor a c t i v i t y i n p s y c h o t i c s . Selected cases of s c h i z o -phrenia, mania, and t o x i c and s e n i l e psychosis respond to treatment w i t h t h i s drug. I t i s of value a l s o i n the treatment of severe asthmatic a t t a c k s . The wide pharmacological p r o p e r t i e s of chlorpromazine have been reviewed by J a r v i k (1970). Chlorpromazine hydrochloride i s w e l l absorbed from the g a s t r o i n t e s t i n a l t r a c t and p a r e n t e r a l s i t e s . A f t e r a b s o r p t i o n , the drug i s r a p i d l y d i s t r i b u t e d i n a l l body t i s s u e s . Most i n v e s t i g a t o r s have found that b r a i n concentrations are r e l a t i v e l y low compared to those i n other organs but con-s i d e r a b l y higher than i n plasma; the highest concentrations of the drug are found i n the lungs, followed by the l i v e r , the adrenal gland, and the spleen (Wechsler and R o i z i n , 1960). Hydroxylation i n the 3 and 7 p o s i t i o n s and subsequent conjugation with glucuronic a c i d represent the p r i n c i p a l metabolic pathway. Sulfoxides are formed i n the metabolic process, and metabolic a l t e r a t i o n s i n the side chain a l s o occur. One hundred and s i x t y - e i g h t p o s s i b l e metabolites of chlorproma-zine have been postulated and many have been a c t u a l l y i s o l a t e d i n human urine (Williams and Parke, 1964). About h a l f of the metabolites are found i n the ur i n e and the r e s t i n feces. - 77 -Studies of concentrations of chlorpromazine hydrochloride i n plasma have been delayed by the l a c k of s u i t a b l e chemical methods of drug a n a l y s i s . I n v e s t i g a t i o n s of concentrations of t h i s drug i n plasma have l a t e l y been i n i t i a t e d (Curry and Brodie, 1967; Curry and M a r s h a l l , 1968; and Curry, 1968a). The a n a l y s i s of unchanged chlorpromazine from plasma i n v o l v e s (1) e x t r a c t i o n with a non-polar s o l v e n t ; (2) con c e n t r a t i o n of the e x t r a c t by successive back-extractions i n t o aqueous and organic s o l v e n t s ; and (3) gas l i q u i d chromatography of the concentrated e x t r a c t using an e l e c t r o n capture d e t e c t o r (Curry, 1968b). Concentrations as low as 0.005 micrograms per ml. are claimed to be detected by t h i s method. c Curry et a l . (1970c) and H o l l i s t e r et a l . (1970) compared concentrations of unchanged chlorpromazine a f t e r s i n g l e doses i n a v a r i e t y of dosage forms. Concentrations were highest a f t e r intravenous i n j e c t i o n and s u c c e s s i v e l y lower a f t e r intramuscular and o r a l a d m i n i s t r a t i o n of the drug i n l i q u i d , t a b l e t and sustained-release form. Curry et a l . (1969) observed great d i f f e r e n c e s i n drug c o n c e n t r a t i o n i n plasma of d i f f e r e n t p a t i e n t s i n d i c a t i n g a v a r i a b l e f r a c t i o n (1 to 70%) of an o r a l dose reaching the general c i r c u l a t i o n as unchanged chlorpromazine. Since chlorpromazine undergoes extensive metabolism, the unchanged drug i s r a r e l y detectable i n urine or feces (Emmerson and Miya, 1963; Williams and Parke, 1963; Curry et a l . , 1970a). Urinary e x c r e t i o n of metabolites was r e l a t i v e l y constant when - 78 -measured as a pro p o r t i o n of a dose of chlorpromazine, both i n comparisons between p a t i e n t s r e c e i v i n g s i m i l a r doses and i n comparisons w i t h i n p a t i e n t s r e c e i v i n g the same dose i n two or more d i f f e r e n t forms ( H o l l i s t e r et a l . , 19 70). The v a r i a b l e plasma concentrations of the drug, and the observation that the u r i n a r y e x c r e t i o n data i n d i c a t e d 100 per cent absorption from the s i t e of a d m i n i s t r a t i o n , r a i s e d the question of the ul t i m a t e d i s p o s i t i o n of the drug. In animal experiments c a r r i e d out by Curry et a l . (1970a) and Curry (19 70) i t was found t h a t the drug concentrations i n plasma of r a t s and dogs, a f t e r o r a l and intravenous doses, were very d i f f e r e n t and that concentrations a f t e r intravenous, i n t r a -muscular, and i n t r a p e r i t o n e a l doses were s i m i l a r . The apparent l o s s of m a t e r i a l was b e l i e v e d to take place between the i n t e s t i n a l lumen and the p o r t a l c i r c u l a t i o n , s ince a l a r g e proportion of an i n t r a p e r i t o n e a l dose reaches the general c i r c u l a t i o n v i a the p o r t a l c i r c u l a t i o n as the unchanged drug. This concept was supported by the recent observation that chlorpromazine i s destroyed e i t h e r c h e m i c a l l y o r b i o c h e m i c a l l y during t r a n s f e r across the i n t e s t i n a l w a l l i n - v i t r o (Curry et a l . , 1970b). The v a r i a b l e absorption p a t t e r n of chlorpromazine hydrochloride and the apparent l a c k of success of studies of r e l a t i o n s h i p s between e x c r e t i o n and e f f e c t s (Green et a l . , 196 5; Kurland et a l . , 1965; Levine et a l . , 1969; Rose et a l . , 1964) i n d i c a t e the d i f f i c u l t y i n v o lved i n comparative c l i n i c a l - 79 -e v a l u a t i o n of d i f f e r e n t brands of i t s dosage forms. Hence a c l i n i c a l assessment of the pharmacological responses to d i f f e r e n t drugs or dosage forms of the same drug may be the only p o s s i b l e approach f o r purposes of comparison. Such a study was c a r r i e d out at the H o s p i t a l f o r Mental Disease i n S e l k i r k , Manitoba, by Dr. R.G. Bankier and Dr. F.A.L. Mathewson (1972). The above c l i n i c a l study was c a r r i e d out on f i f t y - s e v e n chronic schizophrenic p a t i e n t s (23 males, 34 females). Types of schizophrenia were: paranoid - 11, simple - 2, hebephrenic - 14, c a t o t o n i c - 14, and u n d i f f e r e n t i a t e d - 16. The p a t i e n t s were d i v i d e d i n t o three groups comprising 14, 22, and 21 s u b j e c t s . Previous a n t i p s y c h o t i c medications were withdrawn i n three stages over a period of two weeks a f t e r which a placebo preparation was s u b s t i t u t e d . The dose of the placebo was maintained at one capsule three times a day f o r a l l p a t i e n t s and continued u n t i l r e l a p s e to f l o r i d psychosis. At t h i s p o i n t , the placebo was supplemented by a d d i t i o n of Drug A (Chlorpromazine Hydrochloride Tablets (CPZ), Maney - 14 p a t i e n t s ) , Drug B (Mesoridazine (MRZ) Sandoz - 22 p a t i e n t s ) or Drug C (Chlorpromazine Hydrochloride Tablets (CPZ), Poulenc - 21 p a t i e n t s ) according to the group i n which the p a t i e n t belonged. The dosage of Drugs A, B and C was adjusted accord-i n g to the needs of the p a t i e n t i n an e f f o r t to o b t a i n optimal c o n t r o l of psychotic symptoms. - 80 -C l i n i c a l assessments were c a r r i e d out using the B r i e f P s y c h i a t r i c Rating Scale (BPRS) ( O v e r a l l and Gorham, 1962) and the Nurses' Observational Scale f o r Inpatient E v a l u a t i o n (NOSIE) (Honigfeld and K l e t t , 1965). A b r i e f d e s c r i p t i o n of these scales i s given below. The BPRS i s a technique used i n the e v a l u a t i o n of p a t i e n t change due to treatment. Sixteen symptoms are l a i d out f o r r a t i n g on seven-point ordered category r a t i n g s c a l e s . See F i g . 8. The degree of symptomatology i n each of the r e l a t i v e l y indepen-dent symptom areas i s c l a s s i f i e d by the same s c a l e (with seven gradings). Each of the symptom areas i s i d e n t i f i e d with a c o n s t r u c t which has high consensual v a l i d i t y among p r o f e s s i o n a l l y t r a i n e d persons i n p s y c h i a t r y and psychology. The users of the B r i e f Scale have to become thoroughly f a m i l i a r with the d e f i n i -t i o n s and d e l i n e a t i o n s of symptom areas as set f o r t h i n the r a t i n g s c a l e items. A r a t i n g team of two w i l l standardize t h e i r procedures and achieve a consensual understanding of r a t i n g constructs through r a t i n g i n t e r v i e w s and r a t i n g s of s e v e r a l p a t i e n t s , before i n t e r v i e w i n g the research p a t i e n t s . Following the i n t e r v i e w of the i n d i v i d u a l p a t i e n t , the team members make independent r a t i n g s i n the s i x t e e n symptom areas. In r a t i n g the degree of symptomatology, the r a t e r should use as a reference group a l l p a t i e n t s who 'have the p a r t i c u l a r symptom i n question. "As compared with the population of p a t i e n t s who do have the symptom i n question, what i s the degree of s e v e r i t y of the symptom i n t h i s p a r t i c u l a r p a t i e n t ? " Some of the r a t i n g s are based upon observation of the p a t i e n t , while others are based on v e r b a l r e p o r t s . - 81 -B R I E F P S Y C H I A T R I C R A T I N G S C A L E O V E R A L L A N O G OR H A M DRAW A CIRCLE ANOUNO THE TERM UNDER tACH SYMPTOM WHICH BEST DESCRIBES THE PATIENT'S MUtMT CONDITION. t. S O M A T I C C O N C E R N -I * P S R C S I V S D A PROBLEM N O T P R E S E N T OESRCC O F C C H C I H N OVER niMNi B O O I L Y H E A L T H . R A T I tMt DEGREE T O W B Y TM* FATIWT, N H m W COM»t_A|MT» H A V E R E A L I S T I C B A S I S OR MOT, *ICN PHYSICAL H E A L T H V E R Y M I L D MOO, SEVERS SEVER! EXTREMELY IIVUI t* A N X I E T Y * W O R R Y , F I M , ON O V E R - C O N C E R N FOR P R E S E N T cm rufuRi. R A T I S O L E L Y ON r u t B A S I S o r V E R B A L REPORT o r Mtitnt ' i O W N tuuienvi tArfniiMef i . Do MOT mwtn A M I I I T Y F R O M M W I M M , S I O N * H M O M Hiu*otic S I ' I N S I M I C H A N I I M I . N O T m i i i N T v i x -I . E M O T I O N A L W I T H D R A W A L T O WHICH TMt MTUNT O W E S TMt I MODERATE MOO, SEVERS SlVIM E X T R E M E L Y S E V E R E ' D E F I C I E N C Y I N R E L A T I N G TO T H E I N T E R V I E W E R A M T H E I N T E R V I E W S I T U A T I O N . R A T I ONLY O E S R I I I P R E S S I O N OR F A I L I N S T O BE I N I M O T I O N A L C O N T A C T W I T H O T H E R P E O P L E I N T H K I N T E R V I E W S I T U A T I O N , NOT P R E S E N T Vl»Y M I L D MlLO M O O E R A T S M O O . S E V E R ! S E V E R S ElTKtMtLV ItVtHI 4 , C O N C E P T U A L D I S O R G A N I Z A T I O N - O I O N E B T O W H I C H T H E THOUGHT P R O C E S S E S A R E C O N F U S E D , o i i c o K x r c r i a m o n o M M i u a , RATI CM T H E B A S I S or 'INTEGRATION or T N E V E R B A L PRODUCTS O F T H E P A T I E N T ^ DO HOT H A T E ON T H E S A S I S or T H E P A T I E N T ' S » OBJECTIVE; I M P R E S S I O N O P H I S OWN L E V E L Or F U N C T I O N I N G . N O T P R E S E N T VM» MILD MlLO Moot* ATE M o o , S E V E R E S E V E R E E M T R C M S L Y S E V E R E 8 . G U f L T F E E L I N G S - O V E R - C O N C E R H OR R E M O R S E FOR P A S T B E H A V I O R . R A T E OH T H E B A S I S or T H E P A T I E N T ' S S U B J E C T I V E EXPERIENCES Or O U I L T AS E V I D E N C E D BY V E R B A * . R I P O N T W I T H A P P R O P R I A T E A F F E C T 1 OO H O T I N F E R G U I L T rEELINGS P R O M O S P H S S S < O M A A N X I E T Y , O N N E U R O T I C OfFEMSE*. NOT PRESENT M O D E R A T E M O D . S E V E R E S E V E R E E X T R E M E L Y S E V E R E • , T E N S I O N - PHYICAL A N O MOTOR MANIFESTATIONS OF TENSION, "NERVOUSNESS", AND HE IGMTXHSO ACTIVATION LEVEL. TENSION •MOULD BE RATED SOLELY ON THE BASIS OP P H Y S I C A L BNtHS ANO MOTOR BEHAVIOR AND NOT ON THE BASIS OT SUBJECTIVE EXPERIENCES OF TEHSIOH REPONTEO BY THE PATIENT. Nor PRE S E N T V E R Y M I L O Moo, S E V E R E S E V E R S EXTREMELY SEVER* - ? . M A N N E R I S M S A N D P O S T U R I N G - U N U S U A L A N D U N N A T U R A L M O T O N B E H A V I O R , T M T Y P E or M O T O R B E H A V I O R W H I C H C A U M S C E R T A I N M E N T A L P A T I E N T S TO S T A N D OUT I N A CROWD O T N O R M A L P E O P L E , R A T E ONLY A B N O R M A L I T Y OP M O V E M E N T S ; OO N O T R A T I S I M P L E . NCIOMTCNtO MOTOR A C T I V I T Y H E R E . N O T P R E S E N T M O D E R A T E M o o . S E V E R S S E V E R E E X T R E M E L Y S E V E R S f. GRANDIOSITY - EXAGERATED SELF-OPrHIOM. CONVICTION Or UNUSUAL ABILITY OR POWERS, RATE ONLY ON THE SASIS OP PATIENT* STATE MS NTS ABOUT HIMSELF ON SELr-IM-RELATtOH- TO- OTHERS, NOT ON THE BASIS