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The biopharmaceutical properties of solid dosage forms : the in vitro characteristics of phenylbutzaone… Searl, Ralph Oswald 1966

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THE  B I O PHARMAGEUTIGAL  PROPERTIES  OP  S O L I D D O S A G E FORMS The  In Vitro  Characteristics  of Phenylbutazone  Tablets  by  RALPH B.Sc, B.S.P.,  OSWALD  University University  of British of B r i t i s h  A T H E S I S SUBMITTED  IN  Columbia, Columbia,  THE D E G R E E  o f S c i e n c e i n Pharmacy In  the  I960 1963  PARTIAL FULFILMENT  T H E R E Q U I R E M E N T S FOR  Master  SEARL  OF  (M.S.P.)  Faculty of  PHARMACY  We  accept t h i s  required  thesis  as conforming  to the  standard  T H E U N I V E R S I T Y OF April,  BRITISH 1966  COLUMBIA  OF  In the  requirements  British  mission  I agree  f o r reference  for extensive  purposes  without  of this  thesis  my w r i t t e n  in partial  degree  fulfilment  of  at the University  of  the Library  and study.  thesis  make  agree  that  gain  of  The U n i v e r s i t y o f B r i t i s h Vancouver 8 , Canada Date  Columbia  A p r i l 26th, 1966  per-  copying  shall  o r by or  publi-  not be a l l o w e d  permission.  PHARMACY  freely  for scholarly  Ralph 0 S e a r l  Department  it  that  o f my D e p a r t m e n t  i s understood  for financial  shall  1 further  of this  by t h e Head  It  thesis  that  copying  may b e g r a n t e d  representatives„  cation  this  f o r an advanced  Columbia,  available  his  presenting  i ABSTRACT Many r e s e a r c h e r s have attempted to r e s o l v e  the problems asso-  c i a t e d w i t h ' t h e c l a i m s t h a t g e n e r i c drugs are t h e r a p e u t i c a l l y active.  The  objective  phenylbutazone - and of t h i s drug on the and  of t h i s study was  to determine the Canadian market.  to i n v e s t i g a t e  one  drug -  o v e r a l l q u a l i t y of 23  brands  Potency, c o n t e n t  a v a i l a b i l i t y of the drug from t h e  in-  uniformity  dosage f o r m were i n v e s t i g a -  ted. A s p e c t r o p h o t o m e t r i c method s u i t a b l e f o r the a n a l y s i s d i v i d u a l phenylbutazone . t a b l e t s was ved  developed.  of the aqueous s o l u t i o n .  The  methods.  The  d i s s o l u t i o n and  by Levy and Hayes (31) The  by two  different  a s t i r r e r method s i m i l a r to t h a t  Food outlined  were used.  r e s u l t s o f i n d i v i d u a l t a b l e t assay showed t h a t f o u r p r o -  ducts would be r e j e c t e d Two  disintegration  o f f i c i a l d i s i n t e g r a t i o n test described i n the  and Drugs R e g u l a t i o n s and  app-  spectrophotometric analy-  c h a r a c t e r i s t i c s of twelve p r o d u c t s were s t u d i e d  ity.  T h i s method i n v o l -  the e x t r a c t i o n of the drug f r o m the t a b l e t s w i t h a l c o h o l ,  r e c i a t e d i l u t i o n w i t h d i s t i l l e d w a t e r and sis  of i n -  on the b a s i s o f potency or c o n t e n t u n i f o r m -  o t h e r p r o d u c t s , a l t h o u g h complying w i t h o f f i c i a l  ments, w o u l d appear to show q u e s t i o n a b l e c h a r a c t e r i s t i c s . p r o d u c t s would be r e j e c t e d  on t h e  basis  of d i s i n t e g r a t i o n  requireTwo times  w h i l e s i x o t h e r s demonstrated e x c e s s i v e v a r i a b i l i t y i n t h e i r d i s i n tegration The  characteristics. o f f i c i a l d i s i n t e g r a t i o n a p p a r a t u s was  ution studies.  A modified version  Levy and Hayes (31)  was  of the  rejected  for dissol-  apparatus d e s c r i b e d  by  c o n s i d e r e d adequate f o r t h i s i n v e s t i g a t i o n .  The  d i s s o l u t i o n p r o f i l e s i n d i c a t e d t h a t one p r o d u c t would  be  c l a s s i f i e d as " e x c e l l e n t " ; seven as "good" and f o u r as "poor" w i t h respect  to drug r e l e a s e i n v i t r o .  P r e l i m i n a r y s t u d i e s i n d i c a t e t h a t t h e r e may c o r r e l a t i o n between i n v i t r o d i s s o l u t i o n and (as measured by drug c o n t e n t i n the This abstract represents  be a d e f i n i t e  i n vivo  availability  blood).  the t r u e content of the t h e s i s sub-  mitted.  M. P e r n a r o w s k i , Supervisor  Ph.D.  iii. TABLE OP CONTENTS I. II.  INTRODUCTION  1  LITERATURE SURVEY  Ij.  1.  The Compressed T a b l e t  k,  a) H i s t o r i c a l resume  k.  b) E s s e n t i a l q u a l i t i e s  5  Tablet V a r i a b i l i t y  5  a) Content u n i f o r m i t y  5  b) Weight v a r i a t i o n  6  c) Potency t e s t s  7  2.  3.  k..  5. III.  d) S t a t i s t i c a l t e s t s  11  In V i t r o Testing  1L|.  a) D i s i n t e g r a t i o n t e s t s  lk.  b) D i s s o l u t i o n t e s t s  18  In V i v o Methods  29  a) Q u a l i t a t i v e t e s t s  30  b) Q u a n t i t a t i v e  31  tests  In Vivo - In V i t r o C o r r e l a t i o n s  EXPERIMENTAL 1.  37  S p e c t r o p h o t o m e t r i c D e t e r m i n a t i o n of P h e n y l butazone  37  a) S p e c t r a l - a b s o r b a n c y curves  37  b) C a l i b r a t i o n curves 2.  33  Assay of phenylbutazone  ij-1 tablets  a) Equipment and r e a g e n t s b)  Procedure  c) R e s u l t s  kb lib  3.  Tablet D i s i n t e g r a t i o n  Lj.7  a) Methodology  k..  IV.  2.  3. V. VI. VII.  b) R e s u l t s  52  Tablet D i s s o l u t i o n  52  a) S o l u b i l i t y of Phenylbutazone  52  b) Methodology  56 66  DISCUSSION 1.  I4.7  Test Procedures  and R e s u l t s  66  a) T a b l e t assay  66  b) D i s i n t e g r a t i o n t e s t s  73  c) D i s s o l u t i o n t e s t s  73  d) D i s i n t e g r a t i o n - D i s s o l u t i o n c o r r e l a t i o n  8l  Product Q u a l i t y  82  a) T a b l e t assay  82  b) T a b l e t d i s i n t e g r a t i o n  82  c) T a b l e t d i s s o l u t i o n  83  I n Vivo Investigations  83  SUMMARY AND CONCLUSIONS  87  BIBLIOGRAPHY  90  APPENDIX  91*.  V.  LIST OP TABLES I. II. III. IV. V.  The E f f e c t o f I n c r e a s e d Sample S i z e on A c c e p t a b i l i t y of L o t s o f Compressed T a b l e t s  12A  D i s i n t e g r a t i o n Times and A v a i l a b i l i t y o f P r e d n i s o n e from C l i n i c a l l y A c t i v e a n d I n a c t i v e T a b l e t s  22A  Wavelengths o f Maximum A b s o r p t i o n and A b s o r p t i v i t y V a l u e s f o r Phenylbutazone i n D i f f e r e n t Media  k$  Assay o f Phenylbutazone T a b l e t s from 23 D i f f e r e n t Samples  I4.8, L ^ 9 , 5 0  D i s i n t e g r a t i o n Times of Phenylbutazone T a b l e t s u s i n g Method I I  $1  VI.  D i s i n t e g r a t i o n Times o f Phenylbutazone T a b l e t s u s i n g Method I  53  VII.  D i s i n t e g r a t i o n Times o f Phenylbutazone T a b l e t s u s i n g Methods I I and I I I  54-  VIII.  D i s i n t e g r a t i o n Times o f Phenylbutazone T a b l e t s u s i n g Methods I V and V  55  IX.  D i s i n t e g r a t i o n Times 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 of Phenylbutazone T a b l e t s u s i n g Methods I I A t o VA inclusive 59  X. D i s i n t e g r a t i o n Times 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 of Phenylbutazone T a b l e t s u s i n g Methods I I A and IVA  61  X I . D i s i n t e g r a t i o n Times 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 of Phenylbutazone T a b l e t s u s i n g Methods V I and V I I 65 XII.  R e l e a s e P a t t e r n s o f Phenylbutazone from T a b l e t s u s i n g Methods I I A and. V I  79A  X I I I . R e l e a s e P a t t e r n s o f Phenylbutazone from T a b l e t s u s i n g Methods IVA and V I I  80A  vi.  L I S T OP FIGURES 1.  2. 3. If.. 5.  S p e c t r o p h o t o m e t r i e C u r v e s f o r ( a ) P h e n y l b u t a z o n e and . (b) P h e n y l b u t a z o n e T a b l e t E x t r a c t , i n A l c o h o l - w a t e r {1% v / v ) S o l u t i o n  38  S p e c t r o p h o t o m e t r y C u r v e f o r Phenylbutazone i n 0.1N and A l c o h o l - S i m u l a t e d G a s t r i c F l u i d S o l u t i o n  39  HC1  S p e c t r o p h o t o m e t r y C u r v e f o r P h e n y l b u t a z o n e i n 0.1N NaOH a n d A l c o h o l - S i m u l a t e d I n t e s t i n a l F l u i d s o l u t i o n C a l i b r a t i o n Curve f o r Phenylbutazone {1% v / v ) S o l u t i o n  I4.O  i n Alcohol-Water 1+3  C a l i b r a t i o n Curves f o r Phenylbutazone i n (a) S i m u l a t e d G a s t r i c F l u i d , U.S.P., ( b ) S i m u l a t e d I n t e s t i n a l F l u i d , U.S.P.  l+k  6.  Sampling Device  58  7.  D i s s o l u t i o n P r o f i l e s of Phenylbutazone Tablets i n S i m u l a t e d G a s t r i c F l u i d u s i n g Method I I A  62  8.  D i s s o l u t i o n P r o f i l e s of Phenylbutazone T a b l e t s . i n S i m u l a t e d I n t e s t i n a l F l u i d u s i n g M e t h o d IVA  63  9.  D i s s o l u t i o n P r o f i l e s o f Phenylbutazone Tablets i n S i m u l a t e d G a s t r i c F l u i d u s i n g Method V I  65A  10.  D i s s o l u t i o n P r o f i l e s o f Phenylbutazone T a b l e t s i n S i m u l a t e d I n t e s t i n a l F l u i d u s i n g Method V I I  65B  APPENDICES  APPENDIX A  Content U n i f o r m i t y - T a b l e t s  (N.F.XII)  APPENDIX B  The D e t e r m i n a t i o n of t h e D i s i n t e g r a t i o n Time of T a b l e t s . (Food and Drug L a b o r a t o r i e s , Ottawa; O f f i c i a l Method)  ACKNOWLEDGEMENTS  The author wishes t o acknowledge the guidance and a s s i s t a n c e g i v e n by Dr. M. P e r n a r o w s k i d u r i n g the course o f t h i s i n v e s t i g a t i o n .  The author  would a l s o l i k e t o thank Mrs. E. Blackmore  ( nee  B r i t t e n ) f o r h e r t e c h n i c a l a s s i s t a n c e i n the laboratory.  I. INTRODUCTION Over the c e n t u r i e s man has attempted  to overcome the u n n a t u r a l  c o n d i t i o n s a s s o c i a t e d w i t h disease by v a r i o u s means a c c o r d i n g to h i s a b i l i t y and knowledge.  To t h i s end, drugs, whether d e r i v e d  from n a t u r a l sources or the present day s y n t h e t i c p r o c e s s e s , have played an important r o l e  i n the development o f treatment methods.  Methods o f drug a d m i n i s t r a t i o n developed slowly and, i n f a c t , most s o l i d dosage forms are a product of the technology a s s o c i a t e d w i t h the i n d u s t r i a l age. tions  The compressed t a b l e t  and i t s m o d i f i c a -  (that i s , the coated and d e l a y e d r e l e a s e forms) are now the  dosage forms of choice and, u n t i l r e c e n t l y , have been used w i t h complete c o n f i d e n c e . W i t h i n the l a s t ten y e a r s , s c i e n t i s t s i n i n d u s t r y and i n the u n i v e r s i t i e s have begun to q u e s t i o n the t h e r a p e u t i c e f f e c t o f these dosage forms.  In too many i n s t a n c e s , the pharmacologist  has been able to demonstrate  the a c t i v i t y of the drug as such but  the pharmacist has been unable  to show t h a t the e f f e c t of the  dosage form p a r a l l e l s that o f the pure substance.  The c o m p e t i t i v e -  ness w i t h i n the drug i n d u s t r y has f u r t h e r complicated the problem. The  same drug may now be i n c o r p o r a t e d i n t o  forms and, depending  a number o f dosage  on the drug, marketed by many manufacturers.  There i s now ample evidence that such dosage forms, a l t h o u g h containing  the same drug, may not behave i n the same way i n the body.  T h i s , then, has l e a d the pharmaceutical s c i e n t i s t i n t o a new d i s c i p l i n e - t h a t of biopharmaceutics. Biopharmaceutics may be d e f i n e d as the study of the r e l a t i o n ships between some o f t h e . p h y s i c a l and chemical p r o p e r t i e s o f the  drug and i t s dosage forms and the b i o l o g i c a l e f f e c t s following forms.  the a d m i n i s t r a t i o n  observed  o f the drug i n i t s v a r i o u s dosage  The d i s c i p l i n e , t h e r e f o r e ,  d e a l s w i t h drug q u a l i t y and  the p r a c t i t i o n e r o f t h i s d i s c i p l i n e must be a b l e t o answer a t l e a s t four questions.  These a r e :  1.  Does the t a b l e t c o n t a i n the a c t i v e s p e c i f i e d on the l a b e l ?  ingredient  2.  How much of the i n g r e d i e n t tablet?  3.  I s t h e a c t i v e i n g r e d i e n t a f f e c t e d by the adj u v a n t s i n the t a b l e t and/or environment?  4..  I s the a c t i v e i n g r e d i e n t patient?  i s p r e s e n t i n the  available  t o the  T h i s t h e s i s d e a l s w i t h t h e f i r s t two and the l a s t o f these questions.  The drug chosen f o r s t u d y was p h e n y l b u t a z o n e and the  reasons f o r t h i s c h o i c e are two i n number.  F i r s t , phenylbutazone  i s marketed i n t a b l e t form by many m a n u f a c t u r e r s and a comparative s t u d y between p r o d u c t s i s , t h e r e f o r e , drug i t s e l f i s p o o r l y s o l u b l e i n t e s t i n a l media.  possible.  S e c o n d l y , the  i n g a s t r i c media but h i g h l y  soluble i n  Drugs i n t h i s c a t e g o r y have been known t o be  unavailable i n vivo. Most s t u d i e s tween a p h y s i c a l  i n t h i s area have c e n t e r e d on a c o r r e l a t i o n be-  t e s t i n g process ( e i t h e r t a b l e t d i s i n t e g r a t i o n or  d i s s o l u t i o n ) and some i n v i v o parameter such as drug b l o o d l e v e l s or m e t a b o l i t e i n the u r i n e .  Coupled to t h i s , p h a r m a c e u t i c a l  s c i e n t i s t s have been c r i t i c a l l y r e - e v a l u a t i n g  t h e i r o v e r - a l l app-  r o a c h t o drug q u a l i t y ; the main emphasis b e i n g on content of  tablets.  uniformity  U n t i l recently,  the pharmacist has been s a t i s f i e d w i t h the  average drug content i n a l o t o f t a b l e t s , but because increased the  of the  potency o f many drugs, he i s now more concerned w i t h  amount o f drug i n each and every t a b l e t .  a l l brands of phenylbutazone  With t h i s i n mind,  t a b l e t s w i l l be assayed i n an  a p p r o p r i a t e manner and comments w i l l be made on the q u a l i t y of these p r o d u c t s .  Comments w i l l  a l s o be made on the i n v i t r o and  i n v i v o a v a i l a b i l i t y o f phenylbutazone Investigations  from these p r o d u c t s .  of t h i s type enable the r e s e a r c h e r to e v a l -  uate t e s t i n g procedxires f o r t a b l e t s .  The inadequacy of such pro-  cedures i s e v i d e n t to the p h a r m a c e u t i c a l s c i e n t i s t and, through r e s e a r c h , b e t t e r methods f o r e v a l u a t i n g w i l l be f o r t h c o m i n g .  the q u a l i t y of t a b l e t s  II.  LITERATURE SURVEY  The Compressed T a b l e t , (a) H i s t o r i c a l resume. T a b l e t s may be d e f i n e d as s o l i d dosage forms prepared by compressing  or moulding.  They have been i n widespread  use s i n c e the l a t t e r p a r t o f the n i n e t e e n t h century and s t i l l remain the most popular o f a l l m e d i c i n a l p r e p a r a t i o n s i n tended f o r o r a l u s e . In  Arabian manuscripts,  w r i t t e n by al-Zahrawi d u r i n g the  l a t t e r h a l f o f the t e n t h century, t a b l e t moulds and a process for  c o n t r o l l i n g the weight of t a b l e t s are d e s c r i b e d .  (25).  However, the word " t a b l e t " has o n l y been i n use s i n c e the e a r l y seventeenth  century.  T h i s word was d e f i n e d i n 1775,  i n Samuel Johnson's f i r s t D i c t i o n a r y o f the E n g l i s h Language, as a "medicine  i n a square f o r m "  (22).  The modern compressed t a b l e t dates from the i n v e n t i o n o f the t a b l e t machine, i n England,  by W i l l i a m Brockedon f o r  which he was granted a patent i n I8J4.3 under the t i t l e ing  "Shap-  P i l l s , Lozenges, and B l a c k Lead by Pressure i n D i e s . "  A r e f e r e n c e t o bicarbonate o f potash compressed i n t o the form o f a p i l l use  i n d i c a t e s that t h i s process was put to e a r l y  (55). The  term "compressed t a b l e t " had i t s o r i g i n i n the U n i t e d  S t a t e s and was coined by John Wyeth and Brother, to whom trade marks were i s s u e d i n 1877.  By 18914., t a b l e t s f o r a l -  most every known d i s e a s e were s o l d i n the European and  American markets.  However, no  t a b l e t r e c e i v e d an  official  stamp of approval u n t i l the n i n t h e d i t i o n of the U n i t e d Pharmacopeia (U.S.P. IX) was 1926  i s s u e d i n 1916.  Even i n the  e d i t i o n of the U.S.P. o n l y one :tablet was  recognised.  The  f i r s t r e a l l y impressive i n 1914-2 when 51  i n t o the U.S. P. occured official  approval  (22).  officially  e n t r y of t a b l e t s t a b l e t s were given  Today, the U n i t e d S t a t e s  (U.S.P.), B r i t i s h Pharmacopeia (B.P.) and u l a r y (N.F.) recognise  over 200  States  Pharmacopeia  the N a t i o n a l Form-  t a b l e t s as o f f i c i a l  prepara-  tions. (b) E s s e n t i a l q u a l i t i e s . The  e s s e n t i a l q u a l i t i e s of a good compressed t a b l e t  the c r i t e r i a which are used to determine the nature lence of t a b l e t s from a g i v e n l o t .  are  or e x c e l -  There i s an i m p l i e d warr-  anty on the p a r t of the manufacturer that such q u a l i t i e s i n f a c t , e x i s t i n the t a b l e t .  Some of these q u a l i t i e s  1.  Accurate  weight.  2.  Accurate and u n i f o r m potency.  3.  Stability.  4..  Ease of d i s i n t e g r a t i o n .  5.  A v a i l a b i l i t y of a c t i v e i n g r e d i e n t for absorption.  6.  Full  Tablet  Variability  (a) Content u n i f o r m i t y .  and uniform  therapeutic  dosage or  activity.  do,  are:  The  compressed t a b l e t has become the most acceptable  dosage form f o r the a d m i n i s t r a t i o n  o f t h e r a p e u t i c agents.  It  p r o v i d e s a convenient and, i f w e l l made, an e f f i c i e n t form of drug a d m i n i s t r a t i o n .  Among the e s s e n t i a l q u a l i t i e s of a w e l l -  made t a b l e t , u n i f o r m i t y of dosage i s considered to be o f prime importance.  In compressed t a b l e t s , t h i s i s dependent  upon the u n i f o r m d i s t r i b u t i o n o f the a c t i v e ingredients ent  (i|5).  pharmacopeias l i s t  of compressed t a b l e t s .  two g e n e r a l t e s t s f o r the c o n t r o l  These a r e :  1. The t a b l e t d i s i n t e g r a t i o n 2. In a d d i t i o n  The weight v a r i a t i o n  t e s t , and  test.  to these t e s t s , the t a b l e t s must c o n t a i n the l a b e -  l l e d amount o f a c t i v e  ingredient.  T h i s i s measured by the  potency t e s t s i n the i n d i v i d u a l monographs. integration be  or  throughout the t a b l e t m a t r i c e s and upon a c o n s i s t -  t a b l e t weight The  ingredient  The t a b l e t  dis-  t e s t i s not i n d i c a t i v e o f drug content but i t may  a measure .of drug a v a i l a b i l i t y .  cussed more f u l l y under i n v i t r o  T h i s t e s t w i l l be d i s -  testing.  (b) Weight v a r i a t i o n . Variation  i n i n d i v i d u a l weights w i t h i n  may a r i s e from many f a c t o r s . are  controllable;  ways be expected.  a batch o f t a b l e t s  To a l a r g e measure these  however, c e r t a i n small d e v i a t i o n s To p r o t e c t  the p a t i e n t  factors  can a l -  against excessive  v a r i a b i l i t y i n drug dosage, weight t o l e r a n c e s have been e s t a b l i s h e d by the pharmacopeias.  7.  S p e c i f i c requirements were i n c l u d e d i n the B.P. (19U.8) and, a f t e r a c a r e f u l study l e a d i n g to a s l i g h t m o d i f i c a t i o n to i n c r e a s e the t o l e r a n c e f o r the s m a l l e s t t a b l e t s , requirements were adopted i n the U.S.P. and N.P.  similar  The o f f i -  c i a l weight v a r i a t i o n t e s t f o r t a b l e t s s t a t e s that the weight of not more than two t a b l e t s out of twenty may vary from the average weight by more than the s t a t e d percentage and that no t a b l e t may v a r y more than twice that percentage. The f u n c t i o n of the weight v a r i a t i o n t e s t i s to c o n t r o l the v a r i a t i o n i n weight of t a b l e t s .  I t i s designed f o r un-  coated compressed t a b l e t s which must conform erences u n l e s s otherwise s p e c i f i e d . from 5% to 15% depending  to the g i v e n t o l -  These t o l e r e n c e s v a r y  on the average weight of the t a b l e t s .  However, the t e s t should not g e n e r a l l y be used as a measure of potency since here one i s assuming a completely homogeneous and u n i f o r m mix. (c) Potency  tests.  Although product dosage i s expressed on an i n d i v i d u a l comp r e s s e d t a b l e t b a s i s , potency t e s t i n g u t i l i z e s sample which i s a composite cedure w i l l 2 0 - - - .  of many t a b l e t s .  an a n a l y t i c a l An assay pro-  o f t e n read - "Weigh and f i n e l y powder not l e s s  tablets.  than  Weigh a c c u r a t e l y a p o r t i o n of the powder  e q u i v a l e n t to about  ." .This procedure  i s followed  even though one t a b l e t might be more than s u f f i c i e n t f o r c a r r y i n g out the a n a l y s i s . the average  Such procedures g i v e i n f o r m a t i o n on  t a b l e t assay or mean potency o f a batch of t a b l e t s .  8. They g i v e no i n f o r m a t i o n on the i n d i v i d u a l t a b l e t s .  