OT HIS DEMEANOM IN THE INTERVIEW SITUATION. N O T P R E S E N T V E R Y M I L O M O D E R A T E M O O . S E V E R E S«Vt*t E X T R E M E L Y S E V E R S 9 . D E P R E S S I V E M O O D - DESPONDENCY I N M O O O ( B A O N S S S . R A T E O N L Y D E G R E E o r D E S P O N D E N C Y ; DO N O T R A T E ON T H E B A S I S o r tHFIMMCtl C O N C E M N I M DEPNEBSION B A S E D U P O N G E N E R A L HE TAR OAT I OH A N D S O M A T I C C O M P L A I N T S . N O T P R E S E N T V E R Y M I L D M I L D M O D E R A T E M O D . S E V E R E S E V E R S E X T R E M E L Y S E V E R S 1 0 . H O S T I L I T Y - A N I M O S I T Y , C O N T E M P T , B E L L I G E R E N C E , O I S O A I N ROR O T H E R P E O P L E O U T B I D S T H E I N T E R V I E W S I T U A T I O N , R A T I S O L E L Y O N T H E B A S I S OP T N E V E R B A L R E P O R T O P P E E L I N G S A N D A C T I O N S OR T H K P A T I E N T T O W M M O T H E R S , DO N O T I N F E R H O S T I L I T Y P R O M N E U R O T I C O E F E H S E B , A N X I E T Y NON S O M A T I C ' C O M P L A I N T S . ( R A T E A T T I T U D E T O W A R D I N T E R V I E W E R UNDER " U N C O O P E R A T R V E M E B S " , ) N O T P R E S E N T V E R Y M I L D M I L O M O D E R A T E M O O . S E V E R E S E V E R E E X T R E M E L Y S E V E R S I T . S U S P I C I O U S N E S S - B E L I E F ( D E L U S I O N A L OR O T H E R W I S E ) T H A T O T H E R S H A V E N O W , OR N A V E MAO I N T H E P A S T , M A L I C I O U S ON D T B * C R I M I N A T O R Y I N T E N T TOW AWO T H E P A T I E N T . O N T H E B A S I B O F V E R B A L R E P O R T , R A T E O N L Y T H O S E S U S P I C I O N S W H I C H A R C C U R R E N T L Y M T L D W H E T H E R T H E Y CONCERN P A S T O N P R E S E N T C I R C U M S T A N C E S , N O T P R E S E N T V E R Y M I L D M O D . S E V E R E S E V E R S E X T R E M E L Y S E V E R E 1 2 . H A L L U C I N A T O R Y B E H A V I O R - P E R C E P T I O N * W I T H O U T N O R M A L E X T E R N A L S T I M U L U S CORRESPONDENCE. R A T E ONLY T H O S S E X P E R I E N C E S W H I C H A R E R E P O R T E D T O N A V E OCCURRED W I T H I N T H E L A S T W E E N A N O W H I C H A R C D E S C R I B E S A S D I S T I N C T L Y O I P F E R C N T F R O M TMEt T H O U G H T A N D I M A G E R Y P R O C E S S E S O F N O R M A L P E O P L E . N O T P R E S E N T V E R Y M I L D M O D E R A T E M O O . S E V E R S S E V E R E EX T R E M E L Y S E V E R E 1 3 . M O T O R R E T A R D A T I O N - R E D U C T I O N I N ENCNOV L E V E L E V I D E N C E D I N S L O W E D MOVCMKNTS A N O S P E E C H , R E D U C E D BODV T O M E , D E C R E A S E D N U M B E R O F M O V E M E N T S . R A T E O H T H E B A S I S or O B S E R V E D B E H A V I O R or T H E P A T I E N T O N L Y ; D O N O T R A T I O N B A S I S o r P A T I E N T ' S S U B J E C T I V E I M P R E S S I O N or O W N ENERGY L E V E L . N O T P R E S E N T M O D . S E V E R S S E V E R S E X T R E M E L Y S S V S R C 1 4 . U N C O O P E R A T I V E N E S S - E V I D E N C E S o r R E S I S T A N C E , U N F R I E N D L I N E S S , R E S E M T M C N T , A N O L A C K O F R E A D I N E S S T O CUUPKHATST . W I T H T N E I N T E R V I E W S * . R A T I O N L Y CM T H E B A S I S o r T H E P A T I E N T ' S A T T I T U D E A N O R E S P O N S E S T O T N E I N T E R V I E W E R A M B T H E I N T W N -V I K W SmMTIOMl DO NOT N A T ! O N B A S I S O F R E P O N T E O WE S E N T Ml N T OR UNCOPSRAriVKMtS  O U T S I D E T H E I N T E R V I E W S I T U A T I O N . V I N Y M I L D M I L O M O D E R A T E M o o , S E V E R S S E V E R E IS. UNUSUAL THOUGHT CONTENT - U N U S U A L , O D D , S T R A N G E , O N B I Z A * » DtVORGaMIZATMN or T H O U G H T P R O C E S S E S . EX T R E M E L Y S S V E N S RATI M I N I T M I D E B H E I OwUSSftSMMtM, NOT T H E DEORXE OF I N o r P R E S E N T V E R Y M I L D - M u M O D E R A T E M o o . S E V E R S S E V S N S E X T R E M E L Y SEYCWK * « . B L U N T E D A F F E C T - R E D U C E D EMOTIONAL TONg, A P P A R E N T LACM OF N O R M A L F E E L I N G ON I N V O L V E M E N T . V n r M S U S ' M t u M O O E N A T I M o o . S E V E N S S E V E R E s^xT*«Msa.v S S Y S R I A !• OVISAL11 D.S. eOSMA* Figure 8. F a c s i m i l e of the B r i e f P s y c h i a t r i c Rating Scale. Scoring of r a t i n g s on the BPRS i s accomplished by a s s i g n i n g equal i n t e r v a l values of 1, 2, 3, 4, 5, 6, and 7 to the r a t i n g c a t e g o r i e s . For e v a l u a t i n g p a t i e n t change during treatment the use of a " t o t a l pathology" score which i s the simple sum of r a t i n g s on the 16 scales i s used. The Nurses' Observational Scale f o r I n p a t i e n t E v a l u a t i o n (NOSIE) i s a procedure i n which extended yet unobtrusive observations of p a t i e n t behaviour are made by nursing personn The s c a l e c o n s i s t s of 80 items covering a wide range of a c t i v i t i e s . The items are adapted to a f i v e - p o i n t "frequency of-occurrence" format as shown i n the NOSIE s c a l e i n Table 1. Based on observations of the p a t i e n t s ' behaviour f o r three consecutive days, the occurrence of each item of behaviour i s r a t e d on t h i s s c a l e : (0) Never, (1) Sometimes, (2) Often, (3) U s u a l l y , (4) Always. The items i n the s c a l e (except 19 experimental ones) are c l a s s i f i e d i n t o seven f a c t o r s as shown i n the l e t t e r s a f t e r each item. Factor names and some i l l u s t r a t i v e items are given below: SOCIAL COMPETENCE (COM) (1) Shaves h i m s e l f . (2) Makes h i s own bed. (3) Knows where he i s . (4) Wets or s o i l s h i s c l o t h e s or bedding. SOCIAL INTEREST (INT) (1) Talks about happenings on the ward. (2) Can be drawn i n t o c o n v e r s a t i o n . (3) Ignores the a c t i v i t i e s around him. (4) Stays by h i m s e l f . - 83 -PERSONAL NEATNESS (NEA) (1) Keeps h i s c l o t h e s neat and c l e a n . (2) Is messy i n h i s eating h a b i t s . COOPERATION (COO) (1) Helps out when asked. (2) Conforms to h o s p i t a l r o u t i n e . IRRITABILITY (IRR) (1) Is impatient. (2) Shouts and y e l l s . (3) Gets angry or annoyed e a s i l y . (4) Complains about the food and care. MANIFEST PSYCHOSIS (PSY) (1) T a l k s , mutters, or mumbles to h i m s e l f . (2) Giggles or smiles t o h i m s e l f without any apparent reason. (3) Assumes strange expressions, postures, or movements. PSYCHOTIC DEPRESSION (DEP) (1) C r i e s . (2) Accuses others of wanting t o hurt him. (3) Says he f e e l s blue or depressed. (4) Says that he i s no good. The complete 8 0-item s c a l e ( i n c l u d i n g 19 experimental items) i s given i n Table 1. The code l e t t e r s a f t e r each item i d e n t i f y the f a c t o r to which the item c o n t r i b u t e s . A l l items are given equal weight, so that each f a c t o r score represents the simple sum of the r a t i n g s f o r a l l items. Those items which r e c e i v e r e f l e c t e d scores (0 =4, 1 = 3, 2 =2, 3 = 1 , 4 =0) are noted with an a s t e r i s k . In t h i s c l i n i c a l study, each p a t i e n t was assessed independently by 2 p s y c h i a t r i s t s (BPRS) and two graduate nurses (NOSIE); (a) before withdrawal of medication, (b) at the point of r e l a p s e to f l o r i d p s ychosis, (c) a f t e r 8 weeks of medication and (d) at t e r m i n a t i o n of the study. Body - 84 -T a b l e 1. N u r s e s ' OnsEnvATioN S c a l e f o h I n p a t i e n t E v a l u a t i o n Dirrrtvms: O n the fo l lowing pages y ou are naked to ra te the behav io r of th is pa t i en t . T h e r e are 80 itons.-which cover a wide range of ac t i v i t i es . Y o u are to base you r rat ings on the pat ient ' s behav i o r curing the Inst three days on ly . F o r each i t em y o u are to est imate whether i n the las t three d ay s t h e description of the pat ient ' s behav io r was t rue: 0 N e v e r 1 Somet imes 1 . •• - 2 O f t en " ' " ' '• . " 3 U s u a l l y 4 A l w a y s Indicate y o u r choice b y p lac ing a c i r c l e a r ound t h e correct n u m b e r before each i t e m . I s s l oppy . ( N E A ) l a impa t i en t . ( I R R ) Accuses others of wan t i ng t o h u r t h i m . ( D E P ) Ignores the ac t i v i t i e s a round h i m . ( I N T ) Cr i es . ( D E P ) D e m a n d s the a t t en t i on of t h e doc tors . ( D E P ) H a s temper t an t r ums . ( I R R ) Res i s t s suggest ions a n d requests. ( I R R ) Shouts a n d ye l l s . ( I R R ) Is exc i ted, no i s y and h i la r ious . ( I R R ) Ge t3 a l ong w i t h other pat ients . T a l k s f ree ly w i t h vo lunteer workers o r o ther v i s i t o r s . ( I N T ) Shows cu r i os i t y and in terest i n ac t i v i t i es a r ound h i m . ( I N T ) K e e p s busy du r i ng the day . Con f o rms t o hosp i t a l rout ine . ( C O O ) Is cheer fu l a n d opt im is t i c . ( I N T ) Hoa r d s th ings (carr ies t h i ngs h i dden i n pape r bags, b i d e s th ings under bed , etc .) . H i t s others. Shaves h imse l f . ( C O M ) Speaks i n shor t phrases o n l y (3 o r 4 words a t a t i m e ) . L o o k s sad . Needs he lp i n dress ing. ( C O M ) Needs he lp i n us ing t he to i le t . ( C O M ) He l p s out when asked . ( C O O ) P l a y s cards w i t h others. S i t s unless d i rec ted i n t o a c t i v i t y . K n o w s where he is . ( C O M ) Cooperates w i t h other people. ( C O O ) T a l k s abou t h imsel f . S t ay s b y h imse l f . ( I N T ) Is hes i tant and uncer ta in in mak i ng u p his m i n d . ( C O M ) I Jokes w i th others. ( I N T ) Gc t3 angry or annoyed eas i ly . ( I R R ) Wets or soi ls his c lothes or bedd ing. ( C O M ) Asks for a pass to leave the hosp i ta l . T a l k s about happenings on the ward . ( I N T ) Answers when spoken to . Hears th ings t ha t are not there. ( P S Y ) Seems content and sat i s6ed. ( D E P ) Keeps h is clothes neat and c lean. ( N E A ) Take s pa r t in back and fo r th conversat ion . ( I N T ) Comp l a i n s about the food and care. ( I R R ) T r i e s t o be f r iend ly w i t h others. ( I N T ) Becomes easi ly upset if someth ing doesn ' t s u i t h i m . ( I R R ) _ Assumes strange expressions, postures, or movemen t s . (PS>Y) Refuses to do the o rd ina ry th ings expected of h i m . Is i r r i tab le and grouchy. ( I R R ) H a s t roub le remember ing . ( C O M ) M a k e s h is own bed. ( C O M ) Refuses to speak. C a n be d r awn in to conversat ion . ( I N T ) j L augh s or smi les a t f u nny comments o r events . ( I N T ) j Vo lunteers to help ou t a round the wa rd . ( C O O ) C l a i m s t ha t he is be ing contro l led b y people o r unusua l forces.! ( D E P ) Is messy i n h is eat ing hab i t s . ( N E A ) Sta r t s up a conversat ion w i t h others. ( I N T ) Savs he feels b lue or depressed. ( D E P ) C o m b s h is ha i r . ( C O M ) T a l k s abou t his interests . ( I N T ) T a k e s pa r t i n recreat ion. Sees th ings tha t are no t there. ( P S Y ) Is f r i end ly w i t h someone on the wa rd . ( I N T ) M H a s unusua l speech (mixes u p words, m a k e s t ip new wordsJ repeats sounds, words, o r phrases i n a meaning less o r i n t e r na? i ca l manner ) . ( P S Y ) ' 7 Shows inappropr ia te fee l ing or l a ck o f fee l ing. "j Reads newspapers or magaz ines. H a s to be reminded w h a t t o do . ( C O M ) -Sleeps, unle3s_ d i rected i n t o a c t i v i t y . Says t ha t he is no good. ( D E P ) H a s t o be t o l d t o fo l low hosp i ta l r ou t i ne . ( C O M ) , / Seems to enjoy l i fe . ( I N T ) / P a y s a t tent ion when spoken to . / Washes himsel f . ( C O M ) / H a 3 d i f f i cu l ty comp le t ing even s imp l e t a sks on h i s o w b * ( C O M ) Is a ler t a nd a t ten t i ve . _ I Ta l k s , mutters , or mumb le s to h imse l f . ( P S Y ) / Appears confused or puzz led . ( C O M ) Is s low mov i ng and s lugg ish. ( C O M ) Gigg les or smi les to himsel f w i t hou t a u v apparent reaaoa) (PSY) Qu i ck to fly off the hand le . ( I R R ) Keeps himsel f neat a n d c lean. ( N E A ) 0 1 2 3 4 * 1 . 0 1 2 3 4 2. 0 I 2 3 4 3 . 0 I 2 3 4 *4. 0 t 2 3 3 5 . 0 I 2 3 4 6. 0 I 2 3 4 7. 0 I 2 3 4 8. 0 t 2 3 4 9. C ] I 2 3 4 10. 0 1 L 2 3 4 11. 0 1 L 2 3 4 12. 0 ] I 2 3 4 13. 0 ] L 2 3 4 14. 0 I 2 3 4 15. 0 ] 2 3 4 16. o 2 3 4 17. 0 ] 2 3 4 18. 0 1 2 3 4 19. 0 ] 2 3 4 20. 0 ] 2 3 4 2 1 . 0 ] 2 3 4 •22 . 0 ] 2 3 4 •23 . 0 ] 2 3 4 24. 0 ] 2 3 4 25. 0 J A . 2 3 4 26. 0 ]f\ 2 3 4 27. 0 ] A . 2 3 4 28. if 3 t\ . 2 3 4 29. U ] 2 3 4 •30. 0 1 •> 3 4 •31. 0 1 2 3 4 32. 0 1 2 3 4 33. 0 1 2 3 4 •34. 0 1 2 3 4 35. 0 1 2 3 4 30. 0 1 2 3 4 37. 0 1 2 3 4 3S. 0 1 2 3 4 •39. 0 1 2 3 4 40. 0 1 2 3 4 . 41 . 0 1 2 3 4 42. 0 1 2 3 4 43. 0 1 L 2 3 4 44. 0 1 t 2 3 4 45. 0 1 [ 2 3 4 40. 0 1 I 2 3 4 47. 0 I I 2 3 4 •48. 0 1 L 2 3 4 49. 0 L 2 3 4 50. 0 ] L 2 3 4 51. u I 2 3 4 52. 0 I 2 3 4 53. 0 1 2 3 4 54. 0 I 2 3 4 •55 . 0 L 2 3 4 50. u L 2 3 4 57. 0 L 2 3 4 53 . 0 I 2 3 4 59. 0 L 2 3 4 00. 0 I 2 3 4 01. 0 I 2 3 4 G2. 0 t 2 o 4 03. 0 I 2 3 4 04. 0 L 2 3 4 05. 0 I 2 3 4 •00. 0 1 2 3 4 07. 0 L 2 3 4 08. 0 L 2 3 4 •09. 0 1 2 3 4 70. 0 1 2 3 4 71. 0 1 2 3 4 72. 0 1 2 3 4 •73. 0 1 2 3 4 74. 0 1 2 3 4 75. 0 1 2 3 4 •70. 0 1 2 3 4 •77. 0 1 2 3 4 78. 0 1 2 3 4 79. 0 1 2 3 4 80. • I tem receives reflected score (0 = 4, 1 = 3, 2 =• 2 , 3 » 1, 4 - 0 ) . - 85 -weight and t o x i c e f f e c t s were noted at s i m i l a r i n t e r v a l s , and the l a t t e r were t r e a t e d as they arose throughout the study. Various blood t e s t s , u r i n e , a n a l y s i s and e l e c t r o c a r d i o g r a p h (EKG) t r a c i n g were a l s o c a r r i e d out. The p a t i e n t s r e c e i v i n g Drug A, Drug B, and Drug C had mean ages of 50.1, 4 5.9 and 48.7 years and i n i t i a l mean weights of 139.8, 138.8, and 140.8 r e s p e c t i v e l y . The mean length of treatment f o r each group of pa t i e n t s was CPZ-generic 176 days, MRZ 177 days, and CPZ-p r o p r i e t a r y 18 7 days. The mean d a i l y .dose of medication per pa t i e n t was 621.4 mg. f o r CPZ-generic, 468 .2 mg. f o r MRZ, and 590.5 mg. f o r CPZ-proprietary. Group mean values of the scores obtained by the BPRS and NOSIE methods were p l o t t e d versus stages of p a t i e n t c o n d i t i o n r e p r e s e n t i n g Pre-study ( 1 ) , Relapse ( 2 ) , 8 weeks of medication (3 ) , and Termination (4) of study. These i n v e s t i g a t o r s claimed t h a t there were c l i n i c a l d i f f e r e n c e s between the two brands of chlorpromazine hydro-c h l o r i d e t a b l e t s and that " d i f f e r e n c e s noted between the two brands of CPZ may be r e l a t e d to the d i f f e r e n t p h y s i c a l prepara-t i o n s or to q u a l i t y standards (which were not assessed)". Samples of the two brands ( h e r e a f t e r designated as Brand A (Chlorpromazine Hydrochloride Tablets - Maney) and Brand B (Chlorpromazine Hydrochloride-Tablets - Poulenc) were obtained f o r use i n t h i s study. In a d d i t i o n the manufacturer of Brand A reformulated the sugar coated t a b l e t s t o a f i l m coated t a b l e t (herein designated as Brand C) and t h i s brand was a l s o included i n t h i s i n v e s t i g a t i o n . IV. EXPERIMENTAL 1. Apparatus (a) USP D i s s o l u t i o n Apparatus A diagram of the apparatus i s shown i n F i g . 9. I t c o n s i s t s of: a r o t a t i n g basket assembly (A), f a b r i c a t e d from type 316 s t a i n l e s s s t e e l ; a 1,000 ml. r e s i n f l a s k (B) to c o n t a i n the d i s s o l u t i o n f l u i d ; a four-hole cover f o r the ves s e l (C); and a high-torque s t i r r i n g motor (D) equipped w i t h a speed-regulating device capable of r o t a t i n g at s p e c i f i e d speeds, +_ 5 per cent, varying from 25 r.p.m. to 150 r.p.m. The assembly i s immersed i n a constant temperature bath maintained at 37 + 0.5° C. The r o t a t i n g basket i s a c y l i n d e r 3.6 cm. i n height and 2.5 cm. i n diameter, the sides and bottom of which are M-0 mesh s t a i n l e s s s t e e l c l o t h . The c y l i n d e r i s j o i n e d at the seam by welding and i s welded at the top and bottom to s t a i n l e s s s t e e l r i n g s . A 6 mm. x 30 cm. s t a i n l e s s s t e e l rod, attached to a 2.5 cm. p l a t e having a 2 mm. vent and three s p r i n g c l i p s , i s used to hold the basket. The s t i r r i n g rod of the r o t a t i n g basket assembly i s placed through the center hole of the ve s s e l cover and i s centered to permit smooth r o t a t i o n and to prevent wobbling. The second hole i s used f o r i n s e r t i n g a thermometer, and the remaining two holes are used f o r sampling and exchange of f l u i d s . - 87 -Figure 9. Diagram of USP Dissolution Apparatus. See text for description. - 88' -(b) Spectrophotometers Beckman DU Beckman'DU-2 Bausch and Lomb Spectronic 50 5 Beckman IR-10 (c) Corning D i g i t a l 112 Research pH Meter (d) Haake Thermoregulator (Type E51) (e) USP D i s i n t e g r a t i o n Apparatus (modified f o r d i s s o l u t i o n as described i n Method I I of NF X I I I ) ( f ) Overhead s t i r r i n g motors (Model 53, Hanson Motor Corporation; F i s h e r stedi-speed) 2. Chemicals and Reagents (a) Chlorpromazine hydrochloride (CPZ-H61). This sub-stance was obtained from Poulenc L i m i t e d , Montreal, Quebec, and was i d e n t i f i e d by i n f r a r e d spectro-photometry. (b) Sodium C h l o r i d e , BDH Chemicals L i m i t e d , A n a l y t i c a l Reagent Grade. (c) H ydrochloric a c i d , Reagent Grade. (d) Potassium C h l o r i d e , F i s h e r S c i e n t i f i c Company, Reagent Grade. (e) Monobasic Potassium Phosphate, M a l l i n c k r o d t Chemical Works, Reagent Grade. ( f ) Sodium hydroxide, BDH Chemicals L i m i t e d , Reagent Grade. - 89 -(g) Simulated g a s t r i c f l u i d USP (without enzyme). (h) B u f f e r s . Volumes of 0.2 M s o l u t i o n s of b u f f e r c o n s t i t u e n t s i n 100 ml. of b u f f e r are shown below: Buffer pH 2.0 - 5.9 5 ml. of HC1 and 4 4.1 ml. of KC1 Buffe r pH 2.8 - 25 ml. of K H2 P O 4 and 3.50 ml. of HC1 Buffer pH 4.0 - 25 ml. of K H 2 P O 4 and 0.2 5 ml. of HC1 Buffer pH 5.1 - 25 ml. of K H 2 P O 4 and 0.2 5 ml. of NaOH 3. A n a l y s i s of Chlorpromazine Hydrochloride (a) I n f r a r e d spectrum of chlorpromazine HC1. Prepare a KBr p e l l e t and record the spectrum on a Beckman IR-10 spectrophotometer. The IR spectrum obtained was compared with a S a d t l e r reference spectrum and found to have the same c h a r a c t e r i s t i c absorption bands. (b) S p e c t r a l C h a r a c t e r i s t i c s of CPZ-HC1. Weigh a c c u r a t e l y 100.0 mg. of CPZ-HC1 and t r a n s f e r i n t o a 100 ml. volumetric f l a s k with the a i d of about 50 ml. of d i s t i l l e d water. D i s s o l v e and make to volume with a d d i t i o n a l water. D i l u t e 10 ml. of the above s o l u t i o n to 1000 ml. (with d i s t i l l e d water). Record the spectrum on a Bausch and Lomb Spectronic 505 spectrophotometer using d i s t i l l e d water as the blank. - 90 -A spectral-absorbance curve (S-A curve) i s shown i n F i g . 10. The maximum absorption of r a d i a n t energy was found to occur at about 254 to 255 mm. Repeat the procedure described above using simulated g a s t r i c f l u i d i n s t e a d of water. The S-A curve i n t h i s case was found to be the same as i n the case of d i s t i l l e d water (see F i g . 10) i n d i c a t i n g that there i s no displacement of the S-A curve w i t h a change i n pH. In order to a c c u r a t e l y determine the wavelength of maximum abs o r p t i o n , the above d i l u t e d s o l u t i o n s were analysed using the Beckman DU-2 spectrophotometer. Absorbance readings of the two s o l u t i o n s over a wavelength range of 250 to 260 mm. were recorded. The wavelength of maximum absorption was found to be a range of 254 to 255 mm. See F i g . 11. (c) Preparation of a C a l i b r a t i o n Curve A c a l i b r a t i o n curve i n d i c a t e s the v a l i d i t y of Beer's Law and, i n order to check such v a l i d i t y , absorbance versus concen t r a t i o n curves were prepared f o r CPZ-HC1 i n d i s t i l l e d water and simulated g a s t r i c f l u i d . D i s s o l v e 100 mg. of CPZ-HC1, a c c u r a t e l y weighed, i n 100.0 ml. of d i s t i l l e d water. D i l u t e a l i q u o t s from 2.0 ml. to 10.0 ml., to 100.0 ml. with d i s t i l l e d water. D i l u t e another s e r i e s of a l i q u o t s (2.0 ml. to 10.0 ml.) with simulated g a s t r i c f l u i d . - .9;i -270. .260 250 240 WAVELENGTH (nm) Figure 10. A Spectral-Absorbance Curve f o r CPZ-H.C1 i n D i s t i l l e d Water and Simulated G a s t r i c F l u i d . - 92. -0.9 -; f ,;•'!. ' ; • i • i : • . - Li' -]•' ---! ; 'i 4 ?• .' i • ! : 1 ' i -: ! • • • - > ; j • ! , •"• 'i ' • 1 ..... } : ZTL:.|_..:_T . 4:r;:..i-V.:;..:.:......;:i • :' 1 •: :\ ' '• • ! -t i ... i ! 1 " '.!.•' ,-.^jqj,:=.;.j...; ...ut.4-:Tav f • " < . _ .J • >" , ; •' •: i " • \ . 1, • j - -r - ;/—'-I----:-!-•-; i • : • j ; !• ; t /I j _ r . .. -i n. R . r - •' • -. i • ] • ! ' • 'W ; . 44 ; ^ 4 ^ g • , 4 LliA- . • r , < ; • ' j : . : ; . !.„ :o. i . . • : ; c q • - • i I • ! ;<-}:.'-.| ,.; i j i .j,..]:. . *.' • I • • • i- \ • • : . I • . , • . 1: • : .• . - -1 . : • -! :444-,|^f4-f -."f^ -^ r-RTft V: • - -.' • •'.<•-  i • j --; ;'B4-r: fN: -4--42f L|^ :4:^ y ;4^l\t-': .._4._J. ' . ' , j ],:.:.. J.-.C. :\.i^L ~ _ ! ' : - ] . : • : ! •" ._:--J.. . .'±- : -0l 7- .  .vki :^Li . - . i : : ' . i : , j 250 • ; ~ R r • r n i r ^ r r ^ ' c i . ] m J i i i ^ i i i i i i i ^ f i i j i i : : ~ ; r ; •••'r -f' :i :cWAVELENGTH (rim) . ; -]--r-_-j'-~.-r-'T f Figure 1 1 . "A''Spectral-Absorbance Curve f o r CPZ-HC1 ; "~ "in" D i s t i l l e d ' Water as obtained by us i n g the •'"':' Beckman DU-2 Spectrophotometer. - 93 -Record the absorbance of each s o l u t i o n at the wavelength of maximum absorption (254 mm.) using the appropriate solvent as the blank. (Beer's Law p l o t s are shown i n F i g . 12). (d) Determination of the a b s o r p t i v i t y value of CPZ-HC1 i n water. Since the s p e c t r a l c h a r a c t e r i s t i c s of CPZ-HC1 i n water are the same as those i n simulated g a s t r i c f l u i d , the absorp-t i v i t y value of CPZ-HC1 was determined i n d i s t i l l e d water. Weigh a c c u r a t e l y 100 mg., 200 mg., and 250 mg. of CPZ-HC1, d i s s o l v e , and make to volume (with d i s t i l l e d water) i n 100 ml., 200 ml., and 250 ml. volumetric f l a s k s , and l a b e l as s o l u t i o n I , I I , and I I I , r e s p e c t i v e l y . From each of the above s o l u t i o n s d i l u t e (with d i s t i l l e d water) 7.0, 8.0, 9.0, 10.0, and 11.0 ml. a l i q u o t s to 1000.0 ml. Record the absorbance readings of each d i l u t e d s o l u t i o n using the Beckman DU and DU-2 spectrophotometers set at 254 mm. Use d i s t i l l e d water as the blank. C a l c u l a t e the a b s o r p t i v i t y value at 2 54 mm. _ 95 -The c a l i b r a t i o n curve was found to be a s t r a i g h t l i n e passing through the o r i g i n ( F i g . 12), and on t h i s b a s i s , the a b s o r p t i v i t y value of CPZ-HC1 i n d i s t i l l e d water (and a l s o i n simulated g a s t r i c f l u i d ) , at the wavelength o f maximum absorption (254 mm.) was found to be 95.95. See Table 2. This value was c a l c u l a t e d using the equation (from Beer's Law): a s = f s (Eq. 22) b c where, a s = A b s o r p t i v i t y value b = C e l l l ength (1 cm.) c = Concentration (Gm./L.) A s = Absorbance In order to avoid p o s s i b l e delays due to instru m e n t a l break-down, absorbance readings on the Beckman DU were p l o t t e d versus absorbance readings on the Beckman DU-2. The equation of the l i n e i s : A ( D U ) = 1-032 A(DU-2) " 0-045 (Eq. 23) where, . A(rju) = Absorbance reading on the Beckman DU spectrophotometer A(DU-2) = Absorbance reading on the Beckman DU-2 spectrophotometer This equation was used i n those instances where i t was necessary to switch from one instrument to the other. Table 2. Data f o r the determination of the a b s o r p t i v i t y value of CPZ-HC1 i n d i s t i l l e d water-'-. S o l u t i o n I S o l u t i o n I I S o l u t i o n I I I Concentration A s Gm./L. a s Concentration Gm./L. As a s Concentration Gm./L. A s as 0.00697 0.670 96. 3 0,00697 0 .672 96.0 0.00697 0. 670 96.1 0.00797 0.762 95. 7 0.00797 0 .770 96.6 0.00797 0. 772 96.8 0£ 00 8 9 7 0.845 94. 5 0,00897 0 .8 90 97.0 0.00897 0. 850 94.8 0.00997 0.950 95. 4 0.00997 0 .970 97.3 0.00997 0. 958 96.2 0.01097 1.050 95. 8 0.01097 1 .050 96.0 0.01097 1. 040 95.0 Mean a s 95. 