F o r ex-  ample, to take an extreme case, i f h a l f of the t a b l e t s were $0%, h i g h i n potency and h a l f 50% low, ple would s t i l l Train ( 6 2 ) ,  assay s a t i s f a c t o r i l y .  tested  the composite  sam-  As p o i n t e d out by  i t i s the content of each and every dosage form  which i s of prime importance  and not the mean content of a  l a r g e number of these dosage forms. Content u n i f o r m i t y has been i n v e s t i g a t e d by Moskalyk, al.  (1+5),  Garrett  et  ( 1 6 ) , E v e r s ( l 5 ) » and Smith, et a l . , ( 5 7 ) .  Suggestions were a l s o made by the Pharmaceutical Manufacturers A s s o c i a t i o n and others to change from the present sample assay to an i n d i v i d u a l t a b l e t assay ( l j . , 5 2 ) .  One  drawback to the  l a t t e r , of course, i s the l a r g e number of assays which would be r e q u i r e d and a l s o the l a c k of s u i t a b l e assay methods. Smith, et a l . ,  ( 5 7 ) attempted  to d e f i n e the nature of the  d i s t r i b u t i o n of dosage v a r i a t i o n i n commercially compressed t a b l e t s . over 9 9 $ conformed  available  Of the 2 1 9 8 t a b l e t s i n d i v i d u a l l y to the then accepted composite  10% and a l l t a b l e t s conformed  assayed,  l i m i t of +  to the wider l i m i t s of + 1S%>  which were suggested by the Committee on I n t e r - T a b l e t Dosage V a r i a t i o n of the Pharmaceutical Manufacturers A s s o c i a t i o n ( 5 2 ) . In Smith's r e p o r t , the average assays were v e r y c l o s e to l a b e l c l a i m , the standard d e v i a t i o n s were small, of l a b e l c l a i m , and the curves o b t a i n e d i n d i c a t e d normal d i s t r i b u t i o n .  1,1+% - 3»®%> essentially  Examination of the data i n d i c a t e d a  r e l a t i o n s h i p between standard d e v i a t i o n and percent  active  ingredient  i n the t a b l e t .  As the percent a c t i v e  ingredient  increased,  the v a r i a t i o n i n i n d i v i d u a l assays decreased.  c o r r e l a t i o n a l s o e x i s t e d between the t a b l e t weight assay f o r ten of the twelve l o t s i n v e s t i g a t e d . t i o n c o e f f i c i e n t s v a r i e d between 0.2  and  The  and 0.5»  e x i s t i n g i n the author's p l a n t  - Merck, Sharp  excellent procedures  and Dohme L t d .  On the o t h e r hand, of the twelve products s t u d i e d Moskalyk, formity  et a l . , (k5),  four f a i l e d  of t a b l e t weight.  those o b t a i n e d b,y Evers that  Moskalyk,  t h e i r r e s u l t s i-jith et a l . ,  observed  the v a r i a t i o n i n assay f o r the l a r g e r t a b l e t s was  l e s s than f o r the s m a l l e r that  by  the U.S.P. t e s t f o r u n i -  In comparing  (15),  tablets.  than could  within  as a r u l e ,  be apparent from the v a r i a t i o n i n i n d i v i -  d u a l t a b l e t weight. age v a r i a t i o n was  also  However, they concluded  the a c t u a l v a r i a b i l i t y of drug dosage was,  greater  tablet  correla-  These  r e s u l t s were a t t r i b u t e d to the good q u a l i t y c o n t r o l  A  These authors a l s o r e p o r t e d  greatest  i n the l i g h t e s t weight  that  the dos-  tablets  a batch.  These r e s u l t s are to be expected s i n c e  one of the main  f a c t o r s a f f e c t i n g the u n i f o r m i t y  of a mixture i s the r e l a t i v e  p r o p o r t i o n s of the i n g r e d i e n t s .  The  i n c r e a s i n g l y more d i f f i c u l t relative  as the p r o p o r t i o n  to another decreases.  r e l a t i v e l y small those which  proportion  contain  task of m i x i n g becomes of one  Since t a b l e t s c o n t a i n i n g  of a c t i v e i n g r e d i e n t  indicated.  a  are u s u a l l y  a very potent drug, the need f o r more  e f f e c t i v e c o n t r o l over dosage v a r i a b i l i t y i n t a b l e t s certainly  ingredient  was  10. D a t a , p r e s e n t e d to the Committee on I n t e r - T a b l e t Dosage Variation  o f the Q u a l i t y  C o n t r o l S e c t i o n o f the P h a r m a c e u t i c a l  Manufacturers A s s o c i a t i o n  (53),  on hZ U.S.P. and 28 N . P .  s i n g l e drug component t a b l e t s demonstrated a c h i e v a b i l i t y o f 85% - 115%  o f the p u r i t y r u b r i c mean t o l e r a n c e .  i n g , t h e committee  A t t h i s meet-  recommended t h a t the compendia c o n s i d e r  e x t e n d i n g the d r u g c o n t e n t u n i f o r m i t y  test  (now a p p l y i n g t o  e i g h t U.S.P. and s i x N . P . s i n g l e drug component t a b l e t s ) t o a l l U.S.P. and N . P . s i n g l e drug component t a b l e t s f o r which a b l e i n d i v i d u a l t a b l e t assay methods are a v a i l a b l e . multiple  suit-  Some  drug component t a b l e t s were a l s o r e p o r t e d t o have  passed the t e s t .  These a r e : A.P.C. T a b l e t s N . F . , T r i s u l f a -  p y r i m i d i n e s T a b l e t s U.S.P., H e x a v i t a m i n t a b l e t s N . P . , and Sulfacetamide-Sulfadiazine-Sulfamerazine.Tablets N . F . As a r e s u l t o f the recommendations o f t h e P h a r m a c e u t i c a l Manufacturers A s s o c i a t i o n XII  and p r e v i o u s s t u d i e s c i t e d , t h e N . F .  (ij.8) has adopted, f o r a s e l e c t e d  group o f t a b l e t s , a t e s t  f o r composition v a r i a t i o n or content u n i f o r m i t y sed t a b l e t s .  (Appendix A').  f o r compres-  E s s e n t i a l l y t h i s test allows f o r  t e n t a b l e t s o f an i n i t i a l sample o f t h i r t y t a b l e t s t o be assayed i n d i v i d u a l l y as d i r e c t e d .  The r e q u i r e m e n t s o f the  t e s t are f u l f i l l e d i f a l l t e n r e s u l t s f a l l w i t h i n of 85% t o 115%  o f the l a b e l e d potency.  the l i m i t s  However, i f one r e s u l t  f a l l s o u t s i d e these l i m i t s , then the r e m a i n i n g twenty are  i n d i v i d u a l l y assayed.  tablets  The r e q u i r e m e n t s a r e met i f n o t  more than one o f t h e t h i r t y t a b l e t s i s o u t s i d e the l i m i t s o f 85% - 115%  of l a b e l  claim.  11. The  Q u a l i t y C o n t r o l S e c t i o n of the Pharmaceutical  f a c t u r e r s A s s o c i a t i o n (53)  i n September 1965  Manu-  noted t h a t :  "As drug content u n i f o r m i t y t o l e r a n c e requirements  begin to  be i n c l u d e d i n the monographs of an expanding number of o f f i c i a l t a b l e t s , i t i s a n t i c i p a t e d t h a t the weight t o l e r a n c e requirement  t e s t f o r such t a b l e t s w i l l become s u p e r f l u o u s  and w i l l probably be d e l e t e d . " At t h i s time, Dr. E. G. Peldman, D i r e c t o r of R e v i s i o n of the N a t i o n a l Formulary  and Dr. L. C. M i l l e r , D i r e c t o r of Phar-  macopeal R e v i s i o n f o r the U n i t e d States Pharmacopeia - a l s o commented about the prospect t h a t the weight v a r i a t i o n  test  would be d e l e t e d where content v a r i a t i o n i s s p e c i f i e d .  Dr.  M i l l e r a l s o commented on the economic aspects of m u l t i p l e assays and the need f o r time-saving methods which might serve adjuncts to the assay methods now (d) S t a t i s t i c a l The  as  specified i n the compendia.  tests.  e f f i c i e n c y of any  s t a t i s t i c a l t e s t may  be  determined  by i t s a b i l i t y to d i f f e r e n t i a t e between good batches  which  should be accepted and bad batches which should be r e j e c t e d . Such t e s t s should have a h i g h p r o b a b i l i t y of a c c e p t i n g the s a t i s f a c t o r y batches unsatisfactory  and  a low p r o b a b i l i t y of a c c e p t i n g the  batches.  Dunnett and C r i s a f i o  (11)  d e r i v e d the  Operating-Character-  i s t i c Curves f o r the o f f i c i a l  t a b l e t weight v a r i a t i o n  u s i n g sample s i z e s - o f 10,  50  i s r e p r e s e n t e d i n Table I .  20,  and 100  They found  tablets.  test  T h i s data  that t h e r e i s an i n -  creased tendency to pass a batch i f the sample s i z e i s  12A  TABLE I .  The E f f e c t of Increased Sample S i z e on A c c e p t a b i l i t y of Lots of Compressed T a b l e t s ,  Lots  Accepted  $ Defective $%  20%  10  93$  1+0$  20  95  23  50  98  ij.  100  99  0  No of T a b l e t s  See Reference  (50).  12. i s low (5$ or l e s s ) .  i n c r e a s e d and the percentage d e f e c t i v e s  On the other hand, an i n c r e a s e i n sample s i z e w i l l r e s u l t i n a decreased tendency of d e f e c t i v e s  to pass batches w i t h a h i g h percentage  (say of the order of 20%).  I n other words,  an i n c r e a s e i n sample s i z e has the e f f e c t o f c o n s i d e r a b l y d e c r e a s i n g the p r o b a b i l i t y o f a non-uniform batch of t a b l e t s being accepted and s l i g h t l y i n c r e a s i n g a highly  uniform b a t c h p a s s i n g the t e s t  From t h i s they suggested that  the p r o b a b i l i t y o f (50).  a two sample weight  t i o n t e s t i s more v a l i d , s t a t i s t i c a l l y , sample t e s t i n which twenty t a b l e t s  than the present one  are weighed i n d i v i d u a l l y  and the a l l o w a b l e l i m i t s depend on the average In t h e i r t e s t , $0 t a b l e t s calculated.  varia-  tablet  weight.  are weighed and the mean weight  Twenty t a b l e t s  are examined, as i n the o f f i c i a l  t e s t , and the b a t c h accepted i f not more than one t a b l e t deviates  from the mean by + 5 $ .  I f more than one t a b l e t d e v i a -  tes from the mean by g r e a t e r than + 5$ then the other 30 tablets  are examined.  The batch i s then accepted i f not more  than f i v e t a b l e t s d e v i a t e from the mean by + 5$ and no t a b l e t d e v i a t e s by more than + 1 0 $ . Grundman and Ecanow (18)  suggested a " t a b l e t  by a double sampling p l a n " i n which they t e s t e d  acceptance 50 t a b l e t s and  accepted the batch i f a l l the t a b l e t s passed the t e s t . all  tablets  tablets  If  d i d not pass the t e s t , they examined 100 more  and accepted the b a t c h i f not more than two  of the 150 t a b l e t s f a i l e d the t e s t .  tablets  13. Brunning  and King  (4.) u t i l i z e d o p e r a t i n g c h a r a c t e r i s t i c  curves i n t h e i r examination pharmaceuticals.  o f an acceptance  sampling p l a n f o r  They employed the p l a n used by the U.S. Array -  MIL-STD-ip.ii which c a l l s f o r the establishment of f o u r b a s i c standards  (4.2): 1. A.Q.L.- An acceptable q u a l i t y l e v e l . A l e v e l o f 10% means that the l o t i s s a t i s f a c t o r y i f i t contains only 10% defectives. 2. U.Q.L.- An unacceptable q u a l i t y l e v e l . A l e v e l o f 4.0% means t h a t the l o t i s unacceptable i f i t c o n t a i n s more than 4.0% defectives. 3. Rp - Producer's r i s k . T h i s i s the r i s k i n v o l v e d i n m i s c l a s s i f y i n g an acceptable lot. 4.. R - Consumer's r i s k . T h i s i s the r i s k i n v o l v e d i n m i s c l a s s i f y i n g an unacceptable l o t . c  Once the values o f these f o u r standards have been decided upon, the corresponding sampling p l a n and hence the sample s i z e i s automatically  determined.  I f the A.Q.L. and U.Q.L. are q u i t e f a r apart and a h i g h r i s k o f m i s c l a s s i f i c a t i o n can be t o l e r a t e d , as might w e l l be the case w i t h sodium c h l o r i d e t a b l e t s , the p l a n w i l l v e r y few u n i t s i n the sample.  call for  I f the A.Q.L. and U.Q.L. are  close together and a very s m a l l r i s k o f m i s c l a s s i f i c a t i o n must be maintained,  as i n the case of the potent s t e r o i d s , a l a r g e  sample w i l l n o r m a l l y be r e q u i r e d . Using the f o u r c h a r a c t e r i s t i c standards upon the c o r r e s ponding  sampling p l a n , - O.C. curves, sample s i z e and accept-  a b i l i t y c r i t e r i a - may be o b t a i n e d from t a b l e t s of the  111.  MIL-STD-I4.II4. (1+2).  The t a b l e t s i n the sample are assayed  i n d i v i d u a l l y and the percent percent  d e f e c t i v e s determined.  I f the  d e f e c t i v e s do not exceed the s t a t e d c r i t e r i a ,  then  the l o t i s accepted. In comparing t h i s v a r i a b l e p l a n to a two-step a t t r i b u t e plan, such as i s now i n the U.S.P. and N . F . f o r assay v a r i a t i o n , i t was found t h a t the v a r i a b l e p l a n was s u p e r i o r f o r d e t e c t i n g cases o f e x c e s s i v e  v a r i a t i o n and f o r e x c e s s i v e  bined w i t h a s h i f t  i n mean.  cases o f mean s h i f t  only.  The two p l a n s  time while  accept  are about equal f o r  F o r example, i t was found that f o r  the U.S.P. p l a n , which cannot detect tions, w i l l  v a r i a t i o n com-  t a b l e t to t a b l e t v a r i a -  a sample w i t h 1+0% d e f e c t i v e s 9l+%> of the  the s t a t i s t i c a l p l a n w i l l  accept  t h i s same sample  only 8% o f the time.  In-Vitro  Testing  (a) D i s i n t e g r a t i o n t e s t s . If  compressed t a b l e t s are expected to provide e f f e c t i v e  m e d i c a t i o n , i t i s obvious that the t a b l e t must d i s s o l v e or d i s i n t e g r a t e w i t h i n a reasonable time.  This f a c t was  n i s e d , s t u d i e d and d i s c u s s e d ,  but o f f i c i a l  exist u n t i l  times.  relatively  recent  recog-  standards d i d n o t  The l a c k o f t e s t i n g  procedures was due, i n l a r g e p a r t , to an i n a b i l i t y  to stand-  a r d i z e methodology and to the v a r i a t i o n s w i t h i n the dosage forms being  examined.  ( i ) Methods and Apparatus Many methods have r e c e n t l y been developed f o r the  15. study of t a b l e t d i s i n t e g r a t i o n though they vary i n the complexity of the apparatus, l i q u i d medium used, ture, a g i t a t i o n and i n d i c a t e d end p o i n t . i s e i t h e r room temperature ture  (37°C).  temperature  Elliot  (12)  The  tempera-  temperature  (22°G - 25°C) or body  tempera-  found t h a t t h i s d i f f e r e n c e , a  i n c r e a s e of 10°C  to 15°G,  accounted f o r a two-  f o l d i n c r e a s e i n the s o l u t i o n r a t e of t a b l e t s . The  simplest apparatus f o r measuring  t i o n time of compressed  the d i s i n t e g r a (69).  t a b l e t s i s a g l a s s of water  Another method, suggested by Trunkel i n 1931  and recom-  mended f o r the r e t a i l pharmacist, u t i l i z e s an apparatus made by c o v e r i n g a small beaker with a screen, p l a c i n g t h i s i n a l a r g e r beaker, and then adding water to cover the screen to a h e i g h t of one c e n t i m e t e r .  The t a b l e t s are  p l a c e d on the screen and the time r e q u i r e d f o r the d i s i n t e g r a t e d t a b l e t to pass through the mesh i s no ted. -«--::Methods w i t h d e f i n i t e end p o i n t s i n c l u d e that p r o posed by Foote i n 1928  i n which a p l a t e i s supported by  the t a b l e t , the p l a t e s i n k i n g to r i n g a b e l l by contact.  Brown i n 1939  suggested the b r e a k i n g of a t a b l e t ,  both i n a i r and i n water, arm of a balance.  electrical  i n a s t i r r u p a t t a c h e d to one  B e r r y i n 19kh  suggested that the  p o i n t be determined by dropping a 20 Gm.  end  weight a t t a c h e d  to a wire loop as i t cuts through the t a b l e t .  The m a t e r i a l i n t h i s paragraph and the next two paragraphs was drawn from r e f e r e n c e ( 5 5 ) .  16. S e v e r a l methods have been used to simulate p e r i s t a l t i c movement.  An e a r l y method put foreward by Lewis i n  1901+ c o n s i s t e d of h o l d i n g the t a b l e t w i t h a wire  spiral  on m u s l i n s t r e t c h e d over a f u n n e l and a l l o w i n g water to drop on the t a b l e t . was  One  of the e a r l i e s t methods which  developed and l a t e r adopted by the B.P.  i n 191+5  con-  s i s t e d of r o t a t i n g the t a b l e t s i n t e s t tubes of l i q u i d . T h i s method was  c r i t i c i z e d by Hoyle f o r having an  n i t e end p o i n t because  indefi-  the cloudy s o l u t i o n obscures the  f i n a l d i s i n t e g r a t i o n of the t a b l e t c e n t e r . The passage  of d i s i n t e g r a t e d t a b l e t s through a wire  screen i m p l i e s a d e f i n i t e end p o i n t and t h i s technique, coupled to some form of movement of the t a b l e t i n the t e s t f l u i d s , has been u t i l i z e d  i n s e v e r a l p u b l i s h e d methods.  In most of these, the wire screen c o n s t i t u t e s the bottom of a basket h a v i n g g l a s s or screen s i d e s . Kay  Evanson and  De-  (ll4.,i|8) i n t r o d u c e d a r o l l i n g d r u m . i n t o ' t h e i r apparatus,  which they c l a i m p r o v i d e s a r o l l i n g wavelike a c t i o n on the t a b l e t s i m i l a r to that of stomach c o n t r a c t i o n s .  This  method was more reproducable than the Gershberg and  Stoll  method (17),  i n which tubes w i t h mesh bottoms were moved  up and down i n simulated g a s t r o - i n t e s t i n a l  juices.  The  l a t t e r method was used i n the e a r l y f o r t i e s f o r t e s t i n g t a b l e t s s u p p l i e d to the U.S.  Army (55).  The  Gershberg-  S t o l l method was m o d i f i e d and l a t e r accepted as i n the U n i t e d S t a t e s and Canada.  official  However, no r e a l  was made to reproduce p h y s i o l o g i c a l  attempt  c o n d i t i o n s i n these t e s t s .  17. (ii)  Official Official  opted  Standards standards  for  tablet  first  in  Sx^itzerland,  Pharmacopea  of  1933  (unless  intended  disintegrate in  water  at  to  test:  100  cold  of  37°G  and  lets  must  end on  of  test The  be  tubes  slowly  The  or  French  tablets* were The  completely  B.P.  i n water,  must  a bath  dissolve  utes  with  exceptions  as  more  than  one  five  is  repeated. The  N.F.,  the  No  tablet  disintegration  and  in  ing  of  six  tom  on  a  ments  of  are  ten  mesh  given  change  in  A  detailed  more  Appendix  end  test  for  the  test can  description  test,  the  case  five  in  fail for  the  the  tablets  which  steel  in  apparatus affect this  test,  the  impinge  If the  test (55).  consist-  at  a  the  is  bot-  measureslight  disintegration apparatus  not  U.S.P.,  Exact  because  test  min-  time  assembly  screen.  a  15  within  second  the  used.  monographs. the  tab-  separate  37°C were  fail  at  at  this at  with  a bath  dissolved  disintegrate  of  in  in  held  the  flask  required  tubes  stainless  or  a  also  a basket-rack  glass  the  use  minutes  required  placed  pass  Swiss  must  1953  tablets  must  specifications  B.  or  1$  in  ad-  internal  mouth)  1937  placed  The  of  stated  Canada u s e s  open  but  the  of  f l a s k was To  for  within  disintegrated  The  in  in  Oodex  were  England.  tablets  dissolve  frequently.  rotating  tablets  dissolve  powder  minutes.  and  that  water.  tablets  Prance  required  Five  agitated  ten  five  a  37°C.  following ml  to  disintegration  times.  given  in  18. Tablets to be tested are placed in each, of the six glass tubes and the apparatus assembled with plungers and discs over the tablets.  The whole basket rack assembly  is then raised and lowered through an 8 cm stroke, 30 times per minute, in a suitable liquid bath at 37°C. At the  end of the prescribed time, as is specified in the in-  dividual tablet monographs or in Canada in the F and D Regulations (Appendix B)j the  basket is inspected.  The tab-  lets are considered to be completely disintegrated i f no residue remains on the screen bottom.  If more than two  tablets f a i l to disintegrate, 12 more tablets must be tested.  Of the 18 tablets then tested, 15 must have dis-  integrated within the given period of time. Surveys by Murphey (ij.6) in 1954a  n  d  Nuppenau (ij.9) in  1961)., comparing the requirements for disintegration of tablets in the various world pharmacopeias,shows the leniency of the U.S.P. standards for disintegration times. The range in most pharmacopeias is between five minutes and 15 minutes.  In contrast, the U.S.P. allows disintegration  times of from 15 minutes to one or more hours. the  In Canada  limits are 30 minutes in simulated gastric fluid and  30 minutes in simulated intestinal fluid for a total time of one hour. (b) Dissolution Tests In 1902 Hance (21) defined solubility with respect to compressed tablets as the power to disintegrate rather than the power to form solutions or to dissolve.  While this definition  19.  may be t r u e f o r s o l u b l e  compounds, i t c e r t a i n l y w i l l n o t be  true f o r only s l i g h t l y soluble Today i t i s g e n e r a l l y  drugs.  r e c o g n i s e d t h a t the i n v i t r o  d i s i n t e g r a t i o n t e s t does n o t n e c e s s a r i l y  bear a r e l a t i o n s h i p  to the i n v i v o a c t i o n o f the s o l i d dosage form. p a s t few y e a r s , s e v e r a l  tablet  During the  a u t h o r s have proposed t h a t t h e s i g n i -  f i c a n t f a c t o r to consider i s not t a b l e t d i s i n t e g r a t i o n but d i s s o l u t i o n o f the drug fromthe t a b l e t . 191+8 and P a r r o t t not  necessarily  Sperandio ( 5 9 ) i n  ( 5 1 ) i n 1 9 5 5 r e a l i z e d that d i s i n t e g r a t i o n d i d mean t h a t the d r u g had d i s s o l v e d ,  the t a b l e t i s  merely broken up i n t o s m a l l e r p a r t i c l e s . W h i l e the d i s i n t e g r a t i o n drug r e l e a s e  time does i n f l u e n c e  the r a t e of  t o the body, the most i m p o r t a n t aspect i s the  rate of release  from t h e p r i m a r y drug p a r t i c l e .  