95 Standard Deviation + 0 .64 Absorbance readings were taken at a wavelength of 2 54 nm. _ 97 _ 4. Determination of Content Uniformity of CPZ-HC1 Tablets The three brands of CPZ-HC1 t a b l e t s used i n t h i s study were t e s t e d f o r content u n i f o r m i t y . Ten t a b l e t s were i n d i v i d u a l l y assayed employing two methods. Method I: F i n e l y powder one tablet- using a mortar and p e s t l e and d i s s o l v e the a c t i v e i n g r e d i e n t i n about 50 ml. of simulated g a s t r i c f l u i d . Q u a n t i t a t i v e l y t r a n s f e r the mixture i n t o a medium p o r o s i t y s i n t e r e d gl a s s f i l t e r f i t t e d to an immersion f i l t e r . T ransfer the f i l t r a t e t o a 100 ml. volumetric f l a s k and make to volume wi t h simulated g a s t r i c f l u i d . D i l u t e 2 ml. of t h i s s o l u t i o n to 100 ml. (with simulated g a s t r i c f l u i d ) and analyse using the Beckman DU-2 spectrophotometer, and employing simulated g a s t r i c f l u i d as the blank. C a l c u l a t e the amount of drug i n each t a b l e t using 95.95 as the a b s o r p t i v i t y value. Method I I : This method i s described i n the assay procedure of the USP. Results of the content u n i f o r m i t y t e s t s of CPZ-HC1 t a b l e t s (Brands A, B and C) as shown i n Tables 3, 4, and 5 i n d i c a t e t h a t a l l the brands conform to the USP s p e c i f i c a t i o n . Table 3. Results of the'content u n i f o r m i t y t e s t of CPZ-HC1 t a b l e t s (Brand A). Tablet A s Assay % Label A s Assay % Label No. (Method I) mg./tablet Claim (Method I I ) mg./tablet Claim 1 0.475 24.75 99.0 0.490 25. 50 102.0 2 0.502 26.10 104.5 0.503 26.20 104 .8 3 0. 504 26.25 105.0 0. 503 26.20 104 .8 4 0.485 25.25 101.0 0.489 25.45 101.8 5 . 0. 500 26.00 104.0 0. 501 26.10 104 .4 6 0.490 25. 50 102.0 0.501 26.10 104 .4 7 0.475 24 .75 99.0 0.490 25.50 102.0 8 0.485 25.25 101.0 0.490 25.50 102.0 9 0.470 24.50 98 .0 0.480 25.00 100.0 10 0.475 24.75 99.0 0.492 25.67 102.6 Table 4. Results of the content u n i f o r m i t y t e s t of CPZ-HC1 t a b l e t s (Brand B). Tablet A s Assay % Label A s Assay % Label No. (Method I) mg./tablet Claim (Method I I ) mg./tablet Claim 1 0.476 24 .80 99.2 0.492 25.60 102 .0 2 0.480 25.00 100.0 0.489 2 5.45 101.8 3 0.492 25.60 102.0 0.490 25.55 102.0 4 0.475 24.75 98.9 0.480 25.00 100.0 5 0.479 . 24,90 99.6 0.489 25.40 101.5 6 0.470 24 .45 97.8 0.470 24.50 98.0 7 0.482 2 5.10 100.5 0.475 24.75 99.0 8 0.490 25.55 . 102.0 0.479 24.90 99.6 9 0.477 24.85 99.5 0.485 25.25 101.0 10 0.479 24 .90 99 . 6 0.482 25.10 100.5 Table 5 . Results of the content u n i f o r m i t y t e s t of CPZ-HC1 t a b l e t s (Brand C). Tablet- A s Assay % Label A s " Assay % Label No. (Method I) mg./tablet Claim (Method I I ) mg./tablet Claim 1 0.482 25.10 100.2 0.495 25.75 103.0 2 0.490 25. 50 102 .0 0.472 24 .60 98.4 3 0.495 25.80 103.0 0.486 25.30 101.0 4 0.479 24.95 99.9 0.484 25.20 100.5 5 0.481 25.09 100.1 0.490 25.50 102.0 6 0.492 25.65 102.5 0.480 25.00 100.0 7 0.470 24.50 98 .0 0.475 24.75 99.0 8 0.475 24 .75 99.0 0.479 24.95 99.9 9 0.485 25.25 101.0 0.485 25.25 100 .9 10 0.475 24 .75 99.0 0.480 25.00 100.0 - 101 -5. Determination of CPZ-HC1 i n D i s s o l u t i o n Media (a) D i s s o l u t i o n C h a r a c t e r i s t i c s of CPZ-HC1 Weigh a c c u r a t e l y 100 mg. of CPZ-HC1 i n a weighing boat. S t a r t the s t i r r e r and l e t the basket r o t a t e at 2 5 r.p.m. Pour the contents of the weighing boat i n t o the d i s s o l u t i o n medium ( d i s t i l l e d water) of a p r e v i o u s l y set-up USP d i s s o l u t i o n apparatus. Take out 5 ml. samples at 2, 3, 4, and 5 minutes, d i l u t e to 50 ml. and analyse using a Beckman DU-2 spectrophotometer. Make c o r r e c t i o n s f o r volume of withdrawn media by adding f r e s h amounts. Record the exact weight of the sample as obtained from the d i f f e r e n c e i n the weights of the weighing boat before and a f t e r t r a n s f e r i n g the contents. (b) Determination of the Rate of D i s s o l u t i o n of CPZ-HC1 from Tablets Put one t a b l e t i n the basket, f i t the l a t t e r to the s t i r r i n g rod, and f i x i t to the s t i r r i n g motor as shown i n F i g . 9. - 102 -S t a r t the motor and l e t the basket r o t a t e at a pre-determined r a t e . Immerse the basket i n t o the d i s s o l u t i o n medium (maintained at 37 +_ 0.5° C.) and adjust the p o s i t i o n of the basket to a s p e c i f i e d distance from the bottom of the d i s s o l u t i o n v e s s e l . Withdraw 5 ml. samples of f i l t e r e d d i s s o l u t i o n medium at s p e c i f i e d i n t e r v a l s o f time, d i l u t e to 50 ml. (with d i s s o l u t i o n medium) i n a volumetric f l a s k and analyse using a Beckman DU-2 spectrophotometer. Make c o r r e c t i o n s f o r withdrawn volume by adding a f r e s h amount of d i s s o l u t i o n medium (maintained at 37° C ) . Concentrations o f the drug i n the consecutive withdrawals f o r a n a l y s i s were c a l c u l a t e d using Nelson's (1957) formula: Cn Cn° + Vw/V (Cn-1) (Eq. 24) where, Cn Corrected c o n c e n t r a t i o n Cn° Concentration a c t u a l l y determined Cn-1 Corrected c o n c e n t r a t i o n of sample withdrawn immediately before the n^h Vw Withdrawn volume V Volume of d i s s o l u t i o n medium. V. RESULTS AND DISCUSSION Three brands of chlorpromazine hydrochloride t a b l e t s (Brands A, B and C) were used i n t h i s i n v e s t i g a t i o n . Brand A (Maney) t a b l e t s were sugar coated; Brands B (Poulenc) and C (Maney) were f i l m coated t a b l e t s . 1. E f f e c t of D i s s o l u t i o n Media Since chlorpromazine hydrochloride i s very s o l u b l e i n water, the f i r s t d i s s o l u t i o n medium employed was 900 ml. of d i s t i l l e d water. The d i s s o l u t i o n p r o f i l e s of each brand of t a b l e t was obtained by using the USP Procedure. The basket was r o t a t e d at 50 r.p.m. and a minimum of three determinations were c a r r i e d out on each Brand. T y p i c a l p r o f i l e s are shown i n F i g . 13. The p r o f i l e s i n F i g . 13 and the r e s u l t s i n Table 6 i n d i c a t e t h a t the d i s s o l u t i o n r a t e becomes slower i n the order C, A, B. The d i s s o l u t i o n p r o f i l e of Brand A shows a l t e r n a t i v e slopes and plateaus and t h i s , t h e r e f o r e , does not produce a smooth curve. Brand B. appears to r e l e a s e the drug at a f a s t e r r a t e than Brand A up to about 46 per cent of l a b e l claims a f t e r which the l a t t e r brand has a higher r a t e of d i s s o l u t i o n . The d i s s o l u t i o n r a t e s of Brands A and B d i d not, t h e r e f o r e , rank i n the same order as i n d i c a t e d .by Bankier and Mathewson (1972) i n t h e i r c l i n i c a l study. Because of t h i s r e v e r s a l of r e l e a s e r a t e s , the e f f e c t of d i s s o l u t i o n medium was i n v e s t i g a t e d . Nine hundred ml. of - 104 -TIME_IN. MINUTES ; Figure 13. D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brand A-S; Brand 5-0.; Brand C.-4 ). as, obtained by using " D i s t i l l e d Water i n the USP Apparatus. The basket was — - r o t a t e d at 50 r.p.m. v P r o f i l e f o r Pure Drup -° ) . - 105 -Table 6. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine hydrochloride t a b l e t s (Brands A, B and C) i n d i s t i l l e d water and simulated g a s t r i c f l u i d using the USP apparatus^. Brand D i s s o l u t i o n Medium D i s s o l u t i o n Values ( M i n u t e s ) 2 T20 Ti+0 T60 T80 A D i s t i l l e d Water 10 20 39 b A Simulated G a s t r i c F l u i d 8 21 40 7 3 B D i s t i l l e d Water 6 11 44 b B Simulated G a s t r i c F l u i d a a a 11 C D i s t i l l e d Water a a 10 15. C Simulated G a s t r i c F l u i d 11 25 . 45 63 Speed of s t i r r e r - 50 r.p.m. Tx values: Time needed f o r x% of drug to d i s s o l v e . (a) l e s s than 5 minutes (b) more than 120 minutes - 106 -simulated g a s t r i c f l u i d was used and the basket of the USP d i s s o l u t i o n apparatus was r o t a t e d at 50 r.p.m. The p r o f i l e s i n F i g . 14 and the r e s u l t s i n Table 6 i n d i c a t e t h a t the rank order of the d i s s o l u t i o n r a t e i n t h i s case i s B, A, and C. Brand B re l e a s e s drug at about the same rat e as Brand C s rel e a s e r a t e i n water; on the other hand, Brand C appears to r e l e a s e drug at the slowest r a t e . However, over the range of 70 to 9 2 per cent drug r e l e a s e , Brand C appears to have a higher r e l e a s e r a t e than Brand A. The r e s u l t s a l s o i n d i c a t e (see Table 6) that a switch from a d i s s o l u t i o n medium of d i s t i l l e d water to that of simulated g a s t r i c f l u i d s l i g h t l y improves, markedly i n c r e a s e s , and d r a s t i c a l l y decreases the d i s s o l u t i o n r a t e s of Brands A, B and C, r e s p e c t i v e l y . From the experimental data described above, i t appears that d i s s o l u t i o n medium plays an important r o l e i n the d i s s o l u t i o n r a t e of a drug from t a b l e t s . The f a c t that a dru i s very s o l u b l e i n a c e r t a i n medium does not n e c e s s a r i l y j u s t i f y the use of t h i s medium f o r the d i s s o l u t i o n t e s t s of dosage, forms of the drug. The p o s s i b l e e f f e c t of the i n t e r -a c t i o n of the medium with t a b l e t e x c i p i e n t s may t h e r e f o r e be s i g n i f i c a n t . Hence the choice of a d i s s o l u t i o n medium s p e c i f i e d i n the monograph of an o f f i c i a l compendium should b a r r i v e d at a f t e r a study of various brands and c o r r e l a t i o n wi i n - v i v o data. - 107 -40 ; 80 120 TIME IN MINUTES : . Figure 14. D i s s o l u t i o n P r o f i l e s of CPZ.-.-HC1 Tabl e t s ~ (Brand A-S; Brand B-0; Brand C- A ) as obtained by usi n g Simulated G a s t r i c F l u i d i n the USP Apparatus. The basket was r o t a t e d a t 50 r.p.m. fipr.ofile f o r Pure Drug -° ). - 108 -2. E f f e c t of Geometry of D i s s o l u t i o n Vessel G i b a l d i and Weintraub (1970) claimed t h a t the USP d i s s o l u t i o n v e s s e l allows the accumulation of d i s i n t e g r a t e d matter on the outside perimeter of i t s convex bottom and that t h i s may d i s t o r t the d i s s o l u t i o n p r o f i l e s of dosage forms. The e f f e c t of geometry of the d i s s o l u t i o n v e s s e l was, t h e r e f o r e , i n v e s t i g a t e d . Simulated g a s t r i c f l u i d was used as the d i s s o l u t i o n medium. One L i t e r , 2 L i t e r , and 3 L i t e r round bottom f l a s k s were used, and 900 ml. of d i s s o l u t i o n f l u i d was employed i n a l l cases. D i s s o l u t i o n p r o f i l e s f o r the three brands i n the various types of ve s s e l s are shown i n F i g . 15. The p r o f i l e s of Brand A ( F i g . 15,1) are e s s e n t i a l l y s i m i l a r up to about 75 per cent r e l e a s e , a f t e r which they diverge out i n decreasing order of re l e a s e r a t e : 2 L. round bottom f l a s k , 1 L. round bottom f l a s k , USP v e s s e l , and 3 L. round bottom f l a s k . The p r o f i l e s of Brand B ( F i g . 15,11) are a l s o q u i t e c l o s e to each other, and have almost the same rank order of drug r e l e a s e r a t e . Except at the i n i t i a l stage, at which the USP apparatus appears to give a s i g n i f i c a n t l y high r e l e a s e r a t e , the e f f e c t of the various v e s s e l s on d i s s o l u t i o n r a t e of Brand B seems to be minimal. The d i s s o l u t i o n p r o f i l e s of Brand C ( F i g . 15,111) show an almost i d e n t i c a l r e l e a s e p a t t e r n i n the case of the USP v e s s e l and the 1 L. round bottom f l a s k ; and about the same magnitude of d i s s o l u t i o n r a t e f o r the 2 L. and 3 L. round bottom f l a s k s . The d i s p a r i t y between the USP and 1 L. vessels o w o CO CO M o Eh W o ( X w C l , 100 Figure | 1 B r and B ' (a - a ) , ' an d 3 ]Li the. t e s t 120 5, D i s s o l u t i o n ; P r o f i l e s of CPZ-HC1: Tablets (Brand A ( I ) , - ( i i ) , Brand : C;-; ( I I I ) ) as obtained by using', the 1 USP D i s s o l u t i o n Vessel 1 : L i t e r Round j Bottom f l a s k " ("0 - 0 ) ,1 andj 2 L i t e r ' Round 'Bottom Flask ( t er Round Bottom j Flask; ( a ~ ° ).| - Simulated' G a s t r i c F l u i d was ;used as medium-.-and:-tliel 40 mesh : basket was r o t a t e d at--50 r.p.m.. -120 - 110 -which show a r e l a t i v e l y higher r e l e a s e r a t e and the 2 L. and 3 L. f l a s k s which show r e l a t i v e l y low r e l e a s e r a t e s may be due to f a c t o r s other than the geometry of the c o n t a i n e r s . F i g . 16 shows that the drug r e l e a s e r a t e of the three brands i s i n a decreasing rank order o f B, (C A) i n which the r e l e a s e p a t t e r n of C and A are not markedly separated. (Where two brand codes are bracketed; e.g., (C A ) , i t i s implied t h a t d i s s o l u t i o n values are e s s e n t i a l l y s i m i l a r ) . This s i t u a t i o n was observed with the USP v e s s e l and the 1 L. round bottom f l a s k . On the other hand, the 2 L. and 3 L. round bottom f l a s k s gave almost i d e n t i c a l r e l e a s e patterns i n which the r e s u l t s of C and A are s i g n i f i c a n t l y d i f f e r e n t , the former showing a higher r e l e a s e r a t e . ^2Qi ^H0» ^60 a n <^ "^ 80 values (time i n minutes needed f o r 20, 40, 60 and 80 per cent of drug to d i s s o l v e ) are given i n Table 7. In order to r u l e out the p o s s i b i l i t y of a cover-up due to a solvent e f f e c t , the i n v e s t i g a t i o n was repeated using d i s t i l l e d water as the d i s s o l u t i o n medium. Table 8 shows tha t the Tgo values f o r the USP v e s s e l and the 1 L. round bottom f l a s k (Brand A) are almost the same. Apart from the high TgO values i n the 2 L. and 3 L. f l a s k s , a l l the other d i s s o l u t i o n values of Brand A obtained w i t h each v e s s e l are comparable. Except f o r the r e l a t i v e l y high T^Q value ( f o r 2 L. f l a s k ) of 49 minutes and r e l a t i v e l y low Tgg value of 44 minutes (USP v e s s e l ) , Brand B appears to have comparable d i s s o l u t i o n c h a r a c t e r i s t i c s i n a l l the v e s s e l s . The d i s s o l u t i o n c h a r a c t e r i s t i c s of Brand C seem to - I l l -"4,0 80 120 ." " • •' ' . " ""' ~ TIME IN MINUTES . Figure 16. D i s s o l u t i o n P r o f i l e s of CPZ-KC1 Tablets' (Brand. A - & - 8; Brand B. - 0- - 0; Brand C. - ^ — A ) -as obtained by using a 1 L i t e r Round Bottom Flask as the D i s s o l u t i o n V e s s e l . Simulated G a s t r i c . F l u i d was used as D i s s o l u t i o n Medium, and the HO mesh basket- was r o t a t e d a t 50. r .p.m. - 112 -Table 7. Comparison of d i s s o l u t i o n values of chlorpromazine hydrochloride t a b l e t s (Brands A, B and C) i n USP v e s s e l and 1 L. , 2 L. and 3 L. round bottom f l a s k s . Simulated g a s t r i c f l u i d was used as the d i s s o l u t i o n medium and the 40 mesh basket was r o t a t e d at 50 r.p.m. Brand Vessel D i s s o l u t i o n Values (Minutes) T 2 0 T40 T60 T80 A USP 8 21 40 73 A 1 L . l 6 17 35 57 A 2 L . l 6 12 32 54 A 3 L . l 7 20 40 7 5 B USP a a a 11 B 1 L . l a 6 7 8 B 2 L . l a 5 6 7 B 3 L . l 5 6 7 12 C USP 11 25 45 63 C 1 L . l 9 12 39 53 C 2 L . l a 7 12 20 C 3 L . l 5 8 11 20 1 Round bottom f l a s k a l e s s than 5 minutes - 113 -Table 8. Comparison of d i s s o l u t i o n values of chlorpromazine hydrochloride t a b l e t s (Brands A, B and C) i n USP v e s s e l and 1 L. , 2 L. and 3 L. round bottom f l a s k s using d i s t i l l e d water as the d i s s o l u t i o n medium. The basket was r o t a t e d at 50 r.p.m.. Brand Vessel D i s s o l u t i o n Values (Minutes) T 20 T40 T60 T80 A USP 10 20 39 b A 1 L . l 9 23 42 b A 2 L . l 10 39 94 b A 3 L. 1 11 32 101 b B USP 6 11 44 b B 1 L . l a 6 b b B 2 L . l 12 49 b b B 3 L . l 8 18 b b C USP a a 10 15 C 1 L. 1 a a 9 14 C 2 L . l 6 10 15 30 C 3 L . l a a 13 24 round bottom f l a s k a l e s s than 5 minutes k more than 12 0 minutes - 114 -be even more comparable except i n the case of the 2 L. f l a s k which gives a r e l a t i v e l y high d i s s o l u t i o n r a t e . The four d i s -s o l u t i o n vessels show re l e a s e p r o f i l e s of the three brands i n the same decreasing rank order of d i s s o l u t i o n r a t e : C, A, B (Table 8). An e v a l u a t i o n of the data discussed above i n d i c a t e s t h a t there i s v i r t u a l l y no d i f f e r e n c e between the r e s u l t s obtained with USP v e s s e l and 1 L. round bottom f l a s k . The d i f f e r e n c e s i n d i s s o l u t i o n values observed i n the case of 2 L. and 3 L. round bottom f l a s k s might suggest the p r o b a b i l i t y t h a t the dimension of the d i s s o l u t i o n v e s s e l can have an i n f l u e n c e on the re l e a s e p a t t e r n . T h i s , however, does not have any bearing on the USP v e s s e l . 3. E f f e c t of Mesh Size In a rep o r t on a comparison of various d i s s o l u t i o n methods, Shah and Moore (1970) and Blythe and Mader (1969) observed that the 40 mesh basket was a source of e r r o r because i t . could be clogged w i t h d i s i n t e g r a t e d t a b l e t m a t e r i a l . That the p o s s i b i l i t y of a i r bubbles trapped i n the 40 mesh basket could r e s u l t i n erroneous d i s s o l u t i o n r a t e data was a l s o reported i n the l i t e r a -t ure (Blythe and Mader, 1969). The e f f e c t of mesh s i z e of the basket on the d i s s o l u t i o n r a t e of the three brands of CPZ-HC1 t a b l e t s was, t h e r e f o r e , i n v e s t i g a t e d using the USP apparatus. Simulated g a s t r i c f l u i d was used as the d i s s o l u t i o n medium and d i s s o l u t i o n c h a r a c t e r i s t i c s based on a 10 mesh basket (2.8 cm. i n length and 2.2 cm. i n diameter) and a 40 mesh USP basket were compared. - 115 -A comparison of the d i s s o l u t i o n p r o f i l e s of the three brands of CPA-HC1 t a b l e t s obtained with the 40 mesh basket (see F i g . 14) with t h a t obtained with the 10 mesh basket (see F i g . 17,11) i n d i -cated that the p r o f i l e of Brand C i s separated from t h a t of Brand A and that the r e l e a s e r a t e of the former was shown to be s i g n i f i c a n t l y higher and q u i t e comparable to the d i s s o l u t i o n r a t e of Brand B. I t can a l s o be seen that the r e l e a s e r a t e of a l l three brands i s increased when the d i s s o l u t i o n t e s t i s c a r r i e d out with the 10 mesh basket. See F i g . 18. The extent to which r e l e a s e r a t e i s increased seems to f a l l i n decreasing rank order of C, A and B. See Table 9. The d i s s o l u t i o n p r o f i l e s of the three brands obtained w i t h a 40 mesh basket and a 10 mesh basket were a l s o compared using d i s t i l l e d water as the d i s s o l u t i o n medium. The 10 mesh data (see F i g . 17,1) i n d i c a t e s that Brand B shows a higher r a t e of re l e a s e than Brand C up to about 52 per cent d i s s o l u t i o n , com-pared to the 4 5 per cent value i n the case of the 40 mesh basket (see F i g . 13). A f t e r t h i s stage, however, Brand A shows a higher r e l e a s e r a t e than Brand B. Though the d i s s o l u t i o n p r o f i l e of Brand A i s smoother i n the case of the 10 mesh basket than shown with the 40 mesh basket, i t appears that the c o n t r i b u t a r y f a c t o r of mesh s i z e (as shown above when simulated g a s t r i c f l u i d was used as the d i s s o l u t i o n medium) i s not apparent i n t h i s case. An i n s p e c t i o n of the 10 mesh data i n Table 10 shows t h a t the r e l e a s e r a t e s i n d i s t i l l e d water, of the three brands i s not increased to any s i g n i f i c a n t extent. P W > c CO CO r-i P C_> w (X, 100 Figure!IS (Bran ds Comparison' of"pi'ss'plutidrr !Prdf:iles;'"oF",CPZ-HCl [Tablet. A- B and C) as obtained;; by'using ;40 rriesh^and llO mesW°1baskets F l u i d ( r o t a t e d -, -a t - 5 0 • [• r I. p [. m;. ) j - i n - - jth e - :U S P- Appa'r a.t u;s'-. •--was used: as the t e s t j medium. \ \ 'J..-'J L':; :]. Simulated- G a s t r i c -1 I J a_ 120 ; I J_.!_.L -i...i. - 118 -Table 9. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s o f c h l o r p r o -mazine hydrochloride t a b l e t s (Brands A, B and C) i n simulated g a s t r i c f l u i d using 1 40 mesh and 10 mesh baskets i n the USP apparatus 1. Brand .Mesh Size D i s s o l u t i o n Values (Minutes) T20 T4 0 T60 T80 A 40 8 21 40 73 A 10 a a 18 35 B 40 a a a 11 B 10 a a 6 7 C 40 11 2 5 45 63 C 10 a 7 9 13 1 Speed of s t i r r e r : 50 r.p.m. a l e s s b more than 5 minutes than 120 minutes Table 10. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s of c h l o r p r o -mazine hydrochloride t a b l e t s (Brands A, B and C) i n d i s t i l l e d water, using 40 mesh and 10 mesh baskets i n the USP apparatus 1. Brand Mesh Size D i s s o l u t i o n Values (Minutes) T20 T4 0 T60 T80 A 140 10 20 39 b A 10 9 19 3 3 b B 40 6 11 44 b B 10 a 10 50 b C 40 a a 10 15 C 10 a a 6 11 1 Speed of s t i r r e r : 50 r.p.m. a less than 5 minutes more than 120 minutes - 119 -The amount of d i s i n t e g r a t e d p a r t i c l e s accumulated at the bottom of the d i s s o l u t i o n v e s s e l w i l l be greater w i t h a d i s -s o l u t i o n t e s t employing a 10 mesh basket than i s the case w i t h a 40 mesh basket. In order to observe the combined e f f e c t of mesh s i z e and geometry of d i s s o l u t i o n v e s s e l , d i s s o l u t i o n t e s t s were c a r r i e d out using a 10 mesh basket, i n 1 L., 2 L. and 3 L. round bottom f l a s k s . Simulated g a s t r i c f l u i d and d i s t i l l e d water were used as the d i s s o l u t i o n media. Table 11 shows t h a t except f o r the r a t h e r high d i s s o l u t i o n values obtained with the 1 L. f l a s k ( i n simulated g a s t r i c f l u i d ) , the T20» T^g, Tgg and Tgg values are e s s e n t i a l l y comparable. The data obtained using d i s t i l l e d water (Table 12) as the d i s s o l u t i o n medium, shows i n most i n s t a n c e s , even more comparable d i s s o l u t i o n values i n the various v e s s e l s . Tables 11 and 12 show a decreasing r e l e a s e r a t e rank order of B, C, A i n simulated g a s t r i c f l u i d , and C (A B) i n d i s t i l l e d water f o r a l l the v e s s e l s . The d i s s o l u t i o n c h a r a c t e r i s t i c s of the three brands, obtained with the 10 mesh basket, i n d i c a t e a higher d i s s o l u t i o n r a t e i n a l l cases. The separation of the d i s s o l u t i o n p r o f i l e s ( i n the case of the 10 mesh basket) of Brands C and A suggests tha t the aggregates of t a b l e t m a t e r i a l have blocked a p o r t i o n of the screen i n the case of the 40 mesh basket. I t appears t h a t a t a b l e t with acceptable d i s s o l u t i o n c h a r a c t e r i s t i c s could be t e s t e d and r e j e c t e d i f i t were to be evaluated i n a 40 mesh basket at or below 50 r.p.m. - 120 -Table 11. D i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine hydrochloride t a b l e t s (Brands A, B and C) as obtained using a 10 mesh basket and a d i s s o l u t i o n medium of simulated g a s t r i c f l u i d 1 . Brand D i s s o l u t i o n D i s s o l u t i o n Values (Minutes) Vessel T20 T40 T60 T80 A USP a a 18 35 A 1 L. 2 a 11 29 43 A 2 L.2 5 16 26 40 A 3 L. 2 6 155 30 47 B USP a a 6 7 B 1 L.2 a 6 11 23 B 2 L.2 a 6 8 9 B 3 L.2 a 6 7 9 C USP a 7 9 13 C 1 L.2 7 16 25 43 c 2 L.2 a a 9 16 c 3 L.2 6 8 11 23 Speed of s t i r r e r : 50 r.p.m. 2 round bottom f l a s k a less than 5 minutes - 121 -Table 12: D i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine hydrochloride t a b l e t s (Brands A, B and C) as obtained using a 10 mesh basket and a d i s s o l u t i o n medium of d i s t i l l e d water-*-. Brand D i s s o l u t i o n D i s s o l u t i o n Values (Minutes) Vessel T20 TU0 T60 T80 A USP 9 19 33 b A 1 L.2 9 21 36 b A 2 L.2 8 23 35 b A 3 L.2 10 19 33 b B USP a 10 50 b B 1 L.2 a 8 56 b B 2 L.2 . 7 18 b b B 3 L.2 6 16 b b C USP a a 6 11 C 1 L.2 a a 8 13 C 2 L.2 a a 7 11 C 3 L.2 a a 7 12 -1 Speed of s t i r r e r : 50 r.p.m. 2 round bottom f l a s k a less than 5 minutes b more than 120 minutes - 122 -4. E f f e c t of S t i r r i n g Rate One of the f a c t o r s that a f f e c t the r a t e of d i s s o l u t i o n of a drug from i t s dosage forms has been e s t a b l i s h e d to be the r a t e of a g i t a t i o n of the d i s s o l u t i o n medium (Hamlin et a l . , 1962; Wurster and T a y l o r , 1965). Many i n v e s t i g a t o r s (Wagner, 1970; Hamlin et a l . , 1962; Steinberg et a l . , 1967; Levy, 1961) have shown that d i s s o l u t i o n procedures i n v o l v i n g a slow a g i t a t i o n of the d i s s o l u t i o n medium allow the d i f f e r e n t i a t i o n of dosage forms which have d i f f e r e n t d i s s o l u t i o n c h a r a c t e r i s t i c s . Therefore, the e f f e c t of speed of a g i t a t i o n on the d i s s o l u t i o n c h a r a c t e r i s -t i c s of the three brands of CPZ-HC1 was i n v e s t i g a t e d . The d i s s o l u t i o n c h a r a c t e r i s t i c s (USP apparatus: d i s s o l u t i o n medium - d i s t i l l e d water) of Brands A, B and C at 25, 50, 100, and 150 r.p.m. are shown i n Table 13. The T20 J ^ H O * Tgo and TQQ values at the various s t i r r i n g speeds i n d i c a t e t h a t Brand C i s r e l a t i v e l y l e s s l i a b l e to a change i n d i s s o l u t i o n r a t e com-pared to Brands A and B. F i g . 