T h i s i s nec-  e s s a r y because i t i s a c c e p t e d t h a t s o l u t i o n o f the drug i s e s s e n t i a l i f absorption i s to take p l a c e .  More r e c e n t l y ,  and Hayes ( 3 D , and Yen (72) have reminded r e s e a r c h e r s d i s i n t e g r a t i o n does n o t i n i t s e l f i m p l y d i s s o l u t i o n .  Levy  that However,  r e g a r d l e s s o f t h e l a c k o f a s i g n i f i c a n t 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 t h e t a b l e t ' s i n v i v o  a c t i v i t y , the test  s t i l l p r o v i d e s a means o f c o n t r o l i n a s s u r i n g t h a t a g i v e n t a b l e t f o r m u l a t i o n i s the same from b a t c h t o b a t c h , w i t h r e g a r d to  disintegration. There i s a m i s t a k e n b e l i e f among many t h a t  the a c t i v e  con-  s t i t u e n t as a c h e m i c a l e n t i t y i s t h e s o l e b a s i s f o r t h e pharmacological effectiveness the  of a pharmaceutical product.  However,  c h o i c e o f dosage form and o f brand can be j u s t as i m p o r t a n t  20. as the c h o i c e o f the a c t u a l t h e r a p e u t i c agent.  In general,  d i f f e r e n c e s i n t h e r a p e u t i c e f f i c a c y between g e n e r i c a l l y i d e n t i c a l drug products, or contamination,  while  sometimes caused by i n s t a b i l i t y  are most f r e q u e n t l y due t o d i f f e r e n c e s i n  the r a t e a t w h i c h the a c t i v e i n g r e d i e n t o r i n g r e d i e n t s become available f o r absorption The  (35).  f i r s t r e l a t i o n s h i p between i n v i t r o t a b l e t d i s i n t e g r a -  t i o n and i n v i v o drug a v a i l a b i l i t y were e s t a b l i s h e d by the Pood and Drug D i r e c t o r a t e i n Ottawa.  Chapman, e t a l ( 8 , 9 ) i n  195i+-1956> u s i n g r i b o f l a v i n and p-amino s a l i c y l i c a c i d i n s e p a r a t e s t u d i e s , d i d show t h a t t h e a v a i l a b i l i t y o f the drug for  a b s o r p t i o n was p r e d i c t a b l e from d i s i n t e g r a t i o n times d e t e r -  mined by t h e U.S.P. t e s t . these r e s e a r c h e r s  According  t o S o h r o e t e r , e t a l (51+)»  were t h e f i r s t t o determine r a t e s o f d i s s o -  l u t i o n a t t h e same time t h a t t h e d i s i n t e g r a t i o n time was b e i n g determined. D i s s o l u t i o n s t u d i e s were n o t again emphasized u n t i l i t became apparent t h a t c e r t a i n t a b l e t s , a l t h o u g h complying w i t h d i s i n t e g r a t i o n r e q u i r e m e n t s , f a i l e d t o demonstrate any^ t h e r a peutic effects.  Around I960, papers began t o appear i n t h e  l i t e r a t u r e i n d i c a t i n g t h a t a d j u v a n t s p l a y e d an i m p o r t a n t r o l e i n the t h e r a p e u t i c  e f f e c t i v e n e s s o f the t a b l e t .  L e v y and N e l s o n ,  ( 3 5 ) , Delgado and Cosgrove (10), Wagner (67) and G w i l t , e t a l . , (19) d i s c u s s e d many aspects o f b i o p h a r m a c e u t i c s and i n d i c a t e d t h a t added substances can have a pronounced e f f e c t on the i n v i v o a v a i l a b i l i t y o f drugs such as t e t r a c y c l i n e , t o l b u t a m i d e and  dicoumarol.  21. Parrot,  e t a l . , (51.) f o u n d t h a t  the d i s s o l u t i o n rate of  b e n z o i c a c i d was d e c r e a s e d when v a r i o u s c o n c e n t r a t i o n s o f sodium c h l o r i d e , the  sodium s u l f a t e  d i s s o l v i n g medium.  a n d d e x t r o s e w e r e added t o  S o d i u m s u l f a t e was m o s t e f f e c t i v e i n  decreasing the dissolution rate. additive,  When u r e a was u s e d a s a n  an i n c r e a s e i n t h e d i s s o l u t i o n  rate  resulted.  L e v y and H a y e s ( 3 1 ) , w o r k i n g w i t h f i v e d i f f e r e n t cially  available  Acetylsalicylic  Acid  commer-  t a b l e t s found that the  i n v i t r o d i s i n t e g r a t i o n t i m e s f o r these t a b l e t s , which i s often  alluded  t o a s an i n d e x o f t h e r a t e  comes a v a i l a b l e i t y or rate  for absorption,  of solution.  products exhibited  i s no c r i t e r i a f o r  In fact  I t was a l s o  the  Hall  of absorption or to  and N e l s o n  good c l i n i c a l istered.  (30) i n v e s t i g a t e d  independently,  prednisone  A patient  showed  r e s p o n s e when one b r a n d o f p r e d n i s o n e was a d m i n -  F o r unknown r e a s o n s , t h e b r a n d was c h a n g e d a n d t h e  symptoms r e a p p e a r e d . r e s p o n s e was g o o d .  tested  subjects.  Campagna, e t a l . , ( 6 ) , t o g e t h e r w i t h L e v y ,  t a b l e t s v f o i c h w e r e r e p o r t e d t o be i n a c t i v e .  the  disintegration  b i o l o g i c a l a v a i l a b i l i t y o f t h e d r u g i n human More r e c e n t l y ,  dissolving  times than the slower  shown t h a t  t i m e s h a d no r e l a t i o n w h a t s o e v e r t o r a t e  drug be-  availabil-  t h e most r a p i d l y  longer disintegration  dissolving products.  a t whichtiie  When t h e o r i g i n a l b r a n d was a g a i n u s e d , These i n a c t i v e p r e d n i s o n e t a b l e t s  against the a c t i v e  ones a n d i t was f o u n d t h a t  were  the e f f e c t -  r e l e a s e d 50% o f i t s c o n t e n t s 2 0 t i m e s a s r a p i d l y a s  ive  tablets  the  c l i n i c a l l y i n e f f e c t i v e ones.  The o f f i c i a l  disintegration  22. time i n both cases were l e s s than s i x minutes as shown i n Table I I . Wagner (67)  r e p o r t s t h a t the n a t u r e and  b i o l o g i c a l response to a drug i s o f t e n  i n t e n s i t y of  thought to be due  to the i n h e r e n t a c t i v i t y of the m o l e c u l a r s t r u c t u r e pound.  Many f a c t o r s  contribute  a only  o f the  com-  to t h i s r e s p o n s e : the d r u g i t -  s e l 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 , dosage forms,  formulation,  method of manufacture, a b s o r p t i o n and  These same  excretion.  f a c t o r s , as r e p o r t e d by S c h r o e t e r , et a l . , (5U-) whether a c o r r e l a t i o n e x i s t s between i n v i t r o d i s s o l u t i o n and uently,  i n vivo  i t i s possible  t i o n but  a v a i l a b i l i t y and  will  determine  disintegration-  absorption.  to c o r r e l a t e d i s s o l u t i o n and  Conseqdisintegra-  t h i s must be done f o r each p r o d u c t s e p a r a t e l y i n o r d e r  to be m e a n i n g f u l .  At some s t a g e , i n v i v o  i n o r d e r to complete the  correlation.  s t u d i e s must be  I f t h i s i s done  there i s a good 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  done  and  dissolution  a v a i l a b i l i t y , then the d i s i n t e g r a t i o n t e s t can be  used  r o u t i n e l y and would more o r l e s s i m p l y d i s s o l u t i o n and  avail-  a b i l i t y f o r a p a r t i c u l a r product. On cal  the b a s i s  of these and  Manufacturers' Association  investigate  (53)  Pharmaceuti-  a p p o i n t e d a committee to  investigations  of about 70 p r o d u c t s , i t  found t h a t of those p r o d u c t s c o n t a i n i n g  ities  the  the problem o f d i s s o l u t i o n of drugs from t a b l e t s .  D u r i n g the p r e l i m i n a r y was  other reports,  drugs w i t h  solubil-  of 1% or more, i n almost every c a s e , a l l of the drug  i n s o l u t i o n when d i s i n t e g r a t i o n was hand, t a b l e t s c o n t a i n i n g  completed.  On  drugswhose s o l u b i l i t y was  the less  was  other than  22A  TABLE I I .  D i s i n t e g r a t i o n Times and A v a i l a b i l i t y of Prednisone from C l i n i c a l l y A c t i v e and I n a c t i v e T a b l e t s  Prednisone Tablets  Disintegration Time (Minutes ) Disks  Active  <6  Inactive *  <6  I n a c t i v e -:B  See Reference •SH:- See Reference  2.5  (30). (6).  No Disks  Average Tims F o r 50% o f the Drug to D i s s o l v e (Minutes)  J+.3 +  1.3  60 - 120  100 *  53  180  173 +  37  23. 1%, d i s s o l v e d  i n most i n s t a n c e s ,  w i t h i n one hour a f t e r the d i s -  i n t e g r a t i o n end p o i n t . I n A p r i l 1963,  the committee suggested t h a t t h e U.S.P.  d i s i n t e g r a t i o n t e s t was o n l y u s e f u l as a t o o l t o c o n t r o l to b a t c h u n i f o r m i t y  o f t a b l e t s and t o keep c o m p l e t e l y  f a c t o r y p r o d u c t s o f f the market.  batch  unsatis-  Much concern was a l s o ex-  p r e s s e d about t h e need f o r o b t a i n i n g  b l o o d l e v e l d a t a t o com-  pare w i t h any proposed d i s s o l u t i o n t e s t d a t a i f such a t e s t i s to be i n d i c a t i v e o f drug a v a i l a b i l i t y . ( i ) Methods and Apparatus The  p r i n c i p l e involved  i n d i s s o l u t i o n studies  same r e g a r d l e s s o f t h e apparatus u s e d .  i s the  E s s e n t i a l l y the  t a b l e t s a r e p l a c e d i n a s u i t a b l e l i q u i d such as w a t e r , simu l a t e d g a s t r i c o r i n t e s t i n a l f l u i d , and a g i t a t e d .  Aliquots  of the l i q u i d a r e t h e n removed, a t v a r y i n g time i n t e r v a l s , for  analysis. I t i s generally  f e l t t h a t any p r o c e d u r e f o r i n v i t r o  t e s t s s h o u l d employ some d e v i c e f o r a g i t a t i n g t h e e l u a n t and  p r o d u c t a t a f i x e d speed.  Since the G e r s h b e r g - S t o l l  apparatus i s the o n l y o f f i c i a l l y r e c o g n i z e d t a b l e t  test  apparatus on t h i s c o n t i n e n t , i t has been w i d e l y u s e d w i t h various modifications.  T h i s i s e s s e n t i a l l y the same app-  a r a t u s d e s c r i b e d i n t h e U.S.P. and by the Canadian Pood and Drug D i r e c t o r a t e  f o rdisintegration studies.  apparatus has been a s t a r t i n g p o i n t f o r many because i t s b a s i c  This  investigators  parts consist o f : a mechanical device  21+. f o r a g i t a t i n g which may i m i t a t e a t h e r m o s t a t i c arrangement  t h e p e r i s t a l t i c movements,  so t h a t body temperature can be  m a i n t a i n e d , an immersion f l u i d such as s i m u l a t e d g a s t r i c and i n t e s t i n a l j u i c e and a s c r e e n t o s u p p o r t t h e t a b l e t s under i n v e s t i g a t i o n u n t i l they have d i s i n t e g r a t e d l e a s e d the a c t i v e  or r e -  substance.  A more d e t a i l e d d e s c r i p t i o n o f t h i s apparatus may be found i n Appendix B.  The main advantage o f the apparatus i s t h a t  d i s i n t e g r a t i o n times as w e l l as d i s s o l u t i o n r a t e s may be o b s e r v e d a t t h e same time on the same t a b l e t s .  Schroeter,  e t a l . , (51+) and M i d d l e t o n , e t a l . , (kO) used the U.S. P. apparatus i n t h e i r i n v e s t i g a t i o n s  on d i s s o l u t i o n r a t e s o f  drugs i n t a b l e t s . I n h i s study on A c e t y l s a l i c y l i c A c i d  t a b l e t s , Levy (31)  used a kOO m l . b e a k e r , 0.1N HC1, a temperature o f  37°C,  and  a c o n t r o l l e d speed s t i r r e r s e t a t 59 r.p.m. w h i c h was f a s t enough f o r homogenous m i x i n g b u t slow enough t o keep s o l i d p a r t i c l e s a t the bottom. f i e d version  Nash and Marcus (4.7) used a modi-  c o n s i s t i n g o f a 600 ml. Buchner type f u n n e l  w i t h a medium p o r o s i t y  f r i t t e d d i s k w h i c h was f i t t e d  into  a 500 m l . s u c t i o n f l a s k w i t h a s t o p c o c k a t t h e bottom. The sample i s p l a c e d i n t h e f u n n e l w i t h kOO m l . of s i m u l a t e d g a s t r i c f l u i d and g e n t l y  agitated  f i x e d i n t e r v a l s , 200 m l . p o r t i o n s for analysis  by a s t i r r e r .  At  o f f l u i d are drawn o f f  and 200 m l . o f f r e s h media added t o the f u n n e l .  The p r o c e s s i s r e p e a t e d f o r t h e d e s i r e d  time i n t e r v a l .  In  25. b o t h c a s e s the r a t e of s t i r r i n g i n f l u e n c e s the r a t e of d i s s o l u t i o n o f the drug from the t a b l e t s . Another method, suggested by W i l e y ( 6 8 ) , c o n s i s t e d of  a s t o p p e r e d c y l i n d r i c a l tube w i t h a g l a s s wool  filter  above the bottom o u t l e t and a s i d e arm f o r r e t u r n of to  a reservoir.  A pump was  employed t o c i r c u l a t e  fluid  the  f l u i d from the r e s e r v o i r t o the tube at a f i x e d r a t e . sample i s f i r s t  e l u t e d f o r one hour w i t h 100 m l . of s i m u l -  ated g a s t r i c f l u i d a t 37°G. ml. of f l u i d  The  At the end of t h i s t i m e , 50  are removed and r e p l a c e d w i t h 50 m l . o f sim-  ulated intestinal f l u i d . hour f o r e i g h t h o u r s .  The procedure i s r e p e a t e d every  T h i s method was  r e j e c t e d as b e i n g  too s l o w , cumbersome and complex and t h e r e f o r e , u n s u i t a b l e for  routine  investigations.  The method d e v e l o p e d i n 1958  by Souder and E l l e n b o g e n  (58) t o determine the r e l e a s e r a t e o f s u s t a i n e d r e l e a s e g r a n u l e s c o n t a i n e d i n c a p s u l e s c o n s i s t s o f b o t t l e s (90 ml. c a p a c i t y ) f a s t e n e d at t h e i r mid p o i n t t o a h o r i z o n t a l a x i s i n a w a t e r b a t h at 3 7 ° C  Samples are p l a c e d i n the b o t t l e s ,  60 m l . of f l u i d added and the b o t t l e s r o t a t e d (end over at I4.O r.p.m. ).  The b o t t l e s are removed a t f i x e d  and the c o n t e n t s f i l t e r e d i m m e d i a t e l y .  intervals  E i t h e r the washed  r e s i d u e o r the f i l t r a t e i s a s s a y e d . The l i m i t a t i o n s of t h i s method are o b v i o u s : 1.  end  The c o n t e n t s of the b o t t l e s must be f i l t e r e d i m m e d i a t e l y upon t h e i r r e moval from the a p p a r a t u s .  2.  The small s i z e - of the b o t t l e s l i m i t s i t s use, e s p e c i a l l y i n the case of s p a r i n g l y s o l u b l e drugs.  3.  The c e n t r i f u g a l f o r c e tends to press the s o l i d s against the bottom of the b o t t l e s a l l o w i n g f o r l i t t l e or no mechanical erosion.  However, t h i s method has been s u c c e s s f u l l y adapted by Smith K l i n e and F r e n c h l.-A.C. (Inter-American C o r p o r a t i o n ) f o r t h e i r spansules and  i s e x t e n s i v e l y used as a c o n t r o l t o o l .  They, however, c l a i m that t h i s apparatus cannot be used to judge other products u n l e s s between t h i s d a t a and Vliet ods  and  (65)  i s a definite correlation  i n v i v o r e s u l t s or c l i n i c a l response.  compared the U.S.P., S.K.F. and Wiley meth-  found that a l l methods, p r o v i d e d  t i o n s contained lease p a t t e r n s . cases.  there  that the  f r e e l y s o l u b l e drugs, produced the The  r e l e a s e was  preparasame r e -  complete i n 8 hours i n a l l  On the other hand t a b l e t s c o n t a i n i n g .sparingly s o l u -  b l e drugs gave d i f f e r e n t r e l e a s e p a t t e r n s . S.K.F. method ^ 100% U.S.P. (no  For  example:  r e l e a s e i n 8 hours  d i s k s ) - 35%-65% r e l e a s e i n 8 hours  Wiley method - 10%-50% r e l e a s e i n 8 hours In a f u r t h e r attempt to standardize ques, Simoons ( 5 6 ) , advantages and  i n 1961-62,  dissolution techni-  a f t e r c o n s i d e r i n g a l l the  disadvantages of the e x i s t i n g techniques,  de-  veloped and worked w i t h 'the r i n g apparatus as d e s c r i b e d  in  h i s book.  (K  From t h i s he  v i t r o ) f o r various  d e r i v e d i n v i t r o r a t e constants  t a b l e t s and from u r i n a r y  excretion  27. s t u d i e S j i n v i v o r a t e constants ted the two values  (K v i v o ) .  He then c o r r e l a -  and determined a r i n g constant  (R) f o r  any p a r t i c u l a r drug. R  =  K vivo K  vitro  Thus, the i n vivo behaviour f o r any p a r t i c u l a r drug could be p r e d i c t e d from i n v i t r o s t u d i e s , provided stant R was p r e v i o u s l y determined.  the r i n g con-  Wagner (67) has c r i t i -  c i z e d t h i s type of c o r r e l a t i o n c l a i m i n g that i t i s spurious and (ii)  artificial  and should  not be u-sed.  Limitations I t i s known t h a t the r e l e a s e r a t e o f a drug from a tab-  l e t depends on v a r i o u s f a c t o r s other the t a b l e t .  than those inherent i n  Such f a c t o r s as the flow o f f l u i d around the  t a b l e t and the movement o f the t a b l e t s i n the c o n t a i n e r could i n f l u e n c e the r e l e a s e r a t e .  I f these are Inadequate,  as i n the Wiley method, the r e l e a s e r a t e i s low. In the modified are s u b j e c t e d  Gershberg-Stoll  apparatus, the t a b l e t s  to up and down strokes which, together  with  the s i z e o f the mesh and weight of the t a b l e t s , determine the amount of mechanical e r o s i o n to which the t a b l e t s are subjected.  I t i s a l s o suggested that s a t u r a t i o n w i t h a i r  as a r e s u l t of the up and down strokes may cause o x i d a t i v e processes i n the substances under i n v e s t i g a t i o n .  This i n  t u r n may l e a d to i n c o r r e c t i n t e r p r e t a t i o n of the r e s u l t s e s p e c i a l l y when the assay used i s s p e c t r o p h o t o m e t r y .  Mix-  i n g and l a y e r i n g may a l s o cause s l i g h t problems w i t h t h i s method.  28. As mentioned b e f o r e , i f a s t i r r e r i s u s e d , as i n t h e L e v y method ( 3 D , the r a t e o f s t i r r i n g i n f l u e n c e s  the r a t e  of d i s s o l u t i o n .  influence  Evaporation of f l u i d could  S c h r o e t e r , e t a l . , (54.) n o t i c e d  results. excipients  also  that  although  i n t a b l e t s i n t r o d u c e d an e r r o r o f l e s s than  t h i s i s w e l l w i t h i n the e r r o r o f the U.S.P. method.  1%,  How-  e v e r l o s s of f l u i d due t o e v a p o r a t i o n o r m e c h a n i c a l l o s s was up t o 10% d u r i n g t e s t s of f o u r h o u r s o r more.  I n the  f i r s t h a l f hour t o one h o u r , 3Oml.-4.Oml. o r k%-5% of a volume of 750 m l . were l o s t . studies  However, on the b a s i s o f  done on an a s p i r i n , a s t e r o i d , and sulfonamide  t a b l e t s , t h e y c o n c l u d e d t h a t , i f the t e s t was r u n f o r l e s s than one h o u r , the e r r o r was n o t s i g n i f i c a n t . I t was a l s o suggested by Wagner t h a t when a l l t h e drug has  been r e l e a s e d  f r o m the sample, the f l u i d s h o u l d be o n l y  25% o r l e s s o f s a t u r a t i o n w i t h r e s p e c t t o the d r u g .  The  s o l u t i o n , under no c i r c u m s t a n c e s , s h o u l d be a l l o w e d t o become s a t u r a t e d the t a b l e t s .  b e f o r e a l l o f t h e drug i s r e l e a s e d  from  I f t h i s 25% o r l e s s s a t u r a t i o n l i m i t i s  m a i n t a i n e d , then the e f f e c t o f c o n c e n t r a t i o n i n t h e s o l u t i o n on the r a t e o f d i s s o l u t i o n a p p a r e n t l y i s n o t s i g n i f i cant . To d a t e , no one has come up w i t h a s a t i s f a c t o r y method o r procedure f o r d e t e r m i n i n g d i s s o l u t i o n and d i s s o l u t i o n r a t e s o f drugs from t a b l e t s which w i l l meet e x a c t l y a l l the c r i t e r i a and  s p e c i f i c a t i o n s f o r such d e t e r m i n a t i o n s .  There i s v a l i d  c r i t i c i s m o f a l l the methods d i s c u s s e d and the g e n e r a l l y a c c -  29.  epted ones are a c c e p t e d more f o r t h e i r ease of f o r any  other reason.  The  evaluation.  The  -  methods w h i c h seem t o meet almost  a l l the c r i t e r i a do take anywhere up f o r one  operation than  to e i g h t hours o r more  o n l y methods now  used by  the  industry  are the U.S.P., S K P and Levy methods. There i s a need f o r some s i m p l e method w h i c h can be r o u t i n e l y to d i s s o l u t i o n s t u d i e s .  applied  At p r e s e n t i t i s f e l t  that  d i s i n t e g r a t i o n t e s t s are not enough t o e f f e c t i v e l y e v a l u a t e s o l i d dosage form f o r i t s b i o l o g i c a l o r t h e r a p e u t i c ity.  a  availabil-  D i s s o l u t i o n s t u d i e s s h o u l d be c o r r e l a t e d w i t h i n v i v o  tests. A l l researchers purposes and,  seem to use procedures adapted t o t h e i r  on the b a s i s of t h e i r own  to advocate g e n e r a l  own  r e s u l t s , are p r e p a r e d  acceptance- of t h e i r p r o c e d u r e .  The  situa-  t i o n today i s s i m i l a r to t h a t of s e v e r a l y e a r s ago when c l a i m s were made t h a t no one evaluate  procedure would be a b l e to a d e q u a t e l y  the d i s i n t e g r a t i o n c h a r a c t e r i s t i c s of t a b l e t s .  one p r o c e d u r e , the G e r s h b e r g - S t o l l the w o r l d .  In-Vivo The  method, i s u s e d throughout  A d i s s o l u t i o n procedure w i l l e v e n t u a l l y  and g a i n the s t a t u s of t h a t now  Today,  evolve  used f o r t a b l e t d i s i n t e g r a t i o n .  Methods c l i n i c a l e f f e c t i v e n e s s of t a b l e t s and o t h e r pharmaceu-  t i c a l dosage forms depends on at l e a s t two  factors.  The  medi-  c a t i o n must be p r e s e n t i n the l a b e l l e d amount and i t must a l s o be a v a i l a b l e t o t h e body.  