19 shows t h a t the r e l e a s e r a t e s of the three brands, at a l l s t i r r i n g r a t e s , f a l l s i n decreasing rank order of C, A and B. I t appears th a t the rank order remains the same regardle s s of the s t i r r i n g r a t e . The r e s u l t s were the same when 1 L., 2 L. and 3 L. round bottom f l a s k s were used in s t e a d of the USP v e s s e l . The above i n v e s t i g a t i o n s were repeated using simulated g a s t r i c f l u i d as the d i s s o l u t i o n medium. The experiments were run using the USP apparatus. F i g . 20,1 shows tha t the d i s s o l u -t i o n p r o f i l e s of Brand A (at s t i r r i n g speeds of 25, 50 and 75 - 123 -Table 13. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine hydrochloride t a b l e t s (Brands A, B and C) as obtained w i t h the USP procedure at d i f f e r e n t s t i r r i n g speeds-*-. Brand RPM D i s s o l u t i o n Values (Minutes) T20 T 4 0 T 6 0 T 8 0 A 25 30 59 100 b A 50 10 20 39 b A 100 7 15 31 83 A 150 a a 12 31 B 25 22 83 b b B 50 6 11 b B 100 a 7 15 b B 150 a a 15 b C 25 a a 12 17 C 50 a a 10 15 c 100 a a 8 14 c 150 a a 6 10 1 d i s s o l u t i o n f l u i d : d i s t i l l e d water a less than 5 minutes b more than 120 minutes 10 0 o C ' J O J I—i H W o K W LOO 8,0. 6 0 uo • -.- •- -I 20 120 * I • | : 4,0^  ; 8 0j-! ' 1 : ! ! ] ] i ' "i" TIME IN MINUTES' ,120 Figure.; 19. D i s s o l u t i o n . P r o f i l e s of; CPZ-EC1 -Tablets (Brand A •-- (I) ; Brand' B Brand C- ( I I I ) ) as obtained by using the USP Apparatus, ;in which the Basket r o t a t i n g at 25 ; r.plnu.. !(®.).,L5Q_>...p.k.L(b) >.. .3.00.. r..p ,im .:...„(< A X,Land. 150 r.p.m. J ( Q D i s t i l l e d Water was used as the D i s s o l u t i o n Medium. T ( I I ) ; > i s )..: 3.20 W > O CO CO M o w o w a. 1-00 80 ; 60 4 0 j 20 .10 0 1 X.8 0 -60 J..-4 0-20 120 --MOO 20 20 ! -40 60 j TIME IN MINUTES i ' I .! • I ''j j i • I ' j ! ' Figure 20; D i s s o l u t i o n P r o f i l e s of CPZ'-HCl Tablets (Brand A .-" ( I ) ; B r a n d B - ( I t ) Brand'C - ( I I I ) ) as obtained!'by using the US'P Apparatus :in which the" Basket was 120, r o t a t e d at 25 r-.p-im(6)•',•-50j-r ypj;my- j(0:) ,|'7 5-r.p.m.;-(] ) ,h"and 100 r.p.m.' Simulated : G a s t r i c i F] uidj was used - as j- the' Di.s s o l u'tibn -Medium .!• ! • i ' ! i - 1 . ! • : i f , . ! ! ; -' i\ t -•Cay: c^n - 126 -r.p.m.) remain e s s e n t i a l l y the same. However, the p r o f i l e at 100 r.p.m. shows a s i g n i f i c a n t increase i n d i s s o l u t i o n r a t e . The p r o f i l e of Brand B (see F i g . 20,11) at 50 r.p.m. shows an. increase i n d i s s o l u t i o n r a t e compared to tha t of a s t i r r i n g r a t e of 25 r.p.m. At s t i r r i n g speeds of or over 75 r.p.m., Brand B re l e a s e s almost 100 per cent of l a b e l c l a i m i n l e s s than f i v e minutes. Brand C appears t o be more s u s c e p t i b l e t o changes i n s t i r r i n g r a t e , as shown i n F i g . 20,111. There i s a s l i g h t d i f f e r e n c e i n d i s s o l u t i o n p r o f i l e s at 25 r.p.m. and at 50 r.p.m. wit h an increase at the higher speed. Considerable increases i n d i s s o l u t i o n r a t e s are observed at 75 r.p.m. and 100 r.p.m. R e l a t i v e changes i n d i s s o l u t i o n values of the three brands at the various s t i r r i n g speeds are shown i n Table 14. The T80 values at 25, 50, 75, and 100 r.p.m. are 61, 59, 53, 38 f o r Brand A; 17, 11, l e s s than 5, l e s s than 5 f o r Brand B; and 83, 71, 30, 7 f o r Brand C, r e s p e c t i v e l y . The d i s s o l u t i o n p r o f i l e s of the three brands were found to be i n decreasing rank order of B, A, C at 25 r.p.m. ( F i g . 21,1) and B, (C A) at 50 r.p.m. ( F i g . 14). In the l a t t e r case, the d i s s o l u t i o n p r o f i l e s of Brand A and Brand C were not s i g n i f i c a n t l y separated. However, at s t i r r i n g speeds of 75 r.p.m. and 100 r.p.m., the rank order was found to be B, C, A. See F i g . 21,11 and I I I . The r e s u l t s were the same f o r the USP v e s s e l , and 1 L., 2 L. and 3 L. round bottom f l a s k s . The i n f l u e n c e of a g i t a t i o n speed on d i s s o l u t i o n r a t e of CPZ-HC1 from.tablets was a l s o studied using a 10 mesh basket - 127 -Table 14. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine hydrochloride t a b l e t s (Brands A, B and C) as obtained using the USP procedure at d i f f e r e n t speeds 1. Brand RPM D i s s o l u t i o n Values (Minutes) T20 T40 T60 T80 A 25 5 19 37 61 A 50 8 21 40 59 A 75 a 17 32 53 A 10 0 a 15 26 38 B 25 a 6 10 17 B 50 a a a 11 B 75 a a a a B 100 a a a a C 25 6 23 53 83 C 50 11 25 45 71 C 75 a 6 15 30 C 100 a a 5 7 d i s s o l u t i o n f l u i d : simulated g a s t r i c f l u i d a less than 5 minutes - 129 -i n the USP apparatus. Simulated g a s t r i c f l u i d was used as the d i s s o l u t i o n medium. The d i s s o l u t i o n p r o f i l e s of the three brands were i n decreasing rank order of B, C, A at 25 r.p.m. ( F i g . 22,1) and 50 r.p.m. ( F i g . 17,11); and C, B, A at 75 r.p.m. and 100 r.p.m. ( F i g . 22, I I and I I I ) . Hence at s t i r r i n g speeds of 75 r.p.m. or above, Brand C appears to have the highest r e l e a s e r a t e . From the above experimental data, i t can be observed t h a t the e f f e c t of d i s s o l u t i o n medium on r e l e a s e r a t e can be greater than a r e l a t i v e l y high s t i r r i n g r a t e (maximum of 150 r.p.m. i n t h i s case). This was shown when Brand B, which has a r e l a t i v e l y high r e l e a s e r a t e (even at 25 r.p.m.) i n simulated g a s t r i c f l u i d does not r e l e a s e as much at a s t i r r i n g speed of 150 r.p.m. i n d i s t i l l e d water. The d i f f e r e n t responses of the three brands to d i f f e r e n t i n t e n s i t i e s of a g i t a t i o n suggest that optimal s t i r r i n g r a t e s which would produce i n - v i t r o data compatible w i t h i n - v i v o parameters have to be e s t a b l i s h e d f o r a compendial d i s s o l u t i o n t e s t of the s o l i d dosage forms of a drug. A s t i r r i n g speed of 75 r.p.m. appears to be acceptable when a M-0 mesh basket i s used. On the other hand, a s t i r r i n g speed of 50 r.p.m. or l e s s can be used i n the case of the 10 mesh basket, f o r CPZ-HC1 t a b l e t s . The response of the three brands t o d i f f e r e n t i n t e n s i t i e s of a g i t a t i o n was found to be e s s e n t i a l l y the same i n a l l the d i s s o l u t i o n v e s s e l s . 1 Figure" 120. il.0.0-. -.8 0. 60 -4 0. 20 TIME Comparison :of the D i s s o l u t i o n ' 100 -j 2 0 4,0 :. 60 'ro f i l e s Brand B - 0; Brand ; C - A) as obtained by | using! the CO o 20 40 60 (Brand A -o f CPZ-HC1 Tablets . USE Apparatus i n which the 10 mesh - J Basket ;was rotated ; at - 25 r.p.m. ( I ) , ; 75 r.p.m;• • ( I I ) v and 100 r|;p.m. •-: ( I I I ) . S i m u l a t e d G a s t r i c F l u i d was used as t h e . D i s s o l u t i o n Medium. ! . i " \- - f r - 131 -5. E f f e c t of B a s k e t - S t i r r e r Depth Blythe and Mader (1969) reported that the d i s s o l u t i o n r a t e (measured as the Tgg value) of a commercial l o t of phenylbuta-zone t a b l e t s was not s i g n i f i c a n t l y a f f e c t e d by b a s k e t - s t i r r e r depth at s t i r r i n g speeds of 75 r.p.m. or more. However, the above workers observed that at 50 r.p.m. the T50 value was s l i g h t l y l e s s when the basket was two cm. from the bottom of the container than when i t was r a i s e d to three and four cm. Since the s t i r r i n g speed r e q u i r e d f o r a f a i r l y r a p i d r a t e o f drug r e l e a s e from the CPZ-HC1 t a b l e t s i s r e l a t i v e l y low, the e f f e c t of b a s k e t - s t i r r e r depth on d i s s o l u t i o n r a t e was i n v e s t i g a t e d . Data was obtained f o r the USP v e s s e l and f o r 1 L., 2 L. and 3 L. round bottom f l a s k s . The data i n Table 15 i n d i c a t e s t h a t the T20> T40> T60 a n d T80 values (at one cm. s e t t i n g ) were l e s s than those observed when the basket was p o s i t i o n e d at two, three and four cm. This shows tha t there i s a s l i g h t increase i n r e l e a s e r a t e when the basket i s nearest to the bottom of the d i s s o l u t i o n v e s s e l . F i g . 23,1 shows t h a t the r e l e a s e r a t e of Brand C appears to be more v a r i a b l e with change i n depth of basket-s t i r r e r assembly. The e f f e c t of distance of the basket from the bottom of the d i s s o l u t i o n v e s s e l was a l s o i n v e s t i g a t e d using 1 L., 2 L. and 3 L. round bottom f l a s k s . The Tgrj values (1 L. round bottom f l a s k ) at one, two, t h r e e , and four cm. were: 27, 35, 37, and 38 minutes f o r Brand A; f i v e , seven, seven, and eight minutes f o r Brand B; and 25, 39, 38, and 37 minutes f o r Brand C - 132 -Table 15. E f f e c t of s t i r r e r depth on the d i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine hydrochloride t a b l e t s as obtained by using simulated g a s t r i c f l u i d i n the USP apparatus-1-. Brand Depth of D i s s o l u t i o n Values (Minutes) S t i r r e r (cm.) T20 Ti+rj T60 T 8 0 A 1 a 10 25 47 A 2 8 21 0 40 73 A 3 7 18 42 57 A 4 8 23 39 60 B 1 a a a a B 2 a a 5 11 B 3 a a 6 8 B 4 5 6 7 9 C 1 a 6 20 30 C 2 11 25 45 63 c 3 • 6 30 42 60 c 4 7 31 41 58 1 Speed of s t i r r e r : 50 r.p.m. a less than 5 minutes CO w Eh < o CD H 50 ..! . 4 0 :".'U 30 ! 20 10 2 . DISTANCE OF ;BASKET-STIRRER FROM iTHE j BOTTOM OF;DISSOLUTION VESSEL (cm.) I I ! 13 Figure"23, : E f f e c t jof Distance jof B a s k e t - S t i r r e r ; from" the bottom of the- D i s s o l u t i o n Vessel (USP Flask -r (I) \ -: 1-pLit'er-i-Round-j Bottom Flask- --•.(•II)-) on! the|-T6GJ Values 'of-- j -CPZ-HCI Table t : s !(Brand A 4 ® ; i Brand ; B! - 1.0 ; ..Brand ...C. -'.&)• i n Simulated .Gastric i F l u i d , The 4 0 mesh basket.was r o t a t e d at i • 1 I : • ; ! • !'• •I I i 1 . ! i --•i; -i • 5.0. _r .p.m... i.L.J_;i. •• -4 CO CO - 134 -r e s p e c t i v e l y (see Table 16). The above r e s u l t s ( F i g . 23,11), as w e l l as the T20s T40 and TQQ v a l u e s , seem to i n d i c a t e , i n general, t h a t above one cm. a change i n distance of basket from the bottom of the 1 L. round bottom f l a s k does not r e s u l t i n any s i g n i f i c a n t d i f f e r e n c e i n the d i s s o l u t i o n r a t e o f the three brands. S i m i l a r data (see Tables 17 and 18) was obtained f o r the 2 and 3 L. c o n t a i n e r s . The general s i m i l a r i t y of the Tgrj valu e s , at two, t h r e e , and four cm., f o r Brands A, B, and C as shown i n F i g . 24, I and I I , a l s o i n d i c a t e s t h a t there i s v i r t u a l l y no d i f f e r e n c e i n d i s s o l u t i o n r a t e i n the case of the round bottom f l a s k s . The r e l a t i v e l y high r e l e a s e r a t e at one cm. observed w i t h the USP f l a s k may be due to a more e f f i c i e n t d i s t r i b u t i o n of d i s i n t e g r a t e d p a r t i c l e s throughout the f l a s k . However, f o r the purpose of u n i f o r m i t y of t e s t r e s u l t s •(since e r r o r s i n p o s i t i o n -i n g the .basket w i l l not be r e f l e c t e d i n d i s s o l u t i o n r e l e a s e r a t e ) , a basket s t i r r e r depth of three cm. from the bottom of the d i s s o l u t i o n v e s s e l appears to be p r e f e r a b l e . 6. E f f e c t of pH The change i n the d i s s o l u t i o n c h a r a c t e r i s t i c s of Brand B, when the d i s s o l u t i o n medium was changed from d i s t i l l e d water to simulated g a s t r i c f l u i d , was discussed p r e v i o u s l y . In order to determine the p o s s i b l e reason f o r the d i f f e r e n t d i s s o l u t i o n c h a r a c t e r i s t i c s of Brand B, the e f f e c t of pH was i n v e s t i g a t e d . Buffers of pH 2.0, 2.8, 4.0, and 5.1 were used. - 135 -Table 16. E f f e c t of s t i r r e r depth on the d i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine h y d r o c h l o r i d e t a b l e t s as obtained by using simulated g a s t r i c f l u i d i n a 1 L. round bottom f l a s k 1 . Brand Depth of S t i r r e r D i s s o l u t i o n Values (Minutes) T20 T40 T60 T80 A 1 a 16 27 51 A 2 6 17 35 57 A 3 7 18 37 50 A 4 7 19 38 53 B 1 a a 5 10 B 2 a 6° 7 8 B 3 5 6 7 8 B 4 6 7 8 9 C 1 8 16 25 37 C 2 9 21 39 53 C 3 7 20 38 51 C 4 7 18 37 55 Speed of s t i r r e r : 50 r.p.m. a less than 5 minutes - 136 -Table 17. E f f e c t of s t i r r e r depth on the d i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine hydrochloride t a b l e t s as obtained by using simulated g a s t r i c f l u i d i n a 2 L. round bottom flask-*-. Brand Depth of D i s s o l u t i o n Values (Minutes) S t i r r e r (cm.) T20 T40 T60 T80 A 1 a 13 25 50 A 2 6 12 32 54 A ' 3 6 20 33 60 A 4 7 20 31 57 B 1 5 6 7 9 B 2 a 5 6 7 B 3 a 6 7 8 B 4 5 6 7 10 C 1 a 9 10 17 C 2 8 17 34 50 C 3 8 21 36 58 C 4 7 16 35 23 1 Speed of s t i r r e r : 50 r.p.m. a less than 5 minutes - 137 -Table 18. E f f e c t of s t i r r e r depth on the d i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine h y d r o c h l o r i d e t a b l e t s as obtained by using simulated g a s t r i c f l u i d i n a 3 L. round bottom f l a s k 1 . Brand Depth S t i r r e r of (cm. ) D i s s o l u t i o n Values (Minutes) T20 T4 0 T60 T80 A 1 a 14 31 52 A 2 7 20 40 75 A 3 a 19 41 53 B 1 5 6 7 9 B 2 5 6 7 12 B 3 5 6 7 8 C 1 5 18 9 49 C 2 5 8 11 20 c 3 6 10 12 33 1 Speed of s t i r r e r : 50 r.p.m. a less than 5 minutes CO 00 ' - 139 -Results are shown i n F i g . 25. The p r o f i l e s o f Brand A ( F i g . 25,1) do not show any s i g n i f i c a n t d i f f e r e n c e under d i f f e r e n t pH c o n d i t i o n s . Brand B ( F i g . 2 5,11) shows a gradual increase i n d i s s o l u t i o n r a t e with a decrease i n pH. On the other hand, the r e l e a s e r a t e of Brand C ( F i g . 2 5,111) decreases with a decrease i n pH. The d i f f e r e n t e f f e c t s of pH on the three brands of CPZ-HC1 t a b l e t s suggests the involvement of the r e s p e c t i v e t a b l e t e x c i p i e n t s i n the c h a r a c t e r i s t i c r e l e a s e p a t t e r n s . 7. E f f e c t of Immersion of the Basket While Rotating The USP d i s s o l u t i o n procedure s p e c i f i e s t h a t the basket be immersed i n the d i s s o l u t i o n medium and then r o t a t e d . D i s s o l u t i o n data obtained with a modified procedure i n which the basket i s immersed while r o t a t i n g was compared wi t h t h a t obtained with the USP procedure. Brand C was used f o r t h i s experiment because i t was observed to be most s u s c e p t i b l e to changes In experimental c o n d i t i o n s . Ten t a b l e t s were t e s t e d using each procedure. Results are shown i n Table 19. The data i n d i c a t e s t h a t a higher r e l e a s e r a t e i s obtained w i t h the USP procedure compared to the modified procedure. I t appears tha t there i s a l s o a higher degree of v a r i a b i l i t y i n the r e s u l t s obtained w i t h the USP procedure compared with the modified method as shown by the r e s p e c t i v e values of standard d e v i a t i o n . A t a b l e t dropped i n t o a basket and immersed i n t o : loo. 80 120 •' j' : .1 40 ' •!'• i 80 ;•' j. ; • r ;:'!. i r.i' j ; TIME IN MINUTES 120 40 80 Figure 25. E f f e c t of nH (2.0 J . . , C h a r a c t e r i s t i c s ; of CPZ-HC1 Tabl e t s 120 2.8 -.;0; 4.0 - & ; 5.1 - a ) on : the D i s s o l u t i o n '!• ^ . J V .. . ., ... (Brand A ( I ) ; J B r a h d i B i - l ( I I ) ;.; Brand Ci - (III)!) as obtained, by using Simulated jGastric j F l u i d i i r i the USP Apparatus ,1 The 4 0 mesh < basket was rot a t e d at 50 r.p.m. '! i - I "• 1 | •. | ^ •• , -h-1 -P O - 141 -Table 19. Comparison of d i s s o l u t i o n values of chlorpromazine hydrochloride t a b l e t s (Brand C) as obtained with the procedure i n which the basket i s not r o t a t e d when.immersed i n t o the d i s s o l u t i o n medium (USP method) and the modified procedure i n which the basket i s immersed wh i l e r o t a t i n g 1 . Tablet No. D i s s o l u t i o n Values (Minutes) Modi f i e d Method USP Method T20 T4 0 . T 6 0 T80 T20 T40 T i60 T80 1 10 25 42 61 4 6 13 23 2 10 24 42 61 5 13 22 33 3 5 19 39 62 7 17 29 43 i+ 5 19 39 62 5 15 30 44 5 8 21 39 61 3 6 13 23 6 8 21 38 58 4 12 23 36 7 6 19 36 58 6 19 36 53 8 6 20 40 62 3 11 20 31 9 5 19 40 62 3 10 19 29 10 i+ 18 38 59 5 16 29 43 Mean 6.7 20.5 39.3 60.6 4.5 12.5 23.4 35.8 Standard ) e v i a t i o n 2.16 2.3 1.83 2.71 1.35 4.42 7.56 10.25 simulated g a s t r i c f l u i d was used as the d i s s o l u t i o n medium and the s t i r r i n g speed was 50 r.p.m. - 142 -the d i s s o l u t i o n medium (while not r o t a t i n g ) s t i c k s to the bottom or edge of the basket and remains there during sub-sequent r o t a t i o n exposing a p o r t i o n of i t s surface area d i r e c t l y to the bulk of the medium. This may r e s u l t i n a higher d i s s o l u t i o n r a t e . The v a r i a b l e p o s i t i o n s t h a t a t e s t t a b l e t may assume when c a s u a l l y dropped i n t o the basket probably can mean v a r i a b l e surface areas exposed to the bulk medium and hence b r i n g about greater v a r i a t i o n s i n d i s s o l u t i o n r e s u l t s . In the modified procedure, however, the t a b l e t keeps moving w i t h i n the basket and thus may tend to behave i n a more uniform manner. 8. D i s i n t e g r a t i o n Data Versus D i s s o l u t i o n Data In order to determine i f there i s any r e l a t i o n s h i p between d i s i n t e g r a t i o n and d i s s o l u t i o n , d i s i n t e g r a t i o n data was obtained f o r Brands A, B, and C. Table 20 shows t h a t a l l the brands conform to the d i s i n t e g r a t i o n time requirements of the USP. The d i s i n t e g r a t i o n values f o r the three brands f a l l , i n most i n s t a n c e s , i n i n c r e a s i n g rank order of C, B, and A. The d i s s o l u t i o n r a t e s obtained w i t h a 10 mesh basket rank i n decreasing order of B, C, and A. - 14 3 -Table 20. D i s i n t e g r a t i o n values of CPZ-HC1 t a b l e t s (Brands A, B and C) i n d i s t i l l e d water and i n simulated g a s t r i c f l u i d , using the USP D i s i n t e g r a t i o n Method and a modified method (USP method without d i s c s ) . 1 Brand D i s i n t e g r a t i o n Values (Minutes) USP Method Modified Method D i s t i l l e d Water Simulated G a s t r i c F l u i d D i s t i l l e d Water Simulated G a s t r i c F l u i d A 9 B 9 C 4 9 6 4 14 8 5 15 10 7 Each of the d i s i n t e g r a t i o n values i s the mean of s i x determinations. The r e l a t i v e d i f f e r e n c e s i n d i s i n t e g r a t i o n time are not s i g n i f i c a n t enough to be considered a f a c t o r i n t h e i r d i s s o l u t i o n r a t e s , because i f only 15 minutes are r e q u i r e d f o r the t a b l e t (Brand A) to d i s i n t e g r a t e , the r e l e a s e c h a r a c t e r i s t i c s of the three brands should have been comparable a f t e r t h i s period of time. However, Brand A re l e a s e s about 55 per cent of drug i n 15 minutes, whereas drug r e l e a s e from Brands B and C are 9 5 per cent and 70 per cent r e s p e c t i v e l y , a f t e r the same period of time (using a 10 mesh basket). I t - 144 -appears th a t d i s i n t e g r a t i o n time i s not i n d i c a t i v e of d i s s o l u t i o n c h a r a c t e r i s t i c s . I t has been reported i n the l i t e r a t u r e t h a t the d i s c s i n the USP apparatus tend to d i s t o r t product c h a r a c t e r i s t i c s (Campagna et a l . , 1963). The general tendency appears to be an increase i n d i s i n t e g r a t i o n times when d i s c s are not i n s e r t e d i n t o the tubes of the apparatus. The data i n Table 2 0 shows that i f such an e f f e c t occurs w i t h the t a b l e t s being t e s t e d , that e f f e c t i s minimal. 9. R e p r o d u c i b i l i t y of D i s s o l u t i o n Values as Obtained by using the USP Method D i s s o l u t i o n t e s t s were run on ten t a b l e t s of each of Brands A, B and C using the USP procedure. The basket was ro t a t e d i n simulated g a s t r i c f l u i d at 50 r.p.m. The r e s u l t s , as shown i n Table 21, i n d i c a t e t h a t v a r i a b i l i t y o f d i s s o l u t i o n c h a r a c t e r i s t i c s decreases with higher d i s s o l u t i o n values. The f i g u r e s f o r each t a b l e t i n each brand appear to be qu i t e comparable. An i n s p e c t i o n of the T60 values of the three brands shows t h a t 9 5 per cent of observations w i l l have a v a r i a b i l i t y of l e s s than +_ 6.98 minutes f o r Brand A; +_ 1.34 minutes f o r Brand B; and +_ 3.66 minutes f o r Brand C. The question of r e p r o d u c i b i l i t y o f the d i s s o l u t i o n v a l u e s , however, in v o l v e s two f a c t o r s : (a) i n d i v i d u a l t a b l e t v a r i a t i o n and (b) v a r i a t i o n due to probable i n c o n s i s t e n c y of the d i s s o l u t i o n apparatus. Despite the p o s s i b l e combined e f f e c t s , the USP apparatus appears to y i e l d s a t i s f a c t o r y r e s u l t s . Table?21. Data f o r d i s s o l u t i o n values of ten t a b l e t s o f each of Brands A, B and C, as obtained by using simulated g a s t r i c f l u i d i n the USP apparatus 1. Tablet D i s s o l u t i o n Values (Minutes) No. Brand A Brand : B Brand C T20 T4O T60 T80 T20 T40 T60 T80 T20 T40 T60 T80 1 9 23 40 63 2 3 5 11 10 25 42 61 2 5 15 31 52. 2 3 5 12 10 24 42 61 3 6 18 34 55 2 4 6 13 5 19 39 62 4 5 14 29 46 2 4 6 13 5 19 39 62 5 6 18 35 58 2 3 5 10 8 21 39 61 6 6 19 35 52 2 4 6 9 8 21 38 58 7 6 20 40 60 2 4 1 5 9 6 19 36 58 8 7 22 40 60 2 3 6 10 6 20 -40 62 9 6 19 35 56 2 3 6 7 5 19 40 62 10 6 18 35 59 3 5 7 11 4 18 38 59 M e an 6.2 18.6 35.4 56.1 2.1 3.6 5.7 10 . 5 6 .7 20 .5 3 9 . 3 60.6 Standard D e v i a t i o n 1.16 2 .75 3.49 4.98 0.31 0. 52 0.67 1.89 2.16 2 .3 1.83 2.71 SpeecU of s t i r r e r : 50 r.p.m. - 146 -10. Comparison of the D i s s o l u t i o n C h a r a c t e r i s t i c s of D i f f e r e n t Brands of CPZ-HC1 Tablets The USP procedure was used and the basket was r o t a t e d at 50 r.p.m. D i s s o l u t i o n values of Brands A, B, C, D ( A t l a n t i c ) , E (Empire), F ( E l l i o t t - M a r i o n ) , and G (Pharmetics) were obtained using d i s t i l l e d water and simulated g a s t r i c f l u i d as the d i s s o l u t i o n media. Data was a l s o obtained using a 10 mesh basket. Table 22 shows tha t the T60 values ( d i s t i l l e d water -40 mesh) i n d i c a t e r e l e a s e r a t e s i n decreasing rank order of Brands F, C, G, E, A, B, and D. This data i n d i c a t e s t h a t Brand B has a r e l e a s e r a t e (90 minutes) o f l e s s than t h a t of Brand A (54 minutes) and appears t o be one of the l e a s t r e l e a s i n g brands. T h i s , however, i s not the case since the c l i n i c a l study shows i t to be b e t t e r than Brand A. There i s no s i g n i f i c a n t d i f f e r e n c e between the 40 mesh and 10 mesh r e s u l t s ( d i s t i l l e d water) f o r a l l the brands except Brand E which shows an increased r e l e a s e r a t e i n the 10 mesh basket. See F i g s . 26 and 27. The data obtained using simulated g a s t r i c f l u i d (40 mesh) i n d i c a t e s a considerable increase i n the d i s s o l u t i o n r a t e o f Brand B; r e l a t i v e l y higher r e l e a s e r a t e s f o r Brands A, E and D; and decreased r e l e a s e r a t e s i n Brands C and F compared wi t h the r e s u l t s obtained using d i s t i l l e d water (40 mesh). See Table 22 and F i g s . 2 8 and 29. However, Brands C and F show increased r e l e a s e r a t e s when t e s t e d i n the 10 mesh basket (simulated g a s t r i c f l u i d ) . The d i s s o l u t i o n r a t e s of the various brands - 147 -20 40 60 80 100 120 TIME TM MINUTES Figure 26.