I t i s apparent, t h e r e f o r e , t h a t i n  a d d i t i o n to i n v i t r o e x a m i n a t i o n of o r a l dosage forms f o r amount, i d e n t i t y , and p u r i t y , there must a l s o be some e v a l u a t i o n  30.  of the 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  active  ingredients.  In v i v o methods u s e d to determine p h y s i o l o g i c a l  availability  of drugs have ranged f r o m s i m p l e q u a l i t a t i v e p r o c e d u r e s to sophisticated i n blood or  q u a n t i t a t i v e measurements of d r u g c o n c e n t r a t i o n  urine.  (a) Q u a l i t a t i v e  Tests.  One of the e a r l i e s t attempts to demonstrate the of drugs was  c a r r i e d out by Wruble ( 7 1 ) ,  teric-coated  tablets containing  b l u e to humans. the  I f the  who  administered  c a l c i u m s u l f i d e and  tablet disintegrated  s u b j e c t would e r u c t a t e  availability  i n the  en-  methylene stomach,  hydrogen s u l f i d e ; i f i t d i s i n t e g r a t -  ed i n the i n t e s t i n a l t r a c t , the u r i n e would be b l u e i n c o l o r . C l i n i c a l o b s e r v a t i o n s on Prednisone ( 6 , 3 0 ) and  Tolbutamide  (7)  have been u s e d as i n d i c a t i o n s of drug a v a i l a b i l i t y . ( i ) X-Rays E a r l y workers attempted to use  x - r a y f i n d i n g s as  i n d i c a t i o n of i n v i v o a v a i l a b i l i t y of d r u g s . Kuever ( 3 7 )  Maney  found t h a t i n v i t r o r e s u l t s g e n e r a l l y  with i n vivo findings.  A b b o t t and  Allport (1),  hand, c o n c l u d e d t h a t x - r a y s were u n s u i t a b l e  agreed  subjects  f u r t h e r m o r e , the  are d i f f i c u l t to i n t e r p r e t and  quantitative  treatment.  the  A c t u a l l y ; x - r a y s can o n l y g i v e i n -  f o r m a t i o n on d i s i n t e g r a t i o n and, often  other  f o r t h i s type  the i n a b i l i t y of x - r a y s to d e t e c t many drugs i n  gastrointestinal tract.  and  on the  of work because of the v a r i a b i l i t y between human and  an  are not  pictures  amenable to  31.  More r e c e n t l y , Levy ( 2 8 ) has u s e d x - r a y s t o s t u d y t h e a g i t a t i o n i n t e n s i t i e s e n c o u n t e r e d i n the human stomach by observing  the d i s i n t e g r a t i o n o f t a b l e t s c o n t a i n i n g  opaque m a t e r i a l s .  Using the i n f o r m a t i o n obtained,  radio he was  able to d e v e l o p d i s s o l u t i o n r a t e t e s t s which gave e x c e l l e n t c o r r e l a t i o n b etween i n v i t r o and i n v i v o d a t a (27,31+) • Steinberg,  e t a l . , (60) a l s o u s e d x - r a y s t o study i n v i v o  t a b l e t d i s i n t e g r a t i o n and o b t a i n e d  r e s u l t s which s u b s t a n t i a -  t e d Levy's p r e v i o u s  The g e n e r a l  observations.  conclusion  was t h a t a g i t a t i o n i n the stomach was o f low i n t e n s i t y and the i n v i v o d i s i n t e g r a t i o n t i m e s were s u b s t a n t i a l l y l o n g e r than t h a t o b t a i n e d u s i n g t h e U.S.P. i n v i t r o (b) Q u a n t i t a t i v e (i) Urinary The  apparatus.  Tests. Excretion  s i m p l e s t o f a l l i n v i v o procedures f o r o b t a i n i n g  q u a n t i t a t i v e d a t a i s p r o b a b l y the measurement o f u r i n a r y e x c r e t i o n o f the drug and/or i t s m e t a b o l i t e s i s t r a t i o n o f a t e s t dose.  Melnick,  a f t e r the admin-  et a l . , ( 3 8 ) u s e d u r -  i n a r y e x c r e t i o n d a t a i n t h e i r s t u d y of t h e 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 vitamins  i n pharmaceutical products.  This  concept o f 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 was adopted and f u r t h e r d e v e l o p e d by Chapman, e t a l . , ( 9 ) and M o r r i s o n , (I4J4.)  et a i . ,  who s t u d i e d t h e r e l a t i o n s h i p between i n v i t r o  disin-  t e g r a t i o n time and 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 o f r i b o f l a v i n i n sugar-coated t a b l e t s .  These s t u d i e s were the f i r s t  attempts t o c o r r e l a t e i n v i t r o f i n d i n g s w i t h q u a n t i t a t i v e  32.  in vivo results.  They formed the b a s i s f o r t h e r e g u l a t i o n s  i n t h e Pood and Drugs A c t t h a t r e q u i r e compressed  or sugar-  c o a t e d t a b l e t s t o d i s i n t e g r a t e w i t h i n 6 0 minutes when t e s t e d by the o f f i c i a l t a b l e t d i s i n t e g r a t i o n method. Levy and Jusko ( 3 3 ) employed u r i n a r y e x c r e t i o n d a t a t o study t h e e f f e c t o f v i s c o s i t y on drug a b s o r p t i o n .  They  determined t h e t o t a l amount o f s a l i c y l a t e i n t h e u r i n e o f rats a f t e r administration of s.alicylic acid i n methylc e l l u l o s e s o l u t i o n s of v a r y i n g v i s c o s i t i e s .  The u r i n a r y  e x c r e t i o n t e c h n i q u e was a l s o used by L i b b y , e t a l . ,  (36)  to determine the a v a i l a b i l i t y o f v i t a m i n s from p r e p a r a t i o n s which f a i l e d t o d i s i n t e g r a t e i n v i t r o .  They found Extreme  i n d i v i d u a l v a r i a t i o n s i n t e s t s on the same p r o d u c t and s e v e r a l p r e p a r a t i o n s were found t o be t o t a l l y u n a v a i l a b l e to c e r t a i n  individuals,  ( i i ) Blood L e v e l s . The most p o p u l a r o f a l l i n v i v o procedures i s the measurement o f drug c o n c e n t r a t i o n s i n the b l o o d (serum, plasma).  F o r many d r u g s , the measurement o f b l o o d concen-  t r a t i o n p r o v i d e s a good i n d i c a t i o n o f p h y s i o l o g i c a l ability.  avail-  However, i t s h o u l d be n o t e d t h a t f o r some d r u g s ,  such as c e r t a i n a n t i h i s t a m i n e s , w h i c h have a l a r g e  distri-  b u t i o n volume i n v i v o , t h i s type o f a c o r r e l a t i o n would be invalid. Many w o r k e r s have u s e d b l o o d l e v e l s as a c r i t e r i o n o f drug a v a i l a b i l i t y .  Juncher and Raaschov  ( 2 3 ) found t h a t  two p r e p a r a t i o n s o f p e n i c i l l i n V t a b l e t s , which h a d  33.  d i f f e r e n t i n v i t r o d i s i n t e g r a t i o n times, a l s o gave s i g n i f i c a n t l y d i f f e r e n t b l o o d l e v e l s when t e s t e d i n humans. Wood ( 7 0 ) used t o t a l s a l i c y l a t e serum l e v e l s t o s t u d y the i n vivo release  r a t e o f A c e t y l s a l i c y l i c A c i d from h a r d  g e l a t i n capsules.  Levy, et a l . ,  used  (26,32,33,31+)  a c e t y l s a l i c y l i c a c i d and s a l i c y l a t e as t e s t drugs t o study d r u g a b s o r p t i o n and d i s s o l u t i o n from dosage forms.  In  almost e v e r y case, t h e y used b l o o d l e v e l s and/or u r i n e  con-  tent o f drug o r m e t a b o l i t e as an i n d i c a t i o n o f drug absorption.  M i d d l e t o n , e t a l . , (1+1) u s e d serum l e v e l s t o i n v e s t -  i g a t e t h e a b s o r p t i o n o f o r a l l y a d m i n i s t e r e d i r o n from sustained  release  In Vivo - In V i t r o  preparations.  Correlations.  A l l i n v i t r o t e s t s have no i n t r i n s i c v a l u e p e r se b u t a r e u s e f u l o n l y t o the e x t e n t t h a t in vivo r e s u l t s .  they c o r r e l a t e w i t h  quantitative  I t has been emphasized r e p e a t e d l y t h a t i n  v i t r o d i s i n t e g r a t i o n t i m e s g i v e no d i r e c t i n d i c a t i o n o f the time r e q u i r e d  f o r a product to d i s s o l v e i n v i v o .  s p i t e the w e l l - e s t a b l i s h e d  n a t u r e o f t h e r e l a t i o n s h i p between  i n v i t r o and i n v i v o r e s u l t s , some authors s t i l l i n v i t r o d i s i n t e g r a t i o n times to i n vivo As  However, de-  indicated previously,  tend t o equate  availability.  Chapman, e t a l . , ( 8 , 9 ) f o u n d t h a t  the a v a i l a b i l i t y o f r i b o f l a v i n and p - a m i n o s a l i c y l a t e to humans c o u l d be p r e d i c t e d  tablets  from t h e i r i n v i t r o d i s i n t e g r a -  t i o n t i m e s u s i n g a m o d i f i e d U.S.P. d i s i n t e g r a t i o n t e s t .  Tab-  l e t s d i s i n t e g r a t i n g i n more than 6 0 minutes were n o t f u l l y available i n vivo.  However, E n d i c o t t  and K i r c h m e y e r ( 1 3 )  3k.  r e p o r t e d t h a t r i b o f l a v i n and e r y t h r o m y c i n t a b l e t s w h i c h took l o n g e r than 60 mins. to d i s i n t e g r a t e  i n v i t r o were f u l l y  avail-  able i n v i v o . Levy and Hayes ( 3 1 ) , who conducted e x t e n s i v e s t u d i e s a c e t y l s a l i c y l i c a c i d t a b l e t s , f o u n d t h a t the f a s t e r tablets  ( s h o r t d i s s o l u t i o n h a l f - t i m e ) had l o n g e r  t i m e s than t a b l e t s w h i c h d i s s o l v e d  more s l o w l y .  work, L e v y (27) suggested t h a t the U.S.P. t a b l e t  with  dissolving  disintegration I n subsequent disintegra-  t i o n t e s t be r e p l a c e d by a d i s s o l u t i o n t e s t f o r compressed t a b lets. S c h r o e t e r , e t a l . , (Sk-) d e t e r m i n e d i n v i t r o d i s s o l u t i o n and  rates  d i s i n t e g r a t i o n times f o r 76 l o t s o f t a b l e t s , i n c l u d i n g a  s t e r o i d , a s u l f o n a m i d e , and o r a l a n t i d i a b e t i c agent, and an A s p i r i n - P h e n a c e t i n - C a f f e i n e combination.  Disintegration  were c a r r i e d out w i t h and w i t h o u t the p l a s t i c d i s k s .  tests  They found  t h a t t h e r e was a h i g h degree o f c o r r e l a t i o n between i n v i t r o disintegration the  steroid.  times ( w i t h o u t d i s k s ) and d i s s o l u t i o n r a t e f o r No s i g n i f i c a n t c o r r e l a t i o n was o b s e r v e d f o r the  a n t i d i a b e t i c agent and the A s p i r i n - P h e n a c e t i n - C a f f e i n e p r e p a r a tions.  There was a tendency f o r the f a s t e r d i s s o l v i n g  tablets  to d i s i n t e g r a t e more r a p i d l y and the p r e s e n c e o f sodium c h l o r ide i n some o f the s u l f o n a m i d e p r e p a r a t i o n s markedly the  influenced  results. Campagna, e t a l . , (6) observed t h a t , i n t h e case o f Pred-  n i s o n e t a b l e t s , o m i s s i o n o f d i s k s i n the U.S.P.  Disintegration  apparatus gave v a l u e s w h i c h agreed w i t h i n v i v o r e s u l t s and d i s s o l u t i o n rate values.  C a r t e r (7) and Caminetsky  (5)  35. r e p o r t e d s i m i l a r o b s e r v a t i o n s w i t h Tolbutamide t a b l e t s .  Clin-  i c a l l y i n e f f e c t i v e t a b l e t s demonstrated s u b s t a n t i a l l y  longer  d i s i n t e g r a t i o n times than- c l i n i c a l l y e f f e c t i v e ones.  Levy ( 2 9 )  studied  t h e two t a b l e t brands u s e d by C a r t e r and found marked  differences  i n their i n v i t r o dissolution rates.  Although  many o t h e r workers have i n v e s t i g a t e d  t o l b u t a m i d e , no i n v i v o  d a t a has been p r e s e n t e d t o show t h a t  tablets with different  d i s s o l u t i o n rates vary i n c l i n i c a l effectiveness ( k 3 ) . Middleton, et al.,(kO),  examined t h e r e l a t i o n s h i p between  in v i t r o dissolution rate, disintegration  time, and 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 r i b o f l a v i n i n sugar-coated t a b l e t s . They.found a c l o s e 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  time and  d i s s o l u t i o n r a t e , and b o t h i n v i t r o p r o c e d u r e s c o r r e l a t e d r e asonably w e l l w i t h p h y s i o l o g i c a l ary r i b o f l a v i n excretion.  a v a i l a b i l i t y measured by u r i n -  I t would appear t h a t  i n v i t r o t e s t s i n t h i s i n s t a n c e were a u s e f u l vivo  the r e s u l t s o f  i n d i c a t i o n of i n  availability. Quite r e c e n t l y ,  Levy, e t a l . , ( 3 k ) , r e p o r t e d on an i n v i t r o  d i s s o l u t i o n r a t e t e s t which c o r r e l a t e s  q u a n t i t a t i v e l y w i t h the  g a s t r o - i n t e s t i n a l a b s o r p t i o n o f a c e t y l s a l i c y l i c a c i d from t h r e e markedly d i f f e r e n t types o f dosage f o r m s . the  i n v i t r o conditions  I t was suggested  t h a t y i e l d such m u l t i p l e  correlation  may be e x p e c t e d t o be r e l a t i v e l y s i m i l a r t o d i s s o l u t i o n tions found i n v i v o .  The r e s u l t s o b t a i n e d i n t h i s  condi-  investigation  would suggest t h a t t h e apparent f a i l u r e o f some d i s s o l u t i o n to r e f l e c t the r e s u l t s of i n v i v o s t u d i e s test conditions.  that  tests  may be due t o improper  I t was found t h a t a change o f o n l y 20% i n  36.  stirring  r a t e , from 6 0 r.p.m. to £ 0 r.p.m., r e s u l t e d  successful  in a  correlation.  In s p i t e of these encouraging r e s u l t s and the fundamental relationships  e x i s t i n g between i n vivo a v a i l a b i l i t y and d i s -  solution rates,  there s t i l l  remains the problem of f i n d i n g a  d i s s o l u t i o n t e s t than can be a p p l i e d  to a l l drugs.  37.  III. 1.  Spectrophotometry  EXPERIMENTAL  Determination  of  Phenylbutazone.  Phenylbutazone ( 1 , 2 - D i p h e n y l - i i - b u t y l - 3 , l 4 . - P y r a z o l i d i n e d i o n e ) , a weak o r g a n i c a c i d , pKa ( l e s s than 0 . 7 mg.  i s v e r y s l i g h t l y s o l u b l e i n water  per ml.)  and f r e e l y s o l u b l e i n a l c o h o l (50 mg.  per m l . ) , acetone, e t h e r and e t h y l a c e t a t e ( 3 9 ) . A s o l u b i l i t y o f 2.2  mg.  per ml. at pH 7 . 5 was  r e p o r t e d by B r o d i e  (2,3).  A f t e r a number of t r i a l s , a l c o h o l appeared to be the s o l v e n t o f c h o i c e f o r the e x t r a c t i o n of phenylbutazone f r o m t a b l e t s . l a r g e q u a n t i t i e s o f s o l v e n t are r e q u i r e d f o r  Since  spectrophotometrie  d e t e r m i n a t i o n s , and because d i s s o l u t i o n media are aqueous, a l c o h o l was  r e j e c t e d as a d i l u t i n g s o l v e n t . (a) S p e c t r a l - Absorbancy (S-A) Spectrophotometric  curves.  c u r v e s were determined  in distilled  0 . 1 N H C 1 s o l u t i o n , s i m u l a t e d g a s t r i c f l u i d U.S.P. ( w i t h o u t  water, en-  zyme), 0 . 1 N NaOH s o l u t i o n and s i m u l a t e d i n t e s t i n a l f l u i d U.S.P. ( w i t h o u t enzyme).  A l l s p e c t r a l - a b s o r b a n c y curves were run on a  Bausch and Lomb S p e c t r o n i c 505  r e c o r d i n g spectrophotometer  and  examples o f such curves are shown i n F i g u r e s 1 , 2 and 3 . (i)  Procedure The g e n e r a l procedure  f o r preparing  spectral-absorbancy  c u r v e s i s as f o l l o w s : D i s s o l v e 100 mg. alcohol.  D i l u t e a 25.0  s o l u t i o n t.oi Prepare  o f phenylbutazone i n 2 5 0 . 0 ml. o f  1000.0  ml. a l i q u o t o f the a l c o h o l  ml. w i t h the s o l v e n t s p e c i f i e d .  S-A c u r v e s over the 210 mu.  t o 280 mu.  range  u s i n g 1% v/v a l c o h o l i n the s p e c i f i e d s o l v e n t as the  50  40  30  20  10  220  240 mu.  260  FIGURE 1. Spectrophotometric Curves f o r (a) Phenylbutazone and (b) Phenylbutazone T a b l e t E x t r a c t i n Alcohol-Water (lfo v/v) S o l u t i o n .  50  40  a  s  30 -  20  10  220  240 mu.  FIGURE 2. Spectrophotometric Curve f o r Phenylbutazone Simulated G a s t r i c F l u i d S o l u t i o n s .  260 i n 0.1N  HC1 and A l c o h o l -  ^°  220  240 mu.  260 o  FIGURE 3. Spectrophotometric Curve f o r Phenylbutazone Simulated I n t e s t i n a l F l u i d S o l u t i o n s .  i n 0.1N NaOH and A l c o h o l -  kl, blank. The w a v e l e n g t h o f maximum a b s o r p t i o n i n e a c h s o l v e n t was d e t e r m i n e d f r o m each g r a p h and u s e d i n subsequent  assay "  procedures, (ii)  Results F i g u r e 1 , C u r v e A, r e p r e s e n t s t h e S-A c u r v e f o r p h e n -  y l b u t a z o n e i n a l c o h o l - w a t e r , 1% v / v , s o l u t i o n . is  t h e S-A c u r v e f o r p h e n y l b u t a z o n e t a b l e t  a l c o h o l - w a t e r , 1% v / v s o l u t i o n . tical  except f o r e f f e c t s  Curve B  extract i n  T h e s e two c u r v e s a r e i d e n -  due t o c o n c e n t r a t i o n  differences.  T h e r e i s no s h a r p a b s o r p t i o n maximum b u t t h e p l a t e a u  region,  f r o m 21+5 mu. t o 265 mu., c a n be u s e d a n a l y t i c a l l y . A l l s u b s e q u e n t m e a s u r e m e n t s were c a r r i e d o u t midway b e t w e e n t h e s e two w a v e l e n g t h s , t h a t  i s a t 255  mu.  F i g u r e 2 r e p r e s e n t s t h e S-A c u r v e f o r p h e n y l b u t a z o n e in  simulated gastric f l u i d  U.S.P. ( w i t h o u t e n z y m e ) .  This  c u r v e i s t h e same as t h a t f o r p h e n y l b u t a z o n e i n 0 . 1 N H C 1 solution.  H e r e t h e w a v e l e n g t h o f maximum a b s o r p t i o n i s  237 mu.  The w a v e l e n g t h o f maximum a b s o r p t i o n f o r p h e n y l -  butazone  i n simulated i n t e s t i n a l f l u i d  U.S.P. ( w i t h o u t  enzyme) a n d i n 0 . 1 N NaOH s o l u t i o n was f o u n d t o be 265 mu. T h e s e c u r v e s , r e p r e s e n t e d by F i g u r e s 2 a n d 3 , to  those r e p o r t e d by Sunshine and Gerber  butazone  i n 0.1N H SO^ s o l u t i o n  (b) C a l i b r a t i o n  2  (6l)  a n d 0 . 1 N NaOH  correspond f o r phenylsolution.  Curves  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  o f B e e r ' s Law  and, i n o r d e r t o c h e c k s u c h v a l i d i t y , a b s o r b a n c y - c o n c e n t r a t i o n  4-2. c u r v e s were p r e p a r e d f o r phenylbutazone i n d i s t i l l e d w a t e r , s i m u l a t e d g a s t r i c f l u i d U.S.P. (Without enzyme) and s i m u l a t e d i n t e s t i n a l f l u i d U.S.P. ( w i t h o u t enzyme.)  These c u r v e s are  shown i n F i g u r e s 4. and $. (i)  Procedure The g e n e r a l method f o r the p r e p a r a t i o n o f such c u r v e s  i s g i v e n below: D i s s o l v e 100 mg. o f p h e n y l b u t a z o n e , a c c u r a t e l y weighed, i n 250.0 m l . o f a l c o h o l .  Dilute  aliquots,  from 2 3 . 0 m l . t o 2 7 . 0 m l . , t o 1000.0 m l . w i t h the specified solvent.  R e c o r d the absorbancy ( A ) of c  s  each s o l u t i o n a t the wavelength of maximum absorpt i o n u s i n g 1% v/v a l c o h o l i n the s p e c i f i e d  solvent  as t h e b l a n k . ( i i ) Results A l l curves were found t o be s t r a i g h t l i n e s and,, on t h i s b a s i s , the a b s o r p t i v i t i e s (a ) i n v a r i o u s media and a t the w a v e l e n g t h o f maximum a b s o r p t i o n were  calculated  u s i n g the e q u a t i o n a where a  s  s  =  A  s b c  i s the a b s o r p t i v i t y , b t h e c e l l l e n g t h (1 cm.),  c the c o n c e n t r a t i o n (Gm./L.), and A  the absorbancy.  The wavelengths o f maximum a b s o r p t i o n and the absorpt i v i t y v a l u e s f o r phenylbutazone i n the v a r i o u s media are summarized i n Table I I I .  10  20 mg./L  30  FIGURE 5 . C a l i b r a t i o n Curves f o r Phenylbutazone i n (a) Simulated G a s t r i c F l u i d and (b) Simulated I n t e s t i n a l F l u i d , U.S.P.  TABLE I I I .  Wavelength o f Maximum A b s o r p t i o n and A b s o r p t i v i t y Values f o r Phenylbutazone i n D i f f e r e n t Media-"-  Wavelength of maximum a b s o r p t i o n  Medium  Absorptivity  D i s t i l l e d water  255 mu  0.1N HC1  237  1+2.0  NaOH s o l u t i o n  265  65.14-  Simulated g a s t r i c f l u i d U.S.P. ( w i t h o u t enzyme)  237  1+2.3  Simulated i n t e s t i n a l f l u i d U.S.P. ( w i t h o u t enzyme)  265  66.5  0.1N  solution  Average of f i v e  determinations  k6. 2.  Assay o f Phenylbutazone  Tablets  (a) Equipment and Reagents G l a s s m o r t a r and p e s t l e . Sintered  glass funnel  (medium p o r o s i t y ) .  Suction f l a s k s ( 1 5 0 ml.). V o l u m e t r i c f l a s k s ( 1 0 0 m l . and 1 0 0 0 m l . ) . Pipette  ( 1 0 ml.).  Spectrophotometer. Alcohol  (95%).  D i s t i l l e d water. (b) Procedure Weigh t e n t a b l e t s i n d i v i d u a l l y . ely i n a mortar.  C r u s h each t a b l e t s e p a r a t -  Add 2 5 m l . o f a l c o h o l  and e x t r a c t .  Filter  the a l c o h o l i c s o l u t i o n through t h e s i n t e r e d g l a s s f u n n e l ed i n t o the s u c t i o n f l a s k .  Apply suction i f necessary.  w i t h an a d d i t i o n a l 2 5 m l . o f a l c o h o l .  insertRepeat  R i n s e the m o r t a r and  p e s t l e w i t h a f u r t h e r 2 5 m l . p o r t i o n o f a l c o h o l , and f i l t e r , a t the  same time washing t h e r e s i d u e i n the f u n n e l .  transfer the alcohol  Quantitatively  s o l u t i o n t o a 1 0 0 m l . v o l u m e t r i c f l a s k and  d i l u t e t o volume w i t h a l c o h o l .  Transfer 1 0 . 0 ml.  Mix w e l l .  ( p i p e t t e ) o f t h e a l c o h o l s o l u t i o n to a 1 0 0 0 m l . v o l u m e t r i c f l a s k and d i l u t e t o volume w i t h d i s t i l l e d w a t e r .  Mix w e l l .  absorbancy o f the a q u e o u s - a l c o h o l i c s o l u t i o n a t a 1% v/v a l c o h o l - w a t e r s o l u t i o n as a b l a n k . centration  255  *'<iu.  Calculate  Read t h e using t h e con-  o f phenylbutazone i n the sample and hence t h e amount  per t a b l e t . Gm. p e r t a b l e t  =  10  x  A  J4.5.J+ x  g  1  V7. (c)  Results A  spectral-absorbancy curve  sample  and  ably  with  here  i s that  assayed metry of  that no  when  Tablet  shown  coated  and  results  tablets  twelve (a)  two  tests  brands  are  i n the  these or  to and  different  were  assayed  23  spectrophotobrands  individually.  The  re-  IV.  were  of  Food be  carried  enteric  most  for further and  and  no  d i d not  out  coated  on  23  Drugs  need of  to  the  investigation.  four  Act.  these  one  which had  The  m o d i f i c a t i o n s were  official used  as  in  these the  controls,  depth.  longer  u n i f o r m l y were,  of  with  f o r use  products  sugar-  tablets.  half  complied  Except  products  of  phenylbutazone  Approximately  study  disintegrate  brands  disintegra-  therefore,  tablet  sing-  disintegra-  i n studying  these  products. Methodology Method  I:  regulations in  and  of  u n i f o r m l y , and  method  extracted  from  each  favour-  implication  this  quickly,  times  The  Using  disintegrated  tion  tablet  i s used.  V.  of  tion  i n Table  being  a  compares  1A.  i n Figure are  from  Disintegration  appeared  out  tablets,  curve  i n Table  Some  led  This  substances  tablets,  prepared  shown  regulations there  IB.  drug)  procedure  ten  Disintegration  The  other  this  method,  are  in Figure  ( f o r pure  phenylbutazone  sults  3.  i s shown  was  detail  to  This  i s the  the Food  i n Appendix  B.  and  official Drugs  method  Act.  The  specified method  in  the  i s described  14.8.  TABLE IV Assay Values f o r 23 Brands o f Phenylbutazone Tablets-::-  Mg . o f phenylbutazone p e r t a b l e t Sample Code  A  B  E  1  95.5  98.5  100.0  102.5  97.5  100.0  100.5  2  98.5  99.0  102.0  100.0  99.0  102.0  100.0  3  100.0  98.0  100.0  103.0  98.5  105.0  98.5  k  101.0  101.0  103.0  101 ..0  99.0 -  102.0  96.5  5  99.0  8l.5  98.5  102.0  96.0  100.0  97.0  6  102.5  103.5  100.5  iok. 5  96.5  102.5  98.0  7  99.0  80.0  102.0  102.0  10k. o  10k. o  8  103.0  99.0  96.0  103.0  99.0  10k.0  101.0  9  102.0  91.0  100.0  103.0  95.5  103.5  103.0  10  101.0  102.5  102.0  102.5  97.5  100.5  99.5  Average mg./tab)  100.2  95.4.  100.0  102.2  97.5  102.0  99.8  D  G  a  F  . G..  T a b l e t No.  Standard deviation  2.29  a  a  b  8.36  2.09  1.25  N  96.0  1.38  1.82  a  L a b e l c l a i m = 100 m g . / t a b l e t O u t s i d e t h e a c c e p t a b l e potency range o f 85% t o 115% f o r i n d i v i d u a l t a b l e t s . (N.F.XII)  b  Outside t h e a c c e p t a b l e potency range of 93% t o 107% f o r composite samples. (N.F.XII)  2.8k  i+9.  Table I V C o n t i n u e d  Mg. o f phenylbutazone H  J  K  b  1  99.0  95.0  95.5  2  101.5  1 0 0 . 0  92.o  3  1 0 1 . 0  95.0  ' 14- 98.5 5  L  M  N  0  91+.5  96.7  96.1  98.5  96.7  98.5  96.9  96.5  1 0 0 . 0  99.8  98.0  103.0  1 0 1 . 0  91+. 3  1 0 0 . 0  99.1  101.5  93.5  96.0  101.3  91+. 1  103.5  9.8.1+  99.0  10I4..0  91+.0  98.5  101.5  92.l  6  98.0  99.5  91+.5  99.5  96.9  7  1 0 1 . 0  91+.0  90.5  b  99.0  8  99.0  96.0  88.0  b  9  98.5  100.5  95.0  96.5  98.0  87.5  98.3  92.8  10  Average (ing./tab. )  99.2  Standard deviation 1.55 b  I  per t a b l e t  3.29  b  99.0  97.5  95.0  IOI4..O  95.0  101.3  99.1+  103.7  98.4  97.5  1 0 2 . 1  98.5  1 0 1 . 2  97.5  91|..5  101+. 1  99.8  97.0  98.0  b  102.5  96.7  90.6  105.5  98.0  b  98.3  99.9  95.6  101.2  97.8  3.35  2.92  2.77  b  b  3.01+  2.80  O u t s i d e the a c c e p t a b l e potency range of 93% t o 107$ f o r composite samples. ( N . P . X I I )  1.32  50  Table IV C o n t i n u e d  Mg. o f phenylbutazone p e r t a b l e t P  b  Q  1  91.7  2  89.7 87.8  3  b  102.7  b  101.8  b  100.8  1+ 86.0 5 92. l 6 87.3 7 90.8 8 86.0  b  96.7  b  101+. 7 10li.9 101+.0 101+.8 101.2 105.7 86.8  99.8  101.1 100.0  103.8  98.1 103.1  90.8  b  average rag./tab) b  2.38  b  b  b  10  Y  b  99.1+  100.0  X  b  102.0  b  ¥  101.5 101.3 106.5 102.2 107.7 99.8 100.7 101.5 107.3 101+.5 97.8 100.2 99.8 m . 5 101+.2 100.0 105.2 101+.2 108. l+  b  86.8  T  101.1  101.1  9  Standard deviation  S  106.1  b  b  88.9  R  99.8  b  99.6  102.2  89.3  b  100.0 106.1 106.7  96.9  97.8 98.8 99.2  98.2 99.1+  97.2 99.6  102.0  103.5 102.0 101.5 103.7 103.2 102.7 101.5 101.2 101.2 103.0  98.7 98.1+  101.5  102.3 101.0 101.6 103.6 102.2  98.1+  2.1+7  2.78  1.99 1.88  2.30  8.01 0.29  Outside the a c c e p t a b l e potency range o f 93$ t o 107$ f o r composite samples. (N.P.XII)  TABLE V D i s i n t e g r a t i o n Times of Phenylbutazone Using Method II*-  Sample Code  Average D i s i n t e g r a t i o n Time-"- (Minutes)  A  18 12  11 8  k 20  1  'A 32  65  B C D E P G-  51 39  H  Range (Minutes)  2 5 58 29  5  J  9 10  K  17  lk  L  kl  2k  M  2k  7  N  18  9  0  lk  P  k3  3 61  Q  37 20  I  R S  k 21  T U  Enteric  coated  V  Enteric  coated  k  2k  k 0 10  W  71  7k  X  56  Y  6  71 1  Average of s i x t a b l e t s .  52. Method I I : Method I was m o d i f i e d t o u t i l i z e gastric  only  simulated  fluid.  Method I I I : Method I I was m o d i f i e d by o m i t t i n g t h e d i s c s d e s c r i b e d i n the o f f i c i a l Method I V : intestinal  procedure.  Method I was m o d i f i e d t o u t i l i z e  only simulated  fluid.  Method V :  Method I V was m o d i f i e d by o m i t t i n g the d i s c s  d e s c r i b e d i n the o f f i c i a l  procedure.  An Erweka t a b l e t d i s i n t e g r a t i o n t e s t e r (Type ZT2) and a F i s h e r t h e r m o s t a t i c a l l y c o n t r o l l e d immersion h e a t e r were used i n the above methods.  T h i s equipment complies w i t h the s p e c i f i -  c a t i o n s i n the U.S.P.  A l l t e s t media were p r e p a r e d  without  enzymes. (b) R e s u l t s T a b l e t d i s i n t e g r a t i o n r e s u l t s are shown i n T a b l e s V , ' V I , V I I  and  V I I I .  Tablet D i s s o l u t i o n (a) S o l u b i l i t y o f p h e n y l b u t a z o n e . D i s s o l u t i o n s t u d i e s a r e u s u a l l y c a r r i e d out i n w a t e r , u l a t e d g a s t r i c f l u i d , or i n s i m u l a t e d i n t e s t i n a l f l u i d . i n a r y i n v e s t i g a t i o n s showed t h a t phenylbutazone was i n s o l u b l e i n a l l these media.  Prelim-  relatively  The g e n e r a l procedure u s e d t o  determine such s o l u b i l i t i e s was as f o l l o w s : Add 100 mg. o f phenylbutazone t o 1000 m l . o f media (500 mg. t o 100 m l . i n the case o f s i m u l a t e d i n testinal fluid.)  sim-  M a i n t a i n at 37°G, w i t h  constant  53.  TABLE V I D i s i n t e g r a t i o n Times of Phenylbutazone T a b l e t s U s i n g Method I  T a b l e t No.  1  Sample Code A  2  3  k  5  6  Mean Time (Minutes)  Standard Deviation  Time i n minutes 11  13  17  21  21  22  17  k.7  13  13  11+  16  12  3.3  k  h  h  0.5  B  8  8  C  3  3  1+  D  19  19  20  21  20  21  20  0.9  E  28  18  83*  37  39  kl  4-1  22.3  G  1+5  1+5  1+5  30  k5  k5  k3  6.3  H  1+8  4-5  kS  30  25  20  35  L  28  36  k8  1+2  52  4-0  l+l  8.6  P  55  55  28  kO  38  1*5  1+2  10.6  Q  .39  39  53  39  52  1+1  1+4-  6.8  ¥  59  1+6  71-* 72*  a  59  61*  28.9  X  52  59  58  51  11+.3  4-  23  62-"- 53  * D i s i n t e g r a t i o n time i n excess o f 60 minutes a D i d not d i s i n t e g r a t e w i t h i n 120 minutes  12  TABLE V I I D i s i n t e g r a t i o n Times o f Phenylbutazone T a b l e t s u s i n g Methods I I and I I I .  Method II-::Sample Code  Time  Range. (Minutes)  Method III-::Time  Range (Minutes)  A  17  13  58  b  B  11+  5  a  a  C  k  2  1+  2  D  19  3  19  8  E  35  8  a  a  G-  51  i+5  57  b  H  36  16  1+3  28  L  38  9  38  13  P  36  22  68  b  Q  39  8  61  73  w  80  b  a  a  X  70  80  5i  b  -::- Average o f twelve t a b l e t s a More than two hours f o r a l l t a b l e t s t e s t e d b More t h a n two hours f o r one t o t h r % e t a b l e t s  TABLE V I I I D i s i n t e g r a t i o n Times o f Phenylbutazone T a b l e t s U s i n g Methods IV and V.  Method I V * Sample Code  * a b  Time Range (Minutes)  Method V* Time Range (Minutes) 19  16  1+  a  a  k  2  5  3  D  27  7  3k  17  E  38  1+8  a  a  G  4.1  70  51+  60  H  1+0  5  '50  13  L  28  15  72  b  P  37  13  25  29  Q  79  55  a  a  W  a  a  a  a  X  62  1+3  a  a  A  17  5  B  13  C  Average o f twelve t a b l e t s More than two hours f o r a l l t a b l e t s t e s t e d More than two hours f o r one t o t h r e e t a b l e t s  56. a g i t a t i o n , f o r 21+ h o u r s .  F i l t e r and assay the  f i l t r a t e spectrophotometryally. The r e s u l t s o f these i n v e s t i g a t i o n s i n d i c a t e d t h a t 0.025 rag. of the drug d i s s o l v e d i n one m l . o f w a t e r , 0.018 mg. i n one m l . o f s i m u l a t e d g a s t r i c f l u i d  (pH 1 . 2 ) ,  one m l . o f s i m u l a t e d i n t e s t i n a l f l u i d  and 3.2 mg. i n  (pH 7 . 5 ) .  I t i s customary i n i n v e s t i g a t i o n s o f t h i s type t o determine the  time r e q u i r e d f o r 50$ o f the drug t o d i s s o l v e i n a c e r t a i n  q u a n t i t y o f medium.  From the above r e s u l t s , i t was e v i d e n t  t h a t t h i s would not be p o s s i b l e when s i m u l a t e d g a s t r i c was u s e d as t e s t medium.  fluid  However, the time r e q u i r e d f o r 10$  and 20$ o f t h e drug t o d i s s o l v e t o g e t h e r w i t h mg. o f drug d i s s o l v e d a t v a r i o u s time i n t e r v a l s can e a s i l y be d e t e r m i n e d . (b)  Methodology The twelve p r o d u c t s s e l e c t e d f o r i n t e n s i v e  disintegration  s t u d i e s were a l s o chosen f o r the d i s s o l u t i o n i n v e s t i g a t i o n s . Most o f the methodology vious section.  i s the same as t h a t o u t l i n e d i n the p r e -  The numbering  system i s c o n s i s t e n t w i t h t h a t  p r e v i o u s l y used and the n e c e s s a r y m o d i f i c a t i o n s are o u t l i n e d below; Method I was n o t used i n these i n v e s t i g a t i o n s . Method I I A: T h i s i s t h e same as Method I I e x c e p t t h a t a l i q u o t s o f d i s s o l u t i o n medium are t a k e n , a t v a r y i n g time i n t e r v a l s , f o r analysis,.  These samples ;are t a k e n t h r o u g h a sam-  p l i n g d e v i c e , a diagram o f which i s shown i n F i g u r e 6 .  57.  ( i ) Sampling D e v i c e A sampling d e v i c e was assembled u s i n g a s i n t e r e d g l a s s f u n n e l o f course p o r o s i t y and a s i n t e r e d s a m p l i n g tube o f medium p o r o s i t y .  disk  T h i s was then con-  n e c t e d to vacuum and compressed a i r o u t l e t s as shown i n F i g u r e 6.  B e f o r e a sample was withdrawn, clamp A  was opened and clamp B c l o s e d .  A l l the l i q u i d i n the  d e v i c e was t h e n blown out i n t o the b u l k s o l u t i o n . Clamp A was t h e n c l o s e d  and clamp B opened.  A sample  was then drawn up i n t o the f u n n e l by s u c t i o n and a 10 ml.  aliquot pipetted  off f o r analysis.  The r e m a i n i n g  sample i n the f u n n e l was i m m e d i a t e l y put back i n t o the b u l k s o l u t i o n by c l o s i n g clamp B, opening clamp A, and t u r n i n g on the compressed a i r .  T h i s p r o c e d u r e was  fol-  lowed f o r a l l samples taken f o r a n a l y s i s d u r i n g t h e course o f t h i s i n v e s t i g a t i o n . Method I I I A : T h i s i s the same as Method I I I .  As d e s c r i b e d  above, samples were withdrawn f o r a n a l y s i s . Method IVA:  T h i s i s the same as Method IV.  As d e s c r i b e d  above, samples were withdrawn f o r a n a l y s i s . Method VA:  T h i s i s the same as Method V.  As d e s c r i b e d  above, samples were withdrawn f o r a n a l y s i s . U s i n g the above f o u r methods, 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 a t a was o b t a i n e d f o r s i x t a b l e t s from each o f the twelve p r o ducts.  D i s s o l u t i o n samples were taken a f t e r one and two h o u r s .  The r e s u l t s are l i s t e d i n Table I X .  FIGURE 6.  Sampling Device.  59  TABLE I X D i s i n t e g r a t i o n Times 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 of Phenylbutazone T a b l e t s U s i n g Methods I I t o V Inclusive-s:-'  Sample Code  D i s i n t e g r a t i o n Time (Minutes)  Dissolution Mg. i n solution-*-;:-  Methods II  A  17  B  16  C  a b  IV  V  HA  IIIA  IVA  VA  1  2  l  2  1  2  1  2  17  19  3  14-  2  1+  28  kk  32  51  a  13  a  3  5  1  1  30  38  26  Ul  k  k  k  5  5  6  3  k  80  89  7k  85  D  17  19  27  2  3  2  5  50  68  kl  60  E  29  a  6  9  1+  8  70  77  10  29  G  62  57  Sk  1+  5  3  14. 5 0  72  38  6k  H  32  1+3  ko  50  1+  5  3  i4-  14-9  68  33  55  L  35  38  28  72  14.  5  5  7  51  66  37  1+9  P  28  68  37  25  9  3  5  69  78  65  75  Q  k-o  61  79  a  3  k  2  3  214- 56  13  38  ¥  56  a  a  5  9  1  2  30  kk  6  21 '  X  83  62  a  2  3  2  3  2k  kQ  I4-  11  Pure Drug (Percent) -«  III  Methods  52  b  b  38 b  a 5 i  b  3k  a  30  n  314-  Average of s i x t a b l e t s Mg. i n s o l u t i o n a f t e r one and two h o u r s , More t h a n two hours f o r a l l t a b l e t s t e s t e d , More than two hours f o r one t o two t a b l e t s .  98 1 0 0  60. Dissolution  t e s t s were r e p e a t e d on i n d i v i d u a l t a b l e t s u s i n g  Methods I I A and IVA.  One t a b l e t was p l a c e d i n a tube o f t h e  b a s k e t - r a c k assembly and the apparatus o p e r a t e d i n the u s u a l manner.  T h i s t e s t was r e p e a t e d t w i c e f o r each p r o d u c t .  Sample  a l i q u o t s were o b t a i n e d f o r a n a l y s i s a f t e r 1$ m i n u t e s , 30 minu t e s , 60 m i n u t e s , 90 m i n u t e s , 120 minutes and e v e r y hour t h e r e a f t e r f o r seven h o u r s .  The r e s u l t s are shown i n Table X and  i l l u s t r a t e d i n F i g u r e s 7 and 8 . Methods V I and V I I (i)  Apparatus The apparatus used i n t h i s method i s s i m i l a r t o  t h a t used by Levy and Hayes (31).  I t c o n s i s t s of a con-  stand temperature water b a t h , a F i s h e r S t e d i - S p e e d adjustable s t i r r e r  (Model 1 2 ) ,  a t e f l o n coated three blade  i m p e l l e r (5 cm. i n d i a m e t e r ) , a c y l i n d r i c a l w i r e b a s k e t w i t h a h i n g e d t o p , made from 10 mesh s t a i n l e s s  steel  w i r e c l o t h ( 2 . 2 cm. i n d i a m e t e r and 2.8 cm. i n l e n g t h ) and a t h r e e l i t e r g l a s s c o n t a i n e r s i m i l a r t o t h a t u s e d i n the p r e v i o u s methods.  The w i r e b a s k e t  dimensions  were s i m i l a r t o those o f the tubes used i n the t a b l e t d i s i n t e g r a t i o n apparatus.  The l e n g t h o f t h i s basket  was a p p r o x i m a t e l y the same as t h a t from the w i r e s c r e e n t o t h e bottom of the p l u n g e r i n the o f f i c i a l  apparatus.  ( i i ) Test procedure The t h r e e l i t e r g l a s s j a r c o n t a i n i n g 2.5 l i t e r s  of  t e s t medium was a l l o w e d t o e q u i l i b r a t e i n the c o n s t a n t temperature water b a t h at 37°G t l°C.  A single  61  TABLE X  D i s i n t e g r a t i o n Time 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 of Phenylbutazone T a b l e t s u s i n g Methods I I A and IVA*  Sample Code  D i s i n t e g r a t i o n Time (minutes) IIA  A  15  Dissolution Mg. i n s o l u t i o n * *  IVA  IIA 6..,  2  k  17  10  17  2k  IVA k  6  58  7k  81  2.  B  8  8  11  20  2k  51  68  7k  C  k  5  30  32  33  99 102  102  E  15  32  5  9  13  67  85  93  E  30  37  16  18  19  92  96  98  G  k2  ko  13  21  28  97 106  110  H  35  k-7  9  lk  19  76  92  99  L  37  kO  6  10  lk  65  8k  95  P  ko  30  15  18  22  90  92  92  Q  23  58  6  9  15  67  8k  88  ¥  63  b  lk  21  28  53  8k  99  X  75  70  12  17  21  57  86  95  3k  35  36 100 100  100  (Percent)  * Average of two t a b l e t s . ** Mg. i n s o l u t i o n a f t e r two, f o u r and s i x hours b Tablet slowly dissolves.  FIGURE 7.  D i s s o l u t i o n P r o f i l e s of Phenylbutazone T a b l e t s i n Simulated G a s t r i c F l u i d u s i n g Method I I .A.  IV)  63.  FIGURE 8.  D i s s o l u t i o n . ' P r o f i l e s o f Phenylbutazone T a b l e t s i n Simulated I n t e s t i n a l F l u i d u s i n g Method IV A.  6kphenylbutazone  t a b l e t was p l a c e d i n t o the  cylindrical  w i r e b a s k e t w h i c h i s hung below the i m p e l l e r o f the s t i r r i n g shaft.  The s t i r r e r i s then i n s e r t e d i n t o the  l i q u i d t o a depth o f 10 cm. below the s u r f a c e . speed of a g i t a t i o n i n a l l cases was foreward (clockwise) d i r e c t i o n . t a k e n at 15  minute  100  The  rr..p.m. i n a  Sample a l i q u o t s were 30  i n t e r v a l s f o r the f i r s t hour,  minute i n t e r v a l s f o r the second hour, and, a t h o u r l y i n t e r v a l s f o r seven h o u r s .  The  thereafter, sampling  procedure has a l r e a d y been d e s c r i b e d . D i s i n t e g r a t i o n t i m e s , t h a t i s , the time r e q u i r e d f o r t a b l e t r e s i d u e t o f a l l through the bottom of the b a s k e t , were a l s o determined d u r i n g these d i s s o l u t i o n studies. butazone  Two  t a b l e t s from each of the twelve p h e n y l -  samples were t e s t e d i n d i v i d u a l l y i n b o t h  gastric fluid  (Method V I ) and i n t e s t i n a l f l u i d  V I I ) w i t h o u t enzymes.  (Method  The r e s u l t s are t a b u l a t e d i n  Table X I and i l l u s t r a t e d i n F i g u r e s 9 and  10.  65, TABLE X I D i s i n t e g r a t i o n Times 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 of Phenylbutazone T a b l e t s u s i n g Methods VI and V I I . -:;-:.  Sample Code  Disintegration (minutes) VI  Time Mg.  VII  VI 2  A  20  Dissolution i n solution-:;-:;-  30  6  VII 6  2  1+  6  11+  80  91+  99  60  83  93 99  1+ 11  B  a  30  2  C  1+  5  29  31  33  99  99  30  5  9  12  78  98  101+  2  21  56  76  D  20  E  a  G  1+5  25  H  1+5  1+5  L  30  35  P  25  Q  b  1+  3  1.5  0.5  98 100  10  18  22  7  11  15  75  96  99  11  11+  18  80  91+  99  35  12  18  22  86  87  88  1+5  60  6  12  16  39  59  70  W  a  b  29  61+  88  X  c  c  Pure Drug (Percent)  0.8  0.2  3  26  1.2  11  17  28  29  * Average o f two t a b l e t s -:;--"- Mg. i n s o l u t i o n a f t e r two, f o u r and s i x hours a More t h a n seven h o u r s b Tablet slowly d i s s o l v e s c T a b l e t c o a t i n g i n t a c t f o r t h r e e t o f o u r hours  .  100  7  1+8  99 1 0 0  100  0.5  C, Pure drug & Crushed  1  2  3  4  5  Hours FIGURE 9.  D i s s o l u t i o n P r o f i l e s o f Phenylbutazone Tablets i n Simulated G a s t r i c F l u i d u s i n g Method VI.  65B.  1  2  Hours  3  4  FIGURE 10. D i s s o l u t i o n P r o f i l e s o f Phenylbutazone T a b l e t s in Simulated I n t e s t i n a l F l u i d u s i n g Method V I I .  66. IV.  DISCUSSION  Three t o p i c s , w i l l be d i s c u s s e d i n t h i s s e c t i o n - the t e s t p r o c e d u r e s , the q u a l i t y o f t h e p r o d u c t s i n v e s t i g a t e d , inary release in tablet 1.  c h a r a c t e r i s t i c s o f phenylbutazone  and the p r e l i m -  and phenylbutazone  form.  Test Procedures and R e s u l t s , (a) T a b l e t Assay. All  assay p r o c e d u r e s f o r t a b l e t s i n the o f f i c i a l  compendia  s p e c i f y t h a t n o t l e s s than twenty t a b l e t s s h o u l d be ground up, t h o r o u g h l y mixed, and s u i t a b l e samples t a k e n f o r a n a l y s i s . T h i s procedure g e n e r a l l y  tends t o g i v e r e s u l t s w h i c h f a i l t o  i n d i c a t e any t a b l e t t o t a b l e t c o n t e n t v a r i a t i o n .  Since t a b l e t s  are u s u a l l y a d m i n i s t e r e d s i n g l y , o r a t l e a s t i n q u a n t i t i e s  some-  what l e s s than t h a t s p e c i f i e d i n an assay, i t i s i m p o r t a n t  that  the d r u g c o n t e n t o f each and every t a b l e t comply w i t h t h e l a b e l claim. The N.P. X I I ( k 8 ) has i n t r o d u c e d a t e s t f o r u n i f o r m i t y of drug c o n t e n t i n t a b l e t s .  T h i s t e s t s t a t e s t h a t n o t more t h a n  one out o f t h i r t y t a b l e t s may assay o u t s i d e the l i m i t s o f - l5%> of l a b e l l e d potency.  A l t h o u g h t h i s i s a s t e p i n the r i g h t  d i r e c t i o n , the problem o f e x c e s s i v e v a r i a b i l i t y s t i l l Products which f a l l  remains.  j u s t w i t h i n the extremes o f these l i m i t s  may be t h e r a p e u t i c a l l y t o l e r a b l e ; however, such r e s u l t s would i n d i c a t e poor m a n u f a c t u r i n g p r o c e d u r e s and t h i s s h o u l d not be encouraged. stringent  I n a d d i t i o n t o t h e p r e s e n t r e q u i r e m e n t s , a more  t e s t s h o u l d be a p p l i e d .  E i t h e r a standard  deviation  67. or range l i m i t s h o u l d be i n c l u d e d  i n the t e s t .  As the t e s t  now s t a n d s , a range o f 30% may w e l l be a c c e p t a b l e . The r e s u l t s o f t h i s i n v e s t i g a t i o n i n d i c a t e t h a t a s u i t a b l e test f o r uniformity  o f drug c o n t e n t i n t a b l e t s s h o u l d r e a d :  Assay t e n t a b l e t s i n d i v i d u a l l y .  The average  c o n t e n t o f these t e n t a b l e t s s h o u l d f a l l w i t h i n - 7% o f l a b e l l e d potency.  The s t a n d a r d  d e v i a t i o n f o r t h e t e n i n d i v i d u a l assays s h o u l d be n o t more t h a n k% and no t a b l e t s h o u l d a s s a y l e s s than 85% o r more t h a n 115% o f l a b e l l e d potency. The assay procedure f o r phenylbutazone t a b l e t s i n the N.P. XII  (k8) c a l l s f o r samples c o n t a i n i n g  the e q u i v a l e n t o f s i x t a b l e t s ) .  