- Comparison of the D i s s o l u t i o n P r o f i l e s ' o f CPZ-HC1 Tablets (Brand A - 8; Brand B - 0, Brand C - a ; Brand D -V ; Brand E - O ; Brand F - 0; Brand G -<>) as obtained by using D i s t i l l e d Water m the USP Apparatus. The 40 mesh basket was r o t a t e d at 50 r.p.m. - 148 -20. • 40 60 80 100 120 TIME IN MINUTES Figure 27. Comparison of the D i s s o l u t i o n ' P r o f i l e s o f CPZ-HC1, Tablets (Brand A - ®; Brand B - 0; Brand C - ^ ; Brand D - V ; Brand E - O ; Brand F - 0; Brand G - O ) as obtained by usi n g D i s t i l l e d Water i n the USP Apparatus. The 10 mesh basket was r o t a t e d at 50 r.p.m. - 149 -Table 22. Comparison of d i s s o l u t i o n c h a r a c t e r i s t i c s (T60 value) of seven brands of CPZ-HC1 t a b l e t s as obtained using 40 mesh and 10 mesh baskets D i s t i l l e d water and simulated g a s t r i c f l u i d were used as the d i s s o l u t i o n media and the s t i r r i n g speed was 50 r.p.m. Brand T 6 0 Value (Minutes) D i s t i l l e d Water Simulated G a s t r i c F l u i d 4 0 mesh 10 mesh 40 mesh 10 mesh A 54 45 39 18 B ' 90 100 4 6 C 11 6 41 15 D b b 72 76 E 21 6 10 14 F 7 9 29 15 G 17 11 16 6 b: More than 120 minutes. - L O U -20 40 60 80 100 120 TIME IN MINUTES ' " •" Figure 28. Comparison of the D i s s o l u t i o n P r o f i l e s o f CPZ-HC1 — Tablets (Brand A - ® Brand B - 0; Brand' C - & ; Brand D - ; • Brand E - O ; Brand F - 0; Brand G ) as obtained by using Simulated G a s t r i c F l u i d i n the USP Apparatus. The 40 mesh basket was r o t a t e d at 50 r.p.m. - 151 -i t f i i 20 . 40 60 ; 80 100 120 TIFF IN MINUTES Figure.29. Comparison of the D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brand A - ®; Brand B - 0; Brand. C Brand D - v ;, Brand E -O; Brand F - 0; Brand G -<£.) as obtained by using Simulated G a s t r i c F l u i d i n the USP Apparatus. The 10 mesh/basket was r o t a t e d a t 50 r.p.m. f a l l i n decreasing rank order of B and G, E, C and F, A, D. From the above d i s c u s s i o n i t can be observed that 10 mesh basket o f f e r s l e s s of a mechanical drawback than the 40 mesh basket and simulated g a s t r i c f l u i d i s the d i s s o l u t i o n medium of choice f o r CPZ-HC1 t a b l e t s . The USP d i s s o l u t i o n t e s t r e q u i r e s that the dosage form re l e a s e 60 per cent of i t s drug content i n a s p e c i f i e d period of time. The T60 values of a l l the brands (except Brand D) are very much comparable and any time l i m i t above 15 minutes w i l l mean that a l l brands except D are acceptable. However, the r e l e a s e r a t e of Brand A becomes i n c r e a s i n g l y slower at higher d i s s o l u t i o n values (Tgo» Tgo, etc.) as shown i n F i g . 29. I t appears, t h e r e f o r e , that the USP s p e c i f i c a t i o n f o r d i s s o l u t i o n t e s t i n g does not allo w the d i s c r i m i n a t i o n of brands w i t h con-s i d e r a b l e r e l e a s e r a t e d i f f e r e n c e s and does not permit e l u c i d a -t i o n of the f u l l d i s s o l u t i o n c h a r a c t e r i s t i c s of the dosage form. An e v a l u a t i o n of drug re l e a s e based on d i s s o l u t i o n p r o f i l e s seems to be a more u s e f u l approach f o r the manufacturers as w e l l as the r e g u l a t o r y agencies. A requirement of a TQQ value of 15 minutes means tha t Brands C, E, and F w i l l be acceptable and tha t Brand A w i l l be r e j e c t e d by narrow margins. However, the d i f f e r e n c e s i n d i s s o l u t i o n c h a r a c t e r i s t i c s of Brands C, E, and F, and Brand A become more marked at higher d i s s o l u t i o n values. Hence, a s p e c i f i c a t i o n of a TQQ value of 30 minutes appears to be a b e t t e r index of the considerable r e l e a s e r a t e d i f f e r e n c e s between Brand A and the r e l a t i v e l y f a s t e r r e l e a s i n g brands. 1 1 . Comparison of the USP D i s s o l u t i o n Method wi t h Three Other Methods D i s s o l u t i o n data f o r chlorpromazine HC1 t a b l e t s (Brands A, B and C) obtained by using the USP d i s s o l u t i o n apparatus was compared w i t h : ( i ) the NF D i s s o l u t i o n Method I I , ( i i ) a S t a t i o n a r y Basket Method. This i s a modified USP method i n which the 40 rresh basket i s kept s t a t i o n a r y and a g i t a t i o n i s c a r r i e d out by using a 4-blade p r o p e l l e r , the blades of which, are at a 1 0 ° angle as shown below. Figure 30. A diagramatic r e p r e s e n t a t i o n of the p r o p e l l e r used i n method ( i i ) above. ( i i i ) a S t a i n l e s s S t e e l C y l i n d e r Method. This i s a modified USP d i s s o l u t i o n method i n which the 40 mesh basket i s replaced by a s t a i n l e s s s t e e l c y l i n d e r (5.1 cm. i n le n g t h and 2.2,cm. i n i n t e r n a l diameter) covered at one end w i t h a 40 mesh screen. - 154 -Simulated g a s t r i c f l u i d was used as the d i s s o l u t i o n medium i n a l l cases. The a g i t a t i o n speeds of the basket s t i r r e r of the USP method, the p r o p e l l e r of the s t a t i o n a r y method, and the c y l i n d e r of the s t a i n l e s s s t e e l c y l i n d e r method was 50 r.p.m. Results are shown i n F i g . 31. The p r o f i l e s i n d i c a t e that the NF method ( F i g . 31,11), because of i t s r e l a t i v e l y high i n t e n s i t y of a g i t a t i o n , does not allow a s i g n i f i c a n t d i f f e r e n t i a t i o n between Brands A and B. Up to 80 per cent drug r e l e a s e , a l l three brands appear to have the same ( f a s t ) r e l e a s e r a t e . The data obtained with the s t a t i o n a r y basket method ( F i g . 31,111) shows tha t the p r o f i l e of Brand C i s comparable to t h a t of Brand B. This i s probably so because of the r e l a t i v e l y high a g i t a t i o n i n t e n s i t y created by the p r o p e l l e r . Brand A, however, i s shown to have a s i g n i f i c a n t l y •slower r e l e a s e r a t e (as i n the USP method ( a ) ) . The d i s s o l u t i o n p r o f i l e s obtained with the s t a i n l e s s s t e e l c y l i n d e r method ( F i g . 31,IV) show tha t Brand B r e l e a s e s drug at a higher r a t e r e l a t i v e to Brands A and C and the l a t t e r brands have s i m i l a r p r o f i l e s . The d i s s o l u t i o n c h a r a c t e r i s t i c s of the three brands obtained w i t h the l a s t method are almost i d e n t i c a l to those obtained using the USP d i s s o l u t i o n method ( F i g . 31,1). Brands A and B are d i f f e r e n t i a t e d i n the same rank order i n a l l the methods, wi t h the l a t t e r having the higher d i s s o l u t i o n r a t e . I t appears, t h e r e f o r e , t h a t the USP apparatus i s b a s i c a l l y s a t i s f a c t o r y except f o r some problems l i k e p o s s i b l e c logging of the 40 mesh screen as shown with the r e s u l t s f o r Brand C. •; --- T I M E I N M I-N U T E S '- , -Figure 31. Com.pari.son of the D i s s o l u t i o n P r o f i l e s of CPZ-HC1 Tablets (Brand A - ®; Brand B - 0; Brand C - <a ) as obtained by using the USP Method ( I ) , D i s s o l u t i o n Method I I o f the NF ( I I ) , S t a t i o n a r y Basket Method ( I I I ) , and S t a i n l e s s S t e e l C y l i n d e r Method ( I V ) . .Simulated G a s t r i c F l u i d was used as the D i s s o l u t i o n Medium and the basket was r o t a t e d at .50 r.p.m. - 156 -For purposes of comparison, d i s s o l u t i o n data was a l s o obtained using d i s t i l l e d water as the d i s s o l u t i o n medium and the NF d i s s o l u t i o n method I I as the t e s t procedure. Table 2 3 shows tha t a f t e r 15 minutes Brand A relea s e s 8 6.8 per cent of l a b e l c l a i m and that.Brands B and C r e l e a s e 100 per cent when simulated g a s t r i c f l u i d i s used as the d i s s o l u t i o n medium. On the other hand, a maximum of 6 3.5, 31.2, 31.2, and 78.5 per cent of l a b e l c l a i m i s rele a s e d by Brands A, B and C r e s p e c t i v e l y w ith a d i s s o l u t i o n medium of d i s t i l l e d water. A c i d i f i c a t i o n to a pH of about 1.2, however, appears to permit r e l e a s e of a l l the drug i n the dosage form. The low r e l e a s e r a t e described above i s probably due to an adsorption of the drug molecules onto the f i n e p a r t i c u l a t e t a b l e t m a t e r i a l produced by the r e l a t i v e l y high a g i t a t i o n i n t e n s i t y of the NF d i s s o l u t i o n method I I . 12. Comments on and C r i t i c i s m s of the USP D i s s o l u t i o n Apparatus On the basis of the r e s u l t s discussed i n previous sections the f o l l o w i n g observations may be made about the USP d i s s o l u t i o n apparatus. 1. The 40 mesh basket can be clogged with d i s i n t e g r a t e d t a b l e t m a t e r i a l and hence can d i s t o r t the d i s s o l u t i o n c h a r a c t e r i s t i c s of some brands. A 10 mesh basket i s suggested f o r use i n the USP apparatus. - 157 -Table 23. Comparison of the d i s s o l u t i o n c h a r a c t e r i s t i c s of chlorpromazine hydrochloride t a b l e t s (Brands A, B and C) as obtained by using simulated g a s t r i c f l u i d and water as the d i s s o l u t i o n medial. Time Per cent of Label Claim (Minutes) — Simulated G a s t r i c F l u i d D i s t i l l e d Water Brand A Brand B Brand C Brand A Brand B Brand 5 15 86.8 30 102.0 pH of s o l u t i o n 1.2 75 91 100 101 1.2 1.2 33.4 23.2 61.8 63.5 31.2 78.5 63.5 31.2 78 .5 5.7 2.8 5.1 NF D i s s o l u t i o n Method I I was used - 158 -A comparison of d i s s o l u t i o n data obtained with the USP f l a s k and with 1 L. , 2 L. , and 3 L. round bottom f l a s k s i n d i c a t e s t h a t the geometry of the d i s s o l u t i o n v e s s e l does not a f f e c t d i s s o l u t i o n c h a r a c t e r i s t i c s to any s i g n i f i c a n t extent. A basket p o s i t i o n of 1 cm. from the bottom of the d i s s o l u t i o n v e s s e l was found to produce higher re l e a s e r a t e s . For the purpose of u n i f o r m i t y , i t i s suggested th a t the basket be p o s i t i o n e d 3 cm. from the bottom of the d i s s o l u t i o n v e s s e l . E r r o r s i n depth s e t t i n g of 3 cm. w i l l not produce s i g n i -f i c a n t d i f f e r e n c e s i n d i s s o l u t i o n c h a r a c t e r i s t i c s . Immersion of the basket i n t o the d i s s o l u t i o n medium whil e r o t a t i n g was found to give more re p r o d u c i b l e d i s s o l u t i o n data compared with the USP Procedure i n which the basket i s f i r s t immersed and then r o t a t e d . - 159 -V I . SUMMARY AND CONCLUSIONS 1. Chlorpromazine hydrochloride absorbs a maximum of r a d i a n t energy at 254-255 nanometers when measured i n e i t h e r water or simulated g a s t r i c f l u i d (without enzyme). 2. The a b s o r p t i v i t y value of chlorpromazine hydrochloride at the above wavelength was found to be 9 5.95. This value permits assay of t a b l e t s and/or s o l u t i o n c o n t a i n i n g the drug. 3. The three brands of chlorpromazine h y d r o c h l o r i d e t a b l e t s were found to conform to the USP content u n i f o r m i t y t e s t . 4. Simulated g a s t r i c f l u i d USP (without enzyme) was found to be p r e f e r a b l e as a d i s s o l u t i o n medium f o r chlorpromazine hydrochloride t a b l e t s . D i s t i l l e d water, when used as a d i s s o l u t i o n medium y i e l d e d lower d i s s o l u t i o n values probably due to the hydrophobic p r o p e r t i e s of the t a b l e t e x c i p i e n t s i n c e r t a i n brands. 5. The pH of the d i s s o l u t i o n medium was found to a f f e c t the re l e a s e of drug from t a b l e t s . This appears to be a matter of s o l u b i l i t y i n the case of Brand B and, apparently, The t h i c k e n i n g of the c o a t i n g m a t e r i a l or e x c i p i e n t s at low pH values i n the case of Brand C. 6. Immersion of the basket i n t o the d i s s o l u t i o n medium while r o t a t i n g was found to give more re p r o d u c i b l e d i s s o l u t i o n data compared to the USP procedure i n which the basket i s f i r s t immersed and then r o t a t e d . - I S O -7. The Tgg value requirement i n the USP was found to be inadequate i n the case of chlorpromazine hudrochloride t a b l e t s . A Tgg requirement of 30 minutes using a 10 mesh basket r o t a t e d at 50 r.p.m. i s recommended as the s p e c i f i c a t i o n f o r chlorpromazine hydrochloride t a b l e t s . 8. The i n - v i t r o d i s s o l u t i o n values obtained using the USP apparatus showed the same rank order c o r r e l a t i o n as that obtained i n the i n - v i v o studies c a r r i e d out wi t h the same brands of chlorpromazine hydrochloride t a b l e t s . 9. 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