600 mg. o f drug ( t h a t i s ,  An attempt was made t o a s s a y  i n d i v i d u a l t a b l e t s by t h i s t i t r i m e t r i c p r o c e d u r e . were i n c o n s i s t a n t  The r e s u l t s  p r i m a r i l y because o f the s m a l l q u a n t i t y o f  drug i n each t a b l e t and f o r t h i s reason a s p e c t r o p h o t o m e t r i c procedure was d e v e l o p e d .  T h i s method o f a n a l y s i s was d e s c r i b e d  i n the p r e v i o u s s e c t i o n .  T h i s p r o c e d u r e , on t h e b a s i s o f r e -  s u l t s on pure drug and t a b l e t s c o n t a i n i n g found t o be a c c u r a t e and was t h e r e f o r e  p h e n y l b u t a z o n e , was  used i n a l l s i n g l e  tablet  assays. (i)  Results. The N.P. X I I s e t s l i m i t s o f £' 7% o f l a b e l c l a i m f o r t h e  average assay o f phenylbutazone t a b l e t s . tested,  Of t h e 23 samples  two samples, J and P, assayed 92.8% and 88.9% r e -  s p e c t i v e l y as shown i n Table I V .  I f i n d i v i d u a l t a b l e t assay  68. i s c o n s i d e r e d ( t h e N.F. a l l o w s - 15% o f l a b e l l e d  potency),  one o t h e r sample, B, c o n t a i n e d t a b l e t s a s s a y i n g l e s s  than  85% and, t h e r e f o r e , would be r e j e c t e d a l t h o u g h t h e average assay was w i t h i n t h e l i m i t s However, i f t h e suggested  of 93% t o 107% of l a b e l c l a i m .  c r i t e r i a o f a k% s t a n d a r d d e v i a -  t i o n i s a p p l i e d , one o t h e r p r o d u c t , X, would be r e j e c t e d . Two o t h e r samples, M and R, c o n t a i n e d t a b l e t s which, on an i n d i v i d u a l b a s i s , were o u t s i d e the l i m i t s  s e t f o r average  assay and i t i s d o u b t f u l i f these t a b l e t s c o u l d be c o n s i d ered adequate.  These r e s u l t s would t e n d t o s u b s t a n t i a t e  the o b s e r v a t i o n s made by Brunning  and K i n g ( k ) t h a t the  p r e s e n t o f f i c i a l a t t r i b u t e methods of t a b l e t t e s t i n g cannot d i f f e r e n t i a t e or detect excessive t a b l e t t o t a b l e t v a r i a tion. I t was a l s o noted t h a t a l t h o u g h t h e l a b e l l e d potency of a l l p r o d u c t s was 100 mg. o f phenylbutazone samples, E,J,M,0,P and Y l e s s than t h i s amount. variability  per t a b l e t , s i x  contained t a b l e t s which  assayed  However, sample Y showed t h e l e a s t  (a s t a n d a r d d e v i a t i o n of 0.29) i n t a b l e t  i n d i c a t i n g good c o n t r o l procedures  potency  d u r i n g manufacture.  T h i s may be compared xtfith the v a r i a b i l i t y  shown by samples  B and X ( s t a n d a r d d e v i a t i o n s of 8.36 and 8.01 r e s p e c t i v e l y ) which was more than the k% l i m i t suggested poor q u a l i t y  and would i n d i c a t e  control.  A l l t a b l e t s s t u d i e d are a v a i l a b l e c o m m e r c i a l l y i n Canada and were purchased  through r e g u l a r drug  outlets.  69.  (b) D i s i n t e g r a t i o n T e s t s . (i)  Initial  Investigations  I n i t i a l i n v e s t i g a t i o n s u s i n g Method I I showed t h a t the d i s i n t e g r a t i o n times of the 23 p r o d u c t s v a r i e d f r o m f o u r to 71 minutes as shown i n Table V.  The times f o r f o u r  p r o d u c t s were l e s s than t e n minutes and f o r n i n e p r o d u c t s were g r e a t e r t h a n t h i r t y minutes.  However, o n l y one p r o -  duct f a i l e d t o comply w i t h the r e g u l a t i o n s i n the Food and Drugs A c t . ing  Even though most p r o d u c t s complied w i t h e x i s t -  r e g u l a t i o n s , t h e r e was much i n - p r o d u c t v a r i a t i o n . Sample G i s an example o f a good p r o d u c t , the minimum  d i s i n t e g r a t i o n time b e i n g t h r e e minutes being f o u r minutes.  and the maximum  On the o t h e r hand, many o t h e r p r o d u c t s  showed extreme v a r i a b i l i t y .  F o r example, sample W, w i t h a  d i s i n t e g r a t i o n time of 71 m i n u t e s , showed a minimum time of 1+6 minutes and a maximum t i m e of more than 120  minutes.  These r e s u l t s would i n d i c a t e poor q u a l i t y c o n t r o l .  A re-  asonable  spread o f v a l u e s would be a p p r o x i m a t e l y f i f t e e n  minutes.  U s i n g t h i s a r b i t r a r y l i m i t as a base, e i g h t of  the 23 p r o d u c t s would show e x c e s s i v e v a r i a b i l i t y . Of the twelve p r o d u c t s chosen f o r more i n t e n s i v e s t u d y , one d i s i n t e g r a t e d i n l e s s than t e n m i n u t e s , t h r e e had i n t e g r a t i o n times between t e n minutes  and t h i r t y  seven d i s i n t e g r a t e d between t h i r t y minutes and  dis-  minutes,  sixty  minutes and one showed a d i s i n t e g r a t i o n time o f more than sixty  minutes.  70. ( i i ) Investigations ~  On Twelve P r o d u c t s .  The o f f i c i a l d i s i n t e g r a t i o n t e s t (Method I ) on the  twelve p r o d u c t s i n d i c a t e s t h a t the  sample ¥ f a i l s t o comply  time l i m i t r e q u i r e m e n t o f s i x t y minutes  with  (see Table V I ) .  T h i s p r o d u c t , and sample E, c o n t a i n e d i n d i v i d u a l t a b l e t s w h i c h showed d i s i n t e g r a t i o n t i m e s i n excess o f 75 m i n u t e s . The v a r i a b i l i t y  (measured by one s t a n d a r d d e v i a t i o n ) i n  d i s i n t e g r a t i o n times from t a b l e t t o t a b l e t f o r these two p r o d u c t s was Q0% - 100%, g r e a t e r t h a n f o r t h e p r o d u c t w i t h the next h i g h e s t t i m e .  T h i s would i n d i c a t e  non-uniform  tablet production. D i s i n t e g r a t i o n t e s t s by Methods I I and IV showed no appreciable differences  i n average d i s i n t e g r a t i o n times f o r  e l e v e n o f the t w e l v e p r o d u c t s t e s t e d as shown i n Tables V I I and V I I I .  One p r o d u c t , Q, had an average  disintegration  time o f 39 minutes by Method I I compared to 79 minutes by Method I V . However, w i t h i n a t e s t , some p r o d u c t s showed a h i g h degree o f v a r i a b i l i t y .  Sample G. by Method I I , con-  t a i n e d t a b l e t s r a n g i n g from 30 minutes t o 75 m i n u t e s and by Method I V , from 20 minutes t o 90 m i n u t e s .  Samples E and Q,  by Method IV a l s o showed ranges o f I4.8 minutes and 55 minutes r e s p e c t i v e l y . method.  Sample ¥ d i d n o t d i s i n t e g r a t e by e i t h e r  Sample X had a l o n g d i s i n t e g r a t i o n time c o u p l e d  w i t h a h i g h v a r i a b i l i t y under the same t e s t  conditions.  A comparison o f t h e d i s i n t e g r a t i o n times by Methods I , I I and I V , f o r the t w e l v e p r o d u c t s , showed t h a t sample Q. had a d i s i n t e g r a t i o n time which was 100$ l o n g e r by Method  71.  IV than by e i t h e r o f the o t h e r two methods.  Sample X,  when t e s t e d by Methods I I and IV, showed d i s i n t e g r a t i o n times o f 70 minutes and 62 minutes r e s p e c t i v e l y as compared t o 5 1 minutes o b t a i n e d by Method I . The r e s u l t s would a l s o i n d i c a t e t h a t two p r o d u c t s , W and X, demonstrate  pro-  l o n g e d d i s i n t e g r a t i o n t i m e s under a l l t e s t c o n d i t i o n s . t e n o f the t w e l v e p r o d u c t s , the d i s i n t e g r a t i o n times  For obtain-  by these methods u t i l i z i n g d i s c s , were w i t h i n f i f t e e n minu t e s o f each o t h e r . Three p r o d u c t s C, D, and L, demonstrated  identical  i n t e g r a t i o n times when t e s t e d by Methods I I and I I I .  dis-  The  o t h e r n i n e p r o d u c t s showed d i s t i n c t l y l o n g e r d i s i n t e g r a t i o n times w i t h Method I I I .  By t h i s method, no t a b l e t s from p r o -  d u c t s B, E and ¥ d i s i n t e g r a t e d w i t h i n two h o u r s . A, G, P and X c o n t a i n e d one t o t h r e e t a b l e t s which f a i l e d to disintegrate within this  Products also  time.  The d i s i n t e g r a t i o n times f o r two p r o d u c t s , A and C, were r e l a t i v e l y u n a f f e c t e d by changing from Method IV to Method V.  A l l t a b l e t s o f the f i v e p r o d u c t s B, E. Q, W and  X, f a i l e d t o d i s i n t e g r a t e w i t h i n two hours when t e s t e d by Method V.  Product P d i s i n t e g r a t e d f a s t e r by Method V w h i l e  p r o d u c t s D, G, H and L d i s i n t e g r a t e d f a s t e r by Method IV. T a b l e t s from p r o d u c t s B, E, W and X f a i l e d to d i s i n t e g r a t e w i t h i n two hours when t e s t e d by Methods I I I and V as shown i n T a b l e s V I I and V I I I . I t s h o u l d be noted t h a t one p r o d u c t , C, showed a cons i s t a n t l y low d i s i n t e g r a t i o n time o f f o u r minutes when t e s t e d by any o f the f i v e methods.  72. ( i i i ) Summary o f R e s u l t s The  r e s u l t s o b t a i n e d i n t h i s i n v e s t i g a t i o n would i n -  d i c a t e that the p r e s e n t d i s i n t e g r a t i o n t e s t does not d i s criminate factor. one  s u f f i c i e n t l y when e x c e s s i v e v a r i a b i l i t y i s a There i s an o b v i o u s need f o r a more s t r i n g e n t t e s t ,  w h i c h would i n c l u d e  some measure o f v a r i a b i l i t y such as  range o r s t a n d a r d d e v i a t i o n .  A p r a c t i c a l l i m i t might be a  f i f t e e n minute spread i n d i s i n t e g r a t i o n times between t a b l e t s i n any one t e s t . The  r e s u l t s , o b t a i n e d w i t h and w i t h o u t d i s c s , suggest  t h a t t h e d i s c s were n e c e s s a r y t o keep the d i s i n t e g r a t i o n times w i t h i n r e a s o n a b l e l i m i t s f o r a l l t a b l e t s t e s t e d .  With-  out t h e d i s c s , $0% o f t h e t a b l e t s t e s t e d would have d i s i n t e g r a t i o n times i n excess o f two h o u r s .  The absence o f  d i s c s made no d i f f e r e n c e f o r the other 5 0 $ . t h e r e were no s i g n i f i c a n t d i f f e r e n c e s  I n most c a s e s ,  i n d i s i n t e g r a t i o n times  when g a s t r i c f l u i d o r i n t e s t i n a l f l u i d was u s e d as t e s t medium. The  d i s c s were o r i g i n a l l y i n c l u d e d  i n order to exert gentle p h y s i c a l J b r c e  i n the t e s t procedure on t h e t a b l e t s .  This  was supposed t o s i m u l a t e f o r c e s encountered i n t h e g a s t r o i n t e s t i n a l system. Laboratories  E a r l y i n v e s t i g a t o r s i n t h e Pood and Drugs  i n d i c a t e d t h a t t h i s procedure was v a l i d f o r the  products tested.  However, subsequent i n v e s t i g a t i o n s by  s e v e r a l workers (28,60) i n d i c a t e d t h a t i n v i v o  conditions  were such t h a t t a b l e t s were not s u b j e c t e d t o much p h y s i c a l force while  i n the stomach.  73. The r e s u l t s o f t h i s i n v e s t i g a t i o n would i n d i c a t e t a b l e t s c o u l d be f o r m u l a t e d t o d i s i n t e g r a t e under i n v i t r o c o n d i t i o n s an i n v i v o c l i m a t e .  (without  that discs)  which may be more i n d i c a t i v e of  T h i s t e s t may have some m e r i t i f an  i n v i t r o - i n v i v o r e l a t i o n s h i p i s to be i m p l i e d f r o m the disintegration test.  However, the p r e s e n t d i s i n t e g r a t i o n  t e s t s h o u l d n o t be u s e d as an i n d i c a t i o n o f drug a v a i l a b i l i t y u n l e s s i n v i v o d a t a i s o b t a i n e d and c o r r e l a t e d t o the i n v i t r o r e s u l t s . (c) D i s s o l u t i o n (i)  Tests.  T e s t s on S i x T a b l e t s . The amount o f phenylbutazone i n s o l u t i o n a f t e r two  hours ranged from 3 - 11 mg. and f r o m 1 - 8 mg. when the t a b l e t s were t e s t e d by Methods I I A and I I I A r e s p e c t i v e l y . For most p r o d u c t s , the r e s u l t s i n d i c a t e d t h a t the amount of drug i n s o l u t i o n was lower by Method I I I A than by Method IIA.  However, two p r o d u c t s , A and X, showed no change i n  dissolution rates.  Two o t h e r p r o d u c t s , D and L, showed  h i g h e r r e s u l t s by Method I I I A .  I t was a l s o n o t e d t h a t  tab-  l e t s which d i d not d i s i n t e g r a t e f u l l y w i t h i n the time l i m i t of two h o u r s showed l o w e r l e v e l s of d i s s o l u t i o n . E, when t e s t e d by Method I I I A , seemed t o be an  Product  exception.  The d i s s o l u t i o n l e v e l s were, as e x p e c t e d , h i g h e r by Methods IVA and VA than by Methods I I A and I I I A .  The max-  imum amount o f drug i n s o l u t i o n i n two hours ranged from 38 - 89 mg. and from 11 - 85 mg. as d e t e r m i n e d by Methods IVA  and VA r e s p e c t i v e l y .  Two p r o d u c t s , A and B, showed  71*.  h i g h e r l e v e l s by Method VA than by Method IVA.  This r e -  s u l t seems t o be r e a s o n a b l e f o r p r o d u c t A s i n c e d i s i n t e g r a t i o n of t h e s e t a b l e t s was r e l a t i v e l y r a p i d .  However,  the t a b l e t s o f product B d i d not d i s i n t e g r a t e w i t h i n hours. not  two  The o t h e r p r o d u c t s E, Q, W and X, w h i c h a l s o d i d  d i s i n t e g r a t e , showed low d i s s o l u t i o n r a t e s .  I t was  a l s o n o t e d t h a t f o r p r o d u c t W, whose d i s i n t e g r a t i o n was poor by a l l methods, the presence o f the d i s c s i n Methods I I A and IVA seemed to a i d i n the d i s s o l u t i o n p r o c e s s . Many i n v e s t i g a t o r s have used the G e r s h b e r g - S t o l l appa r a t u s t o study d i s s o l u t i o n of v a r i o u s t a b l e t s .  The r e -  s u l t s o f the p r e s e n t i n v e s t i g a t i o n shows t h a t t e s t s conducted with discs generally tests without d i s c s .  gave h i g h e r d i s s o l u t i o n r a t e s  They a l s o show t h a t r a p i d d i s i n t e g r a -  t i o n a i d e d i n the d i s s o l u t i o n p r o c e s s . discussion  than  on d i s i n t e g r a t i o n s t u d i e s ,  From the p r e v i o u s i t was suggested  the presence o f the d i s c s may tend t o mask the t r u e e r i s t i c s of the t a b l e t s .  that  charact-  T h e r e f o r e , a l t h o u g h the d i s c s  may  be e x p e d i e n t i n d i s i n t e g r a t i o n t e s t s , they s h o u l d be o m i t t e d i f t h i s apparatus i s used f o r d i s s o l u t i o n s t u d i e s .  In t h i s  case, t h e 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 of the t a b l e t s would b e t t e r r e f l e c t the t r u e i n h e r e n t c h a r a c t e r i s t i c s o f the  products.  ( i i ) T e s t s on I n d i v i d u a l  Tablets.  D i s s o l u t i o n p r o f i l e s o f s i n g l e t a b l e t s f r o m each of the  twelve p r o d u c t s were o b t a i n e d u s i n g Methods I I A and IVA.  The r e s u l t s are t a b u l a t e d  i n Table X and i l l u s t r a t e d i n  75. F i g u r e s 7 and 8. the  The d i s i n t e g r a t i o n times l i s t e d are f o r  i n d i v i d u a l tablets tested.  A f t e r s i x h o u r s , t h e max-  imum amount o f pure powdered drug d i s s o l v e d from a g e l a t i n c a p s u l e i n g a s t r i c f l u i d was 36 mg.  One p r o d u c t , C, app-  roached t h i s l i m i t w i t h 33 mg. i n s o l u t i o n a f t e r s i x h o u r s . In  g e n e r a l , the r e s u l t s i n d i c a t e t h a t t h e r e were a t l e a s t  t h r e e d i f f e r e n t p a t t e r n s o f drug r e l e a s e from these t a b lets. Product C and the pure drug d i s s o l v e d r a p i d l y d u r i n g the  first  30 m i n u t e s , more s l o w l y d u r i n g the n e x t 90 minutes  and showed no a d d i t i o n a l s o l u t i o n a f t e r about two h o u r s . At the o t h e r extreme, p r o d u c t s such as D, L and Q seemed t o r e l e a s e the drug a t a c o n s t a n t r a t e over a s i x hour p e r i o d at C.  a l e v e l which was about 60% l o w e r than t h a t f o r p r o d u c t A l l o t h e r p r o d u c t s f e l l between these extremes. I n i t i a l d i s s o l u t i o n r a t e s d u r i n g the f i r s t  90 minutes  appeared t o depend upon the d i s i n t e g r a t i o n t i m e . d i s i n t e g r a t i n g t a b l e t s showing the h i g h e s t r a t e s . this i n i t i a l  The f a s t e r After  p e r i o d , the r a t e o f r e l e a s e o f drug from a l l  p r o d u c t s was observed t o f a l l i n t o t h r e e p a t t e r n s .  The  r a t e o f r e l e a s e from p r o d u c t s D, L, Q, and H were almost identical.  The same may be s a i d o f p r o d u c t s (A,B,X) and  (W,G); and P r o d u c t s (E,P) and C.  The d i f f e r e n c e s i n i n i t i a l  d i s i n t e g r a t i o n times c o u l d account f o r 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 l e v e l s a t t a i n e d by these p r o d u c t s i n s i x h o u r s . It  s h o u l d be noted t h a t a l t h o u g h the d i s i n t e g r a t i o n times  of  p r o d u c t s W and X were i n excess of 60 m i n u t e s , t h e drug  76. r e l e a s e p a t t e r n s , a f t e r d i s i n t e g r a t i o n had occured, were b e t t e r than those o b t a i n e d f o r products w i t h s h o r t e r  disin-  t e g r a t i o n times. Since phenylbutazone i s more s o l u b l e , i n f l u i d than i n g a s t r i c f l u i d , by Method IVA  (Figure 8 ) ,  t a i n e d by Method IIA.  intestinal  the d i s s o l u t i o n l e v e l s  attained  were much higher than those ob-  W i t h i n 30 minutes, 85$ of the drug  from products A, E, G. P, and a pure drug sample had s o l v e d and 100$ was  i n s o l u t i o n a f t e r 90 minutes.  dis-  Products  (A,B) and (D,L.Q) showed a much more g r a d u a l r a t e of r e l e a s e r e a c h i n g l e v e l s of about 75$ f i v e hours.  and 85$ r e s p e c t i v e l y  after  D i s i n t e g r a t i o n times seemed to a f f e c t the r e -  l e a s e of drug from products such as H and X. disintegration,  the r a t e of r e l e a s e was  However, a f t e r  f a i r l y rapid.  Pro-  duct W d i d not d i s i n t e g r a t e but slowly d i s s o l v e d a f t e r the o u t e r coat had broken away. The r e l e a s e p a t t e r n f o r a good phenylbutazone u s i n g Method IIA, appears to be as f o l l o w s :  tablet,  20$ r e l e a s e d  i n 15 minutes, 25$ i n 30 minutes, 27$ i n 60 minutes,  30$  i n 90 minutes, and 33$ between t h r e e and s i x hours.  This  may  be compared with approximately 3U-$ d i s s o l u t i o n f o r pure  i n three hours. the  In i n t e s t i n a l f l u i d  (Method IVA), 75$ of  drug should be i n s o l u t i o n w i t h i n 15 minutes and  100%  between 60 and 90 minutes. The performance  of the t a b l e t p r e p a r a t i o n s when t e s t -  ed by Methods IIA and IVA could be r a t e d as f o l l o w s : Product G demonstrated good 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 by  77. both  methods.  Method  P r o d u c t s E, G a n d P s h o w e d  IVA o n l y .  patterns Starrer  by b o t h  medium u s e d  to  dosage  forms.  of  With  the effect  on d i s s o l u t i o n r a t e  phenylbutazone 100 r.p.m.  surface  have  this  were  the stirrer  any  action.  observed  t o be g e n t l y  forming  Methods  drug  swirled  the  of drug  33  as d e t e r m i n e d  which  s e t 10  i n solution after by Method  d i d not disintegrate,  studies of  stir-  speed  cm. b e l o w t h e f o r homo-  enough  to  avoid  p a r t i c l e s were o f t h e con-  stirrer. to study  the dissolution  from each  The d i s i n t e g r a t i o n t i m e s  amount  from  a stirring  the bottom  of individual tablets  are f o r the i n d i v i d u a l t a b l e t s  mg.  that  but slow  around  and  one b r a n d o f  enough t o a l l o w  V I and V I I were u s e d  samples.  release  and depth  The c o a r s e t a b l e t  a mound b e l o w  characteristics twelve  blade  factors  preliminary  rate  I t was f o u n d  of the dissolved  tainer  i n mind,  that  carried out using  genous m i x i n g  XI  release  of s t i r r e r ,  o f drug  of s t i r r i n g  tablets. (with  depth  the rate  o f t h e l i q u i d ) was f a s t  turbulent  determined  a g i t a t i o n (r.p.m.),  can influence  determine  rer  poor  by  methods.  investigators  as rate/of  solid  a n d Q, s h o w e d  release  method.  Previous such  P r o d u c t s L , D,  good  listed  tested.  Tablets  showed v e r y  i n Table  T h e maximum  s i x hours  VI.  of the  ranged  from  B, E a n d  1.2  W,  low d i s s o l u t i o n  levels. The were  release  patterns  s i m i l a r to those  o b t a i n e d by Method VI  o b t a i n e d by Method  (Figure 9 )  IIA (Figure  7),  -  78. except t h a t the p r o d u c t s a t the v a r i o u s l e v e l s may be i n terchanged.  The presence of the d i s k s i n Method I I A may  have been r e s p o n s i b l e f o r the d i f f e r e n c e between the r e l e a s e p a t t e r n s o b t a i n e d f o r p r o d u c t s B, E and W by t h i s method and those o b t a i n e d by Method V I .  When sample  tab-  l e t s from these p r o d u c t s were c r u s h e d b e f o r e t e s t i n g , the d i s s o l u t i o n p a t t e r n s o b t a i n e d were i d e n t i c a l to those o f t a b l e t s from p r o d u c t C and o f the pure drug sample.  These  r e s u l t s would i n d i c a t e t h a t the drug was a v a i l a b l e from the formulation.  T a b l e t s from p r o d u c t X c o n t a i n e d a c o a t i n g  w h i c h remained i n t a c t f o r t h r e e t o f o u r h o u r s and t h i s would a f f e c t the d i s s o l u t i o n r a t e as seen from the c u r v e . D i s s o l u t i o n p r o f i l e s o b t a i n e d by Method V I I are d e p i c ted  i n F i g u r e 10.  release patterns:  The t r e n d s may be i l l u s t r a t e d by t h r e e t a b l e t s such as those from samples  G and P show i n i t i a l  C,  r a p i d d i s s o l u t i o n to a maximum of  100$  w i t h i n the f i r s t hour; t a b l e t s from samples E, Q, and W do n o t c o m p l e t e l y d i s i n t e g r a t e and hence r e l e a s e t h e i r drug c o n t e n t at a more g r a d u a l r a t e ; the o t h e r samples f a l l where between these two  some-  extremes.  Product X i s e x c e p t i o n a l i n t h a t i t c o n t a i n s a c o a t i n g m a t e r i a l w h i c h i s r e s i s t a n t t o d i s i n t e g r a t i o n by e i t h e r of t h e s e t e s t methods.  I t a l s o showed some r e s i s t a n c e when  t e s t e d by Methods I I I A and VA.  However, once t h i s c o a t i n g  was removed, the drug d i s s o l v e d r a p i d l y .  T a b l e t s from  samples E and W s l o w l y d i s s o l v e d but d i d not d i s i n t e g r a t e into fine p a r t i c l e s .  Sample P i s a good example of a p r o d u c t  79.  which is well formulated and releases its active ingredient.  However, i t is poorly controlled with respect to its  drug content. Disintegration, as observed by this test method, does not automatically imply dissolution.  Five products tested  in simulated gastric fluid disintegrated but showed poor release patterns.  Two products, tested in simulated intes-  tinal fluid, also disintegrated and showed low levels of dissolution. ( i i i ) The Stirrer Apparatus (Methods VI and VII) vs. the F.D.D. Apparatus (Methods IIA and IVA). The release pattern for a good tablet tested by the stirrer method appears to be very similar to that obtained by the F.D.D. apparatus. For product G, using Method IIA, the time for 1 0 % release ( T 1 0 % ) was ten minutes and for 2 0 % release ( T 2 0 % )  was 2 k minutes.  By Method VI, T 1 0 % was also  ten minutes and T 2 0 % was 2 8 minutes.  These results may be  compared with that for pure drug when T 1 0 % was 1 5 minutes and T 2 0 % was 3 1 minutes, as shown in Table XII. Using Method IIA, four products, L, P. Q and X failed to attain 2 0 % dissolution in five hours.  Product Q, did not  even attain a T 1 0 % level in more than five hours. Therefore eight products attained 2 0 % dissolution in five hours or less.  On the other hand, with Method VI, only three pro-  ducts C, G and P showed a T 2 0 % of five hours or less.  Two  of these, G and P, were 3 0 0 and 288 minutes respectively. Hence nine products tested by this method failed to attain 2 0 % dissolution in five hours.  Three of these products,  79A  TABLE X I I R e l e a s e P a t t e r n s f o r Phenylbutazone f r o m T a b l e t s u s i n g Methods I I A and VI.#  Sample Code  Method I I A T 10$  a b c  T 20$ (Minute s)  A  132  278  B  132  297  G  10  D  169  282  E  25  178  G  96  H L  21+  T 10$ T 20$ (Minutes )-::--::21+0  a  b a 10  b a 28 a  291t b  b  289  a 120  a 300  135  288  219  a  255  a  177  a  P  k-o  313  99  288  Q  330  390  198  a  W  72  226  a  X  95  332  17if  15  31  21  •g  -x-  Method VI  b  C  Average o f two t a b l e t s Time f o r 10$ and 20$ o f the drug t o be i n s o l u t i o n More than seven h o u r s T a b l e t e s s e n t i a l l y i n t a c t a f t e r seven hours T a b l e t c o a t i n g i n t a c t f o r t h r e e t o f o u r hours  b a 372° 60  80.  B, E and W, hours.  a l s o f a i l e d t o have a T 1 0 $ of l e s s than f i v e  The t a b l e t s o f t h e s e t h r e e p r o d u c t s were e s s e n t i a l l y  i n t a c t a f t e r seven h o u r s .  However, t h e t a b l e t s of f i v e  p r o d u c t s , A, D, H. L and Q, a l t h o u g h t h e y d i s i n t e g r a t e d , d i d not r e l e a s e  20$ of t h e i r a c t i v e i n g r e d i e n t  i n seven h o u r s .  T e s t s by Method IVA showed t h a t o n l y one p r o d u c t , B,  T?5$  had a  i n excess of f i v e h o u r s .  W i t h Method V I I f o u r  p r o d u c t s , E, Q, W and X, had a T75$ of more than f i v e h o u r s . P r o d u c t s E and W a g a i n f a i l e d t o d i s i n t e g r a t e , however, t h e y dissolved  slowly.  These r e s u l t s are shown i n Table X I I I .  Methods I I A and IVA would appear t o g i v e more f a v o u r a b l e r e s u l t s which may o r may n o t r e p r e s e n t the t r u e o l u t i o n c h a r a c t e r i s t i c s o f the p r o d u c t s .  However, these  two methods were r e j e c t e d f o r d i s s o l u t i o n s t u d i e s presence of t h e d i s c s seemed t o o v e r l y  influence  o l u t i o n r a t e of the drug from the t a b l e t .  diss-  s i n c e the the d i s s -  Previous authors  (8,5>!L) have suggested t h a t a t e s t w i t h o u t d i s c s might be a more a c c e p t a b l e p r o c e d u r e .  However, i n s u f f i c i e n t d a t a was  c o l l e c t e d i n t h i s i n v e s t i g a t i o n t o warrent any d e f i n i t e c o n c l u s i o n s on the m e r i t s of t h i s system a t t h i s t i m e . A l l methods g i v e e s s e n t i a l l y the same type o f d i s s o l u t i o n c u r v e s i n g a s t r i c and i n t e s t i n a l f l u i d s .  The  discs  i n t h e F.D.D. apparatus t e n d t o produce a more r a p i d d i s i n tegration discs.  of the t a b l e t s than would n o r m a l l y o c c u r w i t h o u t  Significant differences  i n d i s s o l u t i o n rates  may  not t h e n show up on d i s s o l u t i o n t e s t i n g u s i n g t h i s apparatus.  T h i s was o b v i o u s i n the case of p r o d u c t s B, E and  80A.  TABLE X I I I Release  Sample Code  P a t t e r n s f o r Phenylbutazone from T a b l e t s u s i n g Methods IVA and VII.-::-  Method IVA T 50%  T 75% (Minutes )-::-*  T 50% T 75% (Minutes )-::--::-  A  83  268  5k  96  B  12k  369  86  188  C  9  20  9  13  D  69  165  57 .  108  E  36  5k  210  G  36  57  31  k2  H  65  122  80  120  L  77  169  5k  97  P  27  kO  36  • k9  Q  86  165  17k  a  b  ¥  113  207  I88  X  72  165  369°  6  10  Drug -::-:H:a b c  Method V I I  b  5  Average o f two t a b l e t s Time f o r 5 0 % and 7 5 % o f the d r u g to be i n s o l u t i o n More than seven hours Tablet slowly d i s s o l v e s T a b l e t c o a t i n g i n t a c t f o r t h r e e t o f o u r hours  352  308 a 10  b  b  W which were shown t o r e l e a s e  the drug o n l y a f t e r b e i n g  crushed. P r o d u c t s D and Q remained a t about the same low .diss'-* o l u t i o n l e v e l w i t h a l l methods a l t h o u g h t h e i r t a b l e t s d i d disintegrate  ( a t t h e time of the t e s t ) w i t h i n  time l i m i t of 60 m i n u t e s .  the o f f i c i a l  C o n v e r s e l y , p r o d u c t C remained  at the same h i g h l e v e l w i t h a l l methods and systems u s e d . I n g e n e r a l , the S t i r r e r method tended t o g i v e d i s s o l u t i o n r e s u l t s w h i c h p r o b a b l y would be more c o n s i s t e n t the  with  a c t u a l i n h e r e n t b e h a v i o r o f the i n d i v i d u a l t a b l e t s .  Here 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 were not marked by d i s i n t e g r a t i o n f o r c e s which may o r may n o t a i d i n the d i s s o l u t i o n process.  I t i s t h e r e f o r e suggested t h a t f o r d i s s o l -  u t i o n t e s t s , the o f f i c i a l d i s i n t e g r a t i o n apparatus s h o u l d be d i s c a r d e d and some o t h e r method, such as the S t i r r e r method, u s e d i n i t s p l a c e . (d) D i s i n t e g r a t i o n  - Dissolution  No s p e c i f i c c o r r e l a t i o n s  Correlations.  c o u l d be found between d i s i n t e g r a -  t i o n times and d i s s o l u t i o n r a t e s o f phenylbutazone from compressed t a b l e t s . grated slowly  I t was o b s e r v e d t h a t  tablets which d i s i n t e -  always showed l o w e r d i s s o l u t i o n r a t e s .  t a b l e t s which d i s i n t e g r a t e d higher dissolution rates.  However,  r a p i d l y d i d not n e c e s s a r i l y One p r o d u c t c o n s i s t e n t l y  show  exhibited  s h o r t d i s i n t e g r a t i o n times and h i g h d i s s o l u t i o n r a t e s .  However,  i n t h e m a j o r i t y of cases the a v a i l a b i l i t y o f t h e d r u g from the t a b l e t s c o u l d n o t be p r e d i c t e d  from t h e i r d i s i n t e g r a t i o n  behavior.  These o b s e r v a t i o n s have a l s o been r e p o r t e d i n the l i t e r a t u r e (1+3, 5l+,67).  82. Product Q u a l i t y (a) T a b l e t Assay. (i)  Two o f t h e 23 p r o d u c t s t e s t e d , J i a n d P, would be r e j e c t  ed on t h e b a s i s o f average c o n t e n t . ( i i ) One o t h e r p r o d u c t , B, would be r e j e c t e d on t h e b a s i s o f individual tablet  assay.  ( i i i ) Product X would a l s o be r e j e c t e d i f the suggested  cri-  t e r i a o f a \+% s t a n d a r d d e v i a t i o n was a p p l i e d . ( i v ) On the b a s i s o f ( I ) , ( i i ) and ( i i i ) above, f o u r o f t h e 23 p r o d u c t s t e s t e d ( a p p r o x i m a t e l y 1 7 $ ) would be r e j e c t e d . (v)  Two p r o d u c t s , I and M, a l t h o u g h complying w i t h o f f i c i a l  r e q u i r e m e n t s , h a d s t a n d a r d d e v i a t i o n s between 3 and I4. and t h e r e f o r e would appear t o show q u e s t i o n a b l e c h a r a c t e r i s t i c s w i t h respect to potency  variations  (b) T a b l e t d i s i n t e g r a t i o n . (i)  By t h e o f f i c i a l procedure  (¥ and E) would f a i l  (Method I ) , two p r o d u c t s  to comply w i t h c u r r e n t r e g u l a t i o n s .  ( i i ) A l l o w i n g f o r a f i f t e e n minute spread i n v a l u e s , s i x p r o ducts ( E , G, H, P, W and X) would ahow e x c e s s i v e i n - p r o d u c t v a r i a b i l i t y when t e s t e d by Methods I , I I o r IV. ( i i i ) C o n s i d e r i n g i n d i v i d u a l p r o d u c t s , o n l y two (Q and X) would show between-methods v a r i a b i l i t y . ( i v ) Two p r o d u c t s  (¥ and X) showed p r o l o n g e d  disintegration  times by a l l methods. (v)  F i f t y p e r cent o f t h e p r o d u c t s t e s t e d would f a i l t o  comply e i t h e r w i t h c u r r e n t r e g u l a t i o n s or the proposed I n product v a r i a b i l i t y c r i t e r i s of - 15  minutes.  83.  (c) T a b l e t D i s s o l u t i o n . (i)  The r e l e a s e o f phenylbutazone from s u g a r - c o a t e d tab-  l e t s f e l l i n t o t h r e e d i s t i n c t p a t t e r n s when t e s t e d by Methods V I and V I I . ( i i ) Three p r o d u c t s (C, G and P) demonstrated an i n i t i a l r a p i d d i s s o l u t i o n r a t e w h i c h produced a maximum o f 100% d i s s o l u t i o n w i t h i n the f i r s t hour when t e s t e d by Method V I I . ( i i i ) Three p r o d u c t s ( E , Q and ¥) r e l e a s e d the drug a t a more g r a d u a l r a t e and a t t a i n e d maximum l e v e l s of about 75% i n f i v e hours. ( i v ) One p r o d u c t ,  C, c o n s i s t e n t l y showed e x c e l l 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 which were comparable t o t h a t found f o r pure drug. (v)  Two p r o d u c t s ,  questionable (vi)  E and ¥, may be c l a s s i f i e d as h a v i n g  d i s s o l u t i o n patterns.  It i sdifficult  t o judge t h e m e r r i t s o f t h e m a j o r i t y  of p r o d u c t s on the b a s i s o f the l i m i t e d i n f o r m a t i o n ed by these i n v i t r o methods.  obtain-  F o r a proper e v a l u a t i o n , i n  v i v o data s h o u l d be o b t a i n e d f o r c o r r e l a t i o n s w i t h these i n vitro findings. 3«  I n Vivo I n v e s t i g a t i o n s This i n v e s t i g a t i o n concerned i t s e l f w i t h the i n v i t r o  e r i s t i c s o f phenylbutazone t a b l e t s .  However, i n v i v o s t u d i e s were  begun i n t h i s l a b o r a t o r y and some o f t h e r e s u l t s o f these gations are reported  charact-  investi-  herein.  Burns, e t a l . ( 7 3 ) r e p o r t e d t h a t peak plasma l e v e l s f o r butazone are r e a c h e d i n about two h o u r s .  phenyl-  I n t h i s same p u b l i c a t i o n  81+.  they c l a i m e d t h a t a l a r g e p o r t i o n of a d m i n i s t e r e d phenylbutazone i s found i n the plasma.  I t was d e c i d e d , t h e r e f o r e , to i n v e s t i g a t e  ser-  um c o n c e n t r a t i o n s a f t e r a d m i n i s t r a t i o n o f the p r o d u c t s e x h i b i t i n g specific dissolution characteristics.  The procedure f o l l o w e d i s  o u t l i n e d below. " A d m i n i s t e r 2 0 0 mg.  o f drug ( o r two 1 0 0 mg.  At the same t i m e , withdraw 1 5 ml.  tablets).  of b l o o d , a l l o w to stand f o r two h o u r s , cent r i f u g e a t 1 5 0 0 r.p.m., and remove the serum. T h i s i s the b l o o d b l a n k .  B l o o d samples are  then t a k e n a t a p p r o x i m a t e l y two, f i v e ,  seven  and 21+ h o u r s a f t e r d r u g a d m i n i s t r a t i o n . " The amount of. phenylbutazone i n the serum i s determined by the p r o cedure o u t l i n e d below. "Add 0 . 5 m l . of 3 N HC1 and 2 0 . 0 m l . of heptane t o 2 . 0 m l . o f serum. minutes.  Shake f o r t h i r t y  E x t r a c t 1 5 . 0 m l . of the heptane  s o l u t i o n w i t h 5 . 0 m l . of 2 . 5 N NaOH.  Record  the absorbancy of t h i s s o l u t i o n at 2 6 5 mu." The d r u g (or drug i n t a b l e t form) was  administered to three  h e a l t h y males. The f i r s t s u b j e c t r e c e i v e d 2 0 0 mg. s u l e form.  of phenylbutazone i n cap-  A peak c o n c e n t r a t i o n of a p p r o x i m a t e l y 3 0 mg./  observed f i v e h o u r s a f t e r a d m i n i s t r a t i o n .  L. was  Twenty-nine hours a f t e r  a d m i n i s t r a t i o n , the c o n c e n t r a t i o n of phenylbutazone i n the serum had f a l l e n to a p p r o x i m a t e l y 1 2 mg.  / L.  .85.T h i s same s u b j e c t r e c e i v e d 200 mg. o f phenylbutazone form (Product Q).  i n tablet  The serum c o n c e n t r a t i o n was a p p r o x i m a t e l y 7 mg.  / L. f i v e hours a f t e r a d m i n i s t r a t i o n .  Twenty-seven hours a f t e r ad-  m i n i s t r a t i o n , serum c o n c e n t r a t i o n had r i s e n to a p p r o x i m a t e l y 15  mg.  / L. A second s u b j e c t r e c e i v e d t h e same p r o d u c t and t h e r e s u l t s were almost i d e n t i c a l . A t h i r d s u b j e c t was g i v e n 200 mg. o f phenylbutazone form ( P r o d u c t A) d a i l y f o r t h r e e days.  i n tablet  The serum l e v e l a f t e r 12  hours was a p p r o x i m a t e l y 16 mg. / L., a f t e r 36 h o u r s , 30 mg. / L., and a f t e r 60 h o u r s , k5 mg. / L.  -  The r e s u l t s o b t a i n e d w i t h phenylbutazone powder would to c o n t r a d i c t l i t e r a t u r e o b s e r v a t i o n s .  appear  Peak l e v e l s were o b t a i n e d (73)  i n f i v e r a t h e r than i n two hours as r e p o r t e d by Burns, e t a l .  F u r t h e r m o r e , these a u t h o r s s t a t e d t h a t the r a t e o f metabolic?! t r a n s f o r m a t i o n ranged from 10 t o 35 p e r cent p e r day. The v a l u e c a l c u l a t e d i n t h i s p r e l i m i n a r y experiment was o f the o r d e r o f 60 p e r c e n t . On t h e o t h e r hand, t h i s was n o t c o n f i r m e d f o r Product Q.  Serum  l e v e l s c o n t i n u e d t o i n c r e a s e (even though these were depressed below those found f o r pure drug) and showed no i n d i c a t i o n o f decrease over the 2k hour i n v e s t i g a t i o n a l p e r i o d . I t i s d i f f i c u l t t o r e l a t e these i n v i v o f i n d i n g s t o t h e i n v i t r o 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 the t a b l e t s These s t u d i e s c o v e r e d o n l y two extremes  - pure phenylbutazone  t a b l e t w i t h v e r y low 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 . can be made. immediate  This p a r t i c u l a r tablet  blood l e v e l s .  investigated. and a  One o b s e r v a t i o n  (Product Q) does n o t produce  On t h e b a s i s o f the r e s u l t ; o b t a i n e d w i t h  Product A (serum l e v e l s i n c r e a s e d over a 60 hour p e r i o d ) , i t i s  86. p r o b a b l e t h a t Product Q would a l s o e x h i b i t s i m i l a r  characteristics.  The i m p l i c a t i o n h e r e i s t h a t , w i t h t i m e , b o t h p r o d u c t s would p r o duce i d e n t i c a l serum l e v e l s .  F o r l o n g term t h e r a p y , t h e r e f o r e ,  t h i s p r o d u c t might w e l l be s a t i s f a c t o r y .  On t h e o t h e r hand, c o n d i -  t i o n s such as acute gout would n o t respond t o t r e a t m e n t w i t h t h i s p a r t i c u l a r product.  I t i s i n t e r e s t i n g t o n o t e t h a t t h e 2LL hour  c o n c e n t r a t i o n f o r b o t h the pure d r u g and P r o d u c t Q are about the same - a p p r o x i m a t e l y 15 mg. / L. I t would be unwise t o attempt any c o r r e l a t i o n w i t h i n v i t r o findings at t h i s point.  However, t h e g e n e r a l t r e n d s would  t h a t such c o r r e l a t i o n s are f e a s i b l e .  indicate  The r e s e a r c h e r would expect a  peak b l o o d l e v e l s h o r t l y a f t e r t h e a d m i n i s t r a t i o n o f phenylbutazone powder.  Such i s the case.  S i m i l a r l y , t h e r e s e a r c h e r would expect  t h a t t h i s l e v e l would be much le ss a f t e r t h e a d m i n i s t r a t i o n o f Product Q.  T h i s was a l s o o b s e r v e d .  Other p r o d u c t s would be e x p e c t -  ed t o f a l l between t h e s e two extremes.  I f they do, and i f t h e s e  l e v e l s i n c r e a s e i n t h e same manner as t h e i n v i t r o  concentrations  o f the r e s p e c t i v e p r o d u c t s i n the d i s s o l u t i o n medium, then an i n v i t r o - i n v i v o c o r r e l a t i o n can be made.  87.  V. 1.  SUMMARY AND CONCLUSIONS  The assay p r o c e d u r e i n the N.P. X I I f o r phenylbutazone was  found t o be u n s a t i s f a c t o r y subsequent 2.  dissolution  studies.  A s p e c t r o p h o t o m e t r i c method was developed and found  f o r t h e purposes o f t h i s 3.  f o r i n d i v i d u a l t a b l e t assays and f o r  investigation.  The l i m i t s s e t i n t h e N.P. X I I f o r c o n t e n t u n i f o r m i t y  encompass a l l cases o f e x c e s s i v e v a r i a b i l i t y . following  suitable  do n o t  Consequently, t h e  t e s t c r i t e r i o n i s suggested:  Assay t e n t a b l e t s i n d i v i d u a l l y .  The average  content  of these t e n t a b l e t s s h o u l d f a l l w i t h i n - 7% o f the l a b e l l e d potency.  The s t a n d a r d d e v i a t i o n  f o r the t e n i n d i v i d u a l  assays s h o u l d be not more than k% and no t a b l e t s h o u l d assay l e s s t h a n 85% o r more than 115% o f the l a b e l l e d potency. k.  Pour o f t h e 23 p r o d u c t s t e s t e d would be r e j e c t e d  drug c o n t e n t o r u n i f o r m i t y  of content.  on the b a s i s o f  Two o t h e r p r o d u c t s , a l t h o u g h  complying w i t h o f f i c i a l r e q u i r e m e n t s , would appear t o show q u e s t i o n able c h a r a c t e r i s t i c s . 5.  The o f f i c i a l t a b l e t d i s i n t e g r a t i o n t e s t apparatus was f o u n d t o  be adequate f o r d i s i n t e g r a t i o n 6.  studies.  The o f f i c i a l r e q u i r e m e n t s f o r t a b l e t d i s i n t e g r a t i o n were i n -  adequate w i t h r e s p e c t t o i n - p r o d u c t v a r i a b i l i t y .  I t i s , therefore,  suggested t h a t a range o f f i f t e e n minutes i s a r e a s o n a b l e limit:.; for a v a r i a b i l i t y  test.  88. 7.  Two p r o d u c t s would be r e j e c t e d on the b a s i s of the p r e s e n t  d i s i n t e g r a t i o n requirements.  However, s i x p r o d u c t s would f a i l t o  comply w i t h the suggested v a r i a b i l i t y 8.  The o f f i c i a l d i s i n t e g r a t i o n apparatus was found t o be u n s u i t -  able f o r d i s s o l u t i o n 9.  test.  studies.  A m o d i f i e d v e r s i o n o f the L e v y and Hayes method (31)  was  used  for dissolution tests. 10. The r e l e a s e p a t t e r n , i n s i m u l a t e d g a s t r i c f l u i d , f o r pure pheny l b u t a z o n e i s as f o l l o w s :  11$  r e l e a s e d i n 15 m i n u t e s ; 16$ i n 30  m i n u t e s ; 2 2 . 5 $ i n 60 minutes; 2 7 . 5 $ i n two hours and 30$ - 33$ i n four to s i x hours. this pattern.  One  of the t w e l v e p r o d u c t s was  observed t o f o l l o w  On the o t h e r hand, three p r o d u c t s r e l e a s e d approx-  i m a t e l y 2$ - 5$ of t h e i r drug c o n t e n t i n s i x h o u r s . 11.  The r e l e a s e p a t t e r n f o r pure phenylbutazone i n s i m u l a t e d i n t e s -  t i n a l f l u i d i s as f o l l o w s : 30$ r e l e a s e i n f i v e m i n u t e s ; 60$ i n t e n m i n u t e s ; 87$ i n 15 m i n u t e s ; 98$ i n 30 minutes and 100$ i n 60 minutes.  Three p r o d u c t s f o l l o w e d t h i s p a t t e r n .  12. F i v e p r o d u c t s ( i n s i m u l a t e d i n t e s t i n a l f l u i d ) showed 50$ s o l u t i o n i n a p p r o x i m a t e l y 50 m i n u t e s , 75$  dis-  i n 96 m i n u t e s , 90$ i n 192  minutes and 100$ i n f i v e to s i x h o u r s . 13.  Three p r o d u c t s d i s s o l v e d a t a steady r a t e t o r e a c h 30$  dissol-  u t i o n i n two hours and 60$ d i s s o l u t i o n i n f o u r h o u r s . 111. The t w e l v e p r o d u c t s t h a t were t e s t e d i n t e n s i v e l y may  be r a t e d  as f o l l o w s : 1.  One p r o d u c t showed e x c e l l e n t c h a r a c t e r i s t i c s i n a l l  2.  F o u r p r o d u c t s demonstrated good c h a r a c t e r i s t i c s i n a l l tests.  tests.  89.  Two p r o d u c t s showed good c h a r a c t e r i s t i c s i n a l l but one test. One product showed f a i r 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 . Pour p r o d u c t s would be r a t e d  as showing poor  t i o n 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 . a l s o be q u e s t i o n e d on the b a s i s  disintegra-  Two of these c o u l d  of content  uniformity.  90. VI.  BIBLIOGRAPHY  1.  A b b o t t , A.H.A. a n d A l l p o r t , N.L., Q u a r t . J . P h a r m . t h r o u g h M o r r i s o n a n d C a m p b e l l (4.3)  2.  B r o d i e , B.B., " A b s o r p t i o n a n d D i s t r i b u t i o n o f D r u g s " , p . 1 6 . e d . T . B . B i n n s , E and S L i v i n g s t o n e L t d . , B d i n o u r g a n d L o n d o n , ( 1 9 6 k )  3.  Brodie,  k.  B r u n n i n g , H.L. and K i n g , E . P . , J . P h a r m . S c i . ,  5.  C a m i n e t s k i , S., C a n . Med. A s s o c . J . , 8 8 , 9 5 0 ( 1 9 6 3 )  6.  B.B. end H o g b e n , A.M., J . P h a r m . P h a r m a c o l  Campagna, F.A., C u r e t o n , G., M i r i g i n a n ,  9,3k5(1957)  51,1187(1962)  R.A. a n d N e l s o n , E . ,  J.Pharm.Sci., 5 2 , 6 0 5 ( 1 9 6 3 )  7.  C a r t e r , A.K., C a n . M e d . A s s o c . J . ,  8.  Chapman, D.G. J . P h a r m . S c i . , kj?, 3 7 k ( 1 9 5 6 )  9.  I6,l83(19k3)  88,98)1963)  Chapman, D.G., C r i s a f i o , n a n a C a m p b e l l , J . A . , J . P h a r m . S c i . , k3,297(195k)  10.  Delgado,  J . N . a n d C o s g r o v e , F . P . , T e x a s S t a t e J . Med., 5 9 , 1 1 0 6  (1963)  11.  Dunnett,  C.W.  and C r i s a f i o ,  12.  E l l i o t t , T. P h a r m . J . , 1 3 1 , 5 l k ( 1 9 3 3 ) A r t o f C o m p o u n d i n g , p.81 ( 5 5 ) .  13.  Endicott,  lk.  Evanson,  R.V. a n d D e k a y , H.G., B u l l . N a t l . 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A s s o c ., j j , 820(1911+) The A r t o f C o m D O u n d i n g , p . 61 (3>5)  25.  K i n g , R.E., Remington's Pharmaceutical sciences P u b l i s h i n g Company, E a s t o n , P e n n . (1965)  26.  Leonards,  J.R.  27.  Levy,  G.,  J.Pharm.Sci.,  50,368(1961)  28.  Levy,  G.,  J.Pharm.Sci.,  52,1039(1963)  29.  Levy,  G.,  Can.Med.Assoc. J . ,  30.  Levy,  G.,  Hall,  31.  Levy,  G.,  and  32.  Levy,  G.  33.  Levy,  G.,  31+.  (1959)  (1964)  Levy  5.,  P h a r m a c e u t i c a l D i s p e n s i n g , Gh.  G.,  H.  and  and  and  N.A.  and  Jusko,  Go.  Scoville's  Gh.  39,  Mack  193,99(1965)  J.-a.M.A.,  90,97&(19614.)  L.E.,  J.R.  through  Am. J.Ho s p . P h a r m .  J.Pharm.Sci.,  J.Pharm.Sci.  and  Procknal,  21,14.02  262,1053(1960)  New.Eng.J.Med.  W.J.,  Publishing  A n t i b i o t .Med., [j., [4.97 (1957)  Nelson, E.,  B.A.,  Hollister,  Leonards,  G.,  Levy,  Hayes,  and  P.,  Raaschov,  Mack  5^,1121(1965)  5^,219(1965)  J.A.,  J.Pharm.Sci.  5l+,  1719(1965) 35.  Levy,  36.  L i b b y , D.A.,  G.  and  Nelson, E., Schertel,  1_77,609(1961)  J.A.M.A.,  M.E.  and  Loy,  H . W . , J . A . O . A . C . 1+6,9cl  (1965) 37.  M a n e y , P.V. a n d K u e v e r , R.A., M o r r i s o n a n d C a m p b e l l (I4.3)  J. Pharm.Sci.  38.  M e l n i c k , D., H o c h b e r g , M. a n d t h r o u g h M o r r i s o n ana C a m p b e l l  Oser,  39.  Merck Inc.,  14.0.  Middleton, E.J., Davie,  14.1.  Midcleton,  (I4.3)  Index (The) o f C h e m i c a l s and R a h w a y , N . J . , U . S . A . (I960)  53,1378(19614.)  S.J.  E . J . , Nagy, E .  2714-,136 (1966)  and  and  B.L.,  Drugs,  3£»  2 7 6  ( 94-1) 1  through  J.Nutr.  30,67(191.1-5)  7th  Merck  Ed.  M o r r i s o n , A.B.,  M o r r i s o n , A.B.,  New  and  Co.,  J.Pharm.Sci.  Eng.J.Med.  92. " M i l i t a r y Standard oampling Procedure and T a b l e s f o r I n s p e c t i o n b y V a r i a b l e s f o r P e r c e n t D e v i a t i o n (MIL-STD-1+11+)". Superintend e n t o f D o c u m e n t s , U.S. G o v e r n m e n t P r i n t i n g O f f i c e , Washington, 25, D.G. A ; v i i 1963 - t h r o u g h O l s o n a n d L e e (50) Morrison,  A.B. a n d C a m p b e l l ,  Morrison,  A . B . , C h a p m a n , D.G.  ^,6314.(1959)  J.A., J.Pharm.Sci. and Campbell,  5ij.,l(1965)  J.A. J.Pharm.Sci.  M o s k a l y k , R . E . , C h a t t e n , L.G., C o x , C . E . a n d P e r n a r o w s k i , J . P h a r m . S c i . , 50,651(1961) Murphey, Nash,  National iation,  Formulary,  (1965)  Nuppenau, Olson,  11,397(19514.)  P., B u l l . A m . S o c . H o s p . P h a r m . ,  R.A. a n d M a r c u s ,  Parrott,  E.L.,  Standards,  X I I R e v . The A m e r i c a n  H., A r d l v .  T.N.T.,  A.D., D r u g  f o r Pharmaci.  M.,  28,1(1960)  Pharmaceutical  o g . Chemi.,  Assoc-  71,607(19614.)  55,1(1966)  and Lee,  I., J.Pharm.Sci.,  Wurster,  D . E . a n d H i g u c h i , T . , J . P h a r m . S c i . 1+1+  f  269(1955) Pharmacetxtical Manufacturers Sub-Committee on I n t e r - t a b l e t s e c t i o n , M a r c h (1963)  Association - "Proceedings dosage v a r i a t i o n " . Q u a l i t y  o f the Control  P . M . A . - M i n u t e s o f t h e 85th M e e t i n g o f t h e Q u a l i t y C o n t r o l s e c t i o n - T h e G r e e n b r i e r , W h i t e S u l p h u r S p r i n g s , W.Va. - S e p t .  27-29  (1965)  S c h r o e t e r , L.G., T i n g s t a d , J.E., J . P h a r m . s c i . , 51,865(1962)  Knoechel,  S c o v i l l e ' s - The A r t o f Compounding, I n c . , New Y o r k , (1957)  E . L . a n d Wagner, J . C .  p. 8 l ,  McGraw-Hill  Book Co.  S i m o o n s , J.R.A., " F o r m u l a t i o n a n d E x p e r i m e n t a l E v a l u a t i o n o f o r a l s u s t a i n e d r e l e a s e m e d i c a t i o n based on t h e p r i n c i p l e o f del a y e d d i f f u s i o n " . D r u k k e r i j Vied. G.Van S o e s t e N . V . A m s t e r d a m  (1962).  Smith, C D . , M i c h a e l s , T . P . C h e r t k o f f , J . P h a x - m o c i ., 52,1182(1963) Souder,  J . C . a n d E l l e n b o g e n , W.C.,  Sperandio,  G.J., E v a n s o n ,  S c i . E d . , 37,71(191+8)  Drug  N . J . and S i n o t t e ,  Standards  R.V. a n d D e K a y ,  H.G.,  L.P.  26,77(1958)  J.Am.Pharm.Assoc  93. 60.  S t e i n b e r g , W.H., F r e y , G.H., M a s c i , J . P h a r m . S c i . 5k,7k7(1965)  61.  S u n s h i n e , I . a n d G e r b e r , S.R. " S p e c t r o p h o t o m e t r i c a n a l y s i s o f d r u g s i n c l u d i n g a t l a s o f s p e c t r a " . C h a r l e s C. T h o m a s , P u b l i s h e r , S p r i n g f i e l d , I l l i n o i s , U.S.A.  62.  Train,  63-  U n i t e d S t a t e s Pharmacopea E a s t o n , P a . (1965)  6k.  Vliet,  E.B., Drug  Standards  27,97(1959)  65.  Vliet,  E.B., Drug  Standards  28,113(1960)  66.  Vliet,  E.B., a n d K r u l g e r ,  67.  Wagner,  68.  W i l e y , F., Communications t o the chairman o f the t a b l e t subcommittee o f t h e c o n t a c t s e c t i o n o f t h e Pharm. M a n u f a c t u r e r s Ass., A u g u s t (1957) - t h r o u g h s i m o o n s (56)  69.  Wood, J . H . , Am. D r u g g i s t , A r t o f Compounding (55)  kk., 105  70.  Wood, J . H . , J . P h a r m . S c i . ,  5k_, 1207(1965)  71.  W r u b l e , M.S., Am^J.Pharm., Campbell (k3)  102,318(1930)  72.  Yen, J.K.C.,  97,25 - k93(196k)  73.  B u r n s , J . J . , R o s e , K.R., C h e n k i n , T . , G o l d m a n , a n d B r o d i e , B., J . P h a r m a c o l a n d E x p t . T h e r a p . ,  D.,  J.Pharm.Sci.,  H.H.,  k9>265(1960)  J.G., J.Pharm.Sci.  Can.Pharm.J.,  J.N. and H u t c h i n s ,  (U.S.P.) 17th  R e v . Mack  E.O., J . P h a r m . S c i . ,  P r i n t i n g Co.,  5l,l8l(1962)  50,359(1961)  (190k),  through  Scoville's  The  through Morrison and  A., S c h u l e r t ,  109(3k6)(1953)  A.  9k.  APPENDIX :A  Content U n i f o r m i t y - T a b l e t s Where d i r e c t e d i n t h e i n d i v i d u a l monographs, s e l e c t a r e p r e s e n t a t i v e sample o f 30 t a b l e t s .  Assay 10 o f these  individually  u s i n g the Assay procedure as d i r e c t e d i n the monograph.  When the  amount o f d r u g i n a s i n g l e t a b l e t i s l e s s than t h a t r e q u i r e d i n the assay method, the degree o f d i l u t i o n o f the s o l u t i o n s and/or the volume o f a l i q u o t s may be a d j u s t e d so t h a t the c o n c e n t r a t i o n of  the drug i n the f i n a l s o l u t i o n w i l l be o f the sarnie, o r d e r as  t h a t o b t a i n e d i n t h e o f f i c i a l assay method.  The r e q u i r e m e n t s a r e  met i f a l l 10 r e s u l t s f a l l w i t h i n the l i m i t s o f 85 p e r c e n t t o 115 per cent o f the mean of the t o l e r a n c e s s p e c i f i e d i n t h e o f f i c i a l monograph.  I f one, but n o t more than one, r e s u l t f a l l s o u t s i d e  these l i m i t s , assay the r e m a i n i n g 20 t a b l e t s i n d i v i d u a l l y .  The  requirement i s met i f not more than one o f the 30 r e s u l t s i s o u t s i d e t h e l i m i t s o f 85; per c e n t t o 115 p e r c e n t .  *  The N a t i o n a l F o r m u l a r y E a s t o n , Pa. page k k 9  (N.F. X I I ) , Mack P r i n t i n g Company,  APPENDIX B V  95 DO-25  O f f i c i a l Method  December 1962. (reprinted January 1965) FOOD AND DRUG LABORATORIES OTTAWA  The Determination of the Disintegration Time of Tablets  Scope:  This method i s applicable to a l l tablets intended to be swallowed whole except those which release their medicament at timed intervals or i n sustaining quantities over a specified period of time.  Apparatus;  (a) A device for raising and lowering the basket-rack assembly i n the immersion f l u i d at a constant frequency rate between 28 and 32 cycles per minute through a distance of not less than 5 cm and not more than 6 cm. (b) A basket-rack assembly consisting of six open-end glass tubes, each 7.75 - 0.25 cm long and having an inside diameter of not less than 21.0 mm and not more than 22.5 mm and a wall approximately 2 mm thick.  The tubes are held in a vertical position by two plastic  plates, each about 9 cm in diameter and 6 mm in thickness,, with six holes, each about 24 mm i n diameter, equidistant from the centre of the plate and equally spaced from one another.  Attached by screws  to the under surface of the lower plate i s a piece of 10-mesh No. 23 (0.025-inch) gauge woven stainless steel wire cloth, of the same diameter as the lower plate.  The glass tubes and the upper plastic  plate are secured in position at the top by means of a stainless steel plate, about 9 cm i n diameter and 1 mm i n thickness, having six perforations, each about 20 mm i n diameter, which coincide with those of the upper plastic plate and the upper open ends of the glass tubes.  A central shaft about 8 cm in length, the upper end of which  terminates in an eye through which a string or wire may be inserted, i s attached to the stainless steel plate.\ The parts of the apparatus  ft o *  - 2 are assembled and r i g i d l y held by means of three bolts passing through the two plastic plates and the steel plate. (c) Each tube i s provided with a slotted and perforated c y l i n d r i c a l disk 9.5 i 0.15 mm thick and 20.7 -t 0.15 mm i n diameter. The disk i s nade of a suitable transparent plastic material having a specific gravity of between 1.18 and 1.20. Five 2 mm holes extend between the ends of the cylinder, one of the holes being through the cylinder axis and the others p a r a l l e l with i t , equally spaced on a 6 mm radius from i t . Equally spaced on the sides of the cylinder are four notches that form V-shaped planes so arranged that their edges are uniformly 2.55 mm from the cylinder's surface. Each notch creates a 1.60 mm square opening on the end of the cylinder to be placed downward i n the tube and widens to 8.5 mm on the top of the cylinder along a chord of the top surface. A l l surfaces of the disk are smooth. The disks described meet the specifications outlined in the U.S.P. XVI. (d) Each tube i s provided with a plunger made by separating two plastic disks with a 1/8 inch stainless steel rod  approximately  3 -J/2 inches i n length. The lower disk i s c y l i n d r i c a l and smooth, 7.5 t 0.15 mm thick and 20.7 £ 0.15 mm i n diameter. Six holes, 5/32 of an inch i n diameter, are bored symmetrically i n one c i r c l e around the axis of the disk. The stainless steel rod i s permanently embedded i n the centre of the disk. The upper disk i s c y l i n d r i c a l , smooth and approximately 7.5 mm thick. The lower half of t h i s disk has a diameter of 20.7 i 0.15 mm and the upper half has a diameter of approximately 24 mm. This provides f o r an indent to enable the seating of the plunger i n the glass tube. Twelve holes, 3/32 of an inch i n diameter, are bored symmetrically i n two circles around the axis of the disk. A hole i s bored i n the centre of the disk, the stainless steel rod inserted through the centre of i t and the two disks permanently positioned with respect to each other so that the lower disk i s 2 8 ± 0.1 cm from the bottom edge of the glass tube when the apparatus i s assembled. 0  0 0 *  DO-25  - 3 -  (e) A c y l i n d r i c a l j a r , P y r e x - t y p e g l a s s , h a v i n g an o u t s i d e d i a m e t e r o f 6 i n c h e s and a h e i g h t o f 8 t o 8 1/2 i n c h e s .  ( f ) A k n i f e - e d g e h e a t e r and t h e r m o s t a t o r s i m i l a r apparatus t o maintain constant temperature. (g) A diagram o f t h e assembled  apparatus i s shown i n A p p e n d i x I.  The assembly d e s i g n may be v a r i e d somewhat p r o v i d e d t h a t t h e b a s i c s p e c i f i c a t i o n s are maintained, (h) A diagram o f a g l a s s t u b e , d i s k and p l u n g e r i s shown i n Appendix I I . Reagents:  ( a ) H y d r o c h l o r i c A c i d , U.S.P. X V I . (b) Sodium C h l o r i d e , U.S.P. X V I . ( c ) P e p s i n , N.F. X I . (d) P o t a s s i u m Phosphate,  Monobasic U.S.P. X V I .  (e) Sodium H y d r o x i d e , U.S.P. X V I . ( f ) P a n c r e a t i n , N.F. X I . (g) S i m u l a t e d G a s t r i c J u i c e .  D i s s o l v e 2.0 g o f sodium c h l o r i d e  and 3*2 g o f p e p s i n i n 500 m l o f w a t e r , add 7»0 ml o f h y d r o c h l o r i c a c i d a n d s u f f i c i e n t w a t e r t o make 1000 ml o f -  simulated gastric j u i c e .  The pH i s a p p r o x i m a t e l y  (h) S i m u l a t e d I n t e s t i n a l J u i c e .  1.2.  D i s s o l v e 6.8 g o f monobasic  p o t a s s i u m phosphate i n 250 ml o f w a t e r .  M i x vxth 190 m l o f  0.2 N sodium h y d r o x i d e s o l u t i o n a n d 400 m l o f w a t e r . 10.0 g o f p a n c r e a t i n , m i x and a d j u s t t h e r e s u l t i n g  Add  solution  w i t h 0.2 N sodium h y d r o x i d e s o l u t i o n t o a pH o f 7.5 i  0.1.  Add s u f f i c i e n t water t o make 1000 m l . ( i ) F r e s h media s h a l l be u s e d f o r e v e r y s i x t a b l e t s .  The enzymes  s h a l l be o m i t t e d i n t h e p r e p a r a t i o n o f s t o c k s o l u t i o n s o f t h e d i g e s t i v e f l u i d s to avoid decomposition.  The p e p s i n and  p a n c r e a t i n c a n be c o n v e n i e n t l y added t o an a l i q u o t o f t h e . r e s p e c t i v e stock s o l u t i o n s i n the proper q u a n t i t y j u s t before use.  - k Procedure:  Uncoated and P l a i n Coated T a b l e t s Assemble  the apparatus when the d e v i c e f o r r a i s i n g and l o w e r i n g  t h e b a s k e t - r a c k assembly i s a t r e s t and t h e c y l i n d e r o f t h e d e v i c e i s i n the down p o s i t i o n .  W i t h 2.5  j a r , a d j u s t the apparatus u n t i l  L o f media i n t h e c y l i n d r i c a l  the l e v e l o f l i q u i d i n t h e j a r  c o i n c i d e s a p p r o x i m a t e l y w i t h the m i d - l i n e o f t h e upper plate.  plastic  M a i n t a i n the temperature o f t h e media a t 37°G 1 2°C  by  means o f a k n i f e - e d g e h e a t e r and t h e r m o s t a t o r o t h e r s u i t a b l e means.  Remove the b a s k e t - r a c k assembly from the media and d i s a s s e m b l e . S e l e c t a t random s i x t a b l e t s from t h e sample and p l a c e one i n each o f t h e t u b e s o f t h e b a s k e t - r a c k assembly.  Place a p l a s t i c  d i s k on each t a b l e t i n the manner s p e c i f i e d under Apparatus and t h e n a p l u n g e r as s p e c i f i e d under  (d).  o f assembled apparatus Appendix  I n s e r t t h e assembly i n 2.5  II).  (See a l s o  (c)  diagram  o f s i m u l a t e d g a s t r i c j u i c e and s e t the machine i n motion. plastic  I  The  d i s k s s h o u l d t r a v e l up and down f r e e l y , e x e r t i n g a g e n t l e  r u b b i n g a c t i o n on each t a b l e t .  At the end o f o n e - h a l f hour o f o p e r a t i o n , i f any t a b l e t s o r remnants remain on the s c r e e n s , g e n t l y r i n s e t h e basket w i t h w a t e r . Replace t h e g a s t r i c j u i c e w i t h 2.5  L of simulated i n t e s t i n a l  juice  and o p e r a t e the apparatus u n t i l no p a r t i c l e s remain above t h e s c r e e n except empty c o a t i n g s h e l l s which cannot pass t h r o u g h .  Disintegration  i s t h e n c o n s i d e r e d t o be complete. . The t a b l e t s pass t h e t e s t  i f the  mean d i s i n t e g r a t i o n time o f t h e s i x t a b l e t s i s not more than t h a t s p e c i f i e d i n p a r a g r a p h C.01.015 and D.01.015 o f t h e R e g u l a t i o n s under the Food and Drugs A c t .  E n t e r i c Coated T a b l e t s Assemble  the a p p a r a t u s as d e s c r i b e d i n t h e f i r s t p a r a g r a p h under  "Uncoated and P l a i n Coated T a b l e t s " .  Remove t h e b a s k e t - r a c k assembly f r o m the media and d i s a s s e m b l e . . S e l e c t a t random s i x t a b l e t s from the sample and p l a c e one i n each  DO-25  of the tubes of the basket-rack assembly.  Place in a plunger i n  each tube as specified under Apparatus (d) and as shown i n Appendix II. Insert the assembly in 2 . 5 I of simulated gastric juice and set the machine in motion. At the end of 60 minutes of operation, remove the basket-rack assembly from the medium and gently rinse with water. be no distinct evidence of disintegration.  There should  Replace the simulated  gastric juice i n the jar with 2 . 5 L of simulated intestinal juice. Remove the plungers, place a plastic disk on each tablet i n the manner specified under Apparatus (c), reinsert the plunger as specified under (d) and continue the test u n t i l no particles remain above the screen except empty coating shells which cannot pass through.  Disintegration i s then considered to be complete.  The  tablets pass the test i f the mean disintegration, time of the six tablets i s not more than that specified i n paragraph C O I 0 O I 6 or DoOl.016 of the Regulations under the Food and Drugs Act. Test Criterion  The test criterion l i s t e d herein apply to a l l tablets subject to the Regulations under the Food and Drugs Act. The disintegration endpoint i s considered to be the point at which no particles, remain above the screen except empty coating shells. In certain instances, however, sticky tenacious masses may occur. Under such circumstances, disintegration i s considered to be complete i f these masses contain no palpably firm core. This latter endpoint definition shall apply only to those tablets which, because of the active ingredient or because of special coating requirements for the active ingredient, form these sticky masses. Examples of such substances are choline, i t s derivatives and salts, bile salts and botanical extracts. The mean disintegration time of six tablets shall be- not more than 6 0 minutes and not more than one tablet shall disintegrate i n more  •o*  - 6than 75 minutes.  If one of the six tablets disintegrates i n more  than 75 minutes, repeat the test with an additional 12 tablets. The average disintegration time of the 18 tablets shall be not more than 60 minutes and not more than one tablet shall disintegrate i n more than 75 minutes. In the case of enteric coated vitamin preparations, the mean disintegration time of six tablets shall be not more than 30 minutes and not more than one tablet shall disintegrate i n more than 4-0 minutes.  If one of the six tablets disintegrates i n more than 4-0  minutes, repeat the test with an additional 12 tablets.  The average  disintegration time of the 18 tablets shall be not more than 30 minutes and not more than one tablet shall disintegrate in more than 4.0 minutes.  APPENDIX I  Diagram of Assembled Apparatus  Knife Edge Heater Basket-Rack Assembly  Cylinder i n down position  Liquid Level  2.5 L of Medium  8" - 8 1/2"  Device for Raising and Lowering Basket-Rack Assembly  Support  I  APPENDIX I I  Diagro.injof Glass_ Tube, P l a s t i c Disk and Plunger  Wire Rod ( l / 8 » x 3 l / 2 " )  i  Holes ( 3 / 3 2 " Dia.) Bored Symmetrically i n Two C i r c l e s Around Axis of Disk (See part (d) of "Apparatus" f o r S p e c i f i c a t i o n s ) 1 2  Holes ( 5 / 3 2 " Dia.) Bored Symmetrically i n One C i r c l e Around Axis of Disk 7 . 5 * 0 . 1 5 mm. thick and 2 0 i 7 £ 0 . 1 5 mm. in' diameter 6  V?  !I  2 mm. Wall  Inside Diameter of not l e s s than 2 1 . 0 mm. and not more than 2 2 . 5 mm. 2 . 8 ±  0 . 1  cm. Disk (See part (c) o f "Apparatus" f o r Specifications)  IX^XVXXXXXXXXX  Screen (See part (b) f o r Specifications)  o f "Apparatus"  

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