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UBC Theses and Dissertations

Biopharmaceutical properties of solid dosage form Woo, Wendy Weng Wah 1968

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THE BIOPHARMACEUTICAL  PROPERTIES OF  SOLID DOSAGE FORMS The O p e r a t i n g C h a r a c t e r i s t i c s o f a Continuous Flow D i s s o l u t i o n  Apparatus  by  WENDY WENG WAH WOO B. S. P., U n i v e r s i t y o f B r i t i s h Columbia, 1 9 6 6  A THESIS SUBMITTED I N PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF M a s t e r o f S c i e n c e i n Pharmacy (M. S. P.) i n the F a c u l t } ' o f Pharmacy  We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d standard.  THE UNIVERSITY OF BRITISH COLUMBIA A p r i l , 196S  In p r e s e n t i n g  for  this  thesis  f u l f i l m e n t of the requirements  an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y  that  the Library  Study.  thesis  shall  I further  make i t f r e e l y  agree that  publication  w i t h o u t my w r i t t e n  Department o f  *7U  thesis  OLA^iOi-H^  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, Canada Date  f7  -  H -  L? fr.  Columbia  I agree  f o r r e f e r e n c e and  for extensive  copying of  It i s understood  for financial  permission.  Columbia,  this  be g r a n t e d b y t h e Head o f my  representatives.  of this  of B r i t i s h  available  permission  f o r s c h o l a r l y p u r p o s e s may  D e p a r t m e n t o r b y h.i.'S  or  in partial  gain  shall  that  n o t be  copying  allowed  ii ABSTRACT A completely automatic continuous f l o w d i s s o l u t i o n procedure  was developed and t e s t e d . P e r t i n e n t d i s s o l u t i o n  c o n d i t i o n s were i n v e s t i g a t e d and chosen t o s t u d y t h e 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 seven brands o f  phenylbutazone  t a b l e t s . A pumping system enabled t h e s i m u l a t e d d i g e s t i v e f l u i d t o f l o w from,the  d i s s o l u t i o n v e s s e l i n t o the flow c e l l  of a r e c o r d i n g spectrophotometer  f o r a continuous recording  of t h e drug c o n c e n t r a t i o n i n t h e d i s s o l u t i o n medium, which was g r a d u a l l y changed from an a c i d i c medium t o a b a s i c one. From t h e " i n v i t r o  t t  d a t a o b t a i n e d by t h i s  test  p r o c e d u r e , a T^Q^ v a l u e o f 120 minutes was chosen as a l i m i t o f acceptance  f o r the t e s t p r o d u c t s . The " i n v i v o "  c h a r a c t e r i s t i c s o f s i x o f t h e brands were compared w i t h t h o s e observed f o r a p h a r m a c e u t i c a l l y a c c e p t a b l e p r o d u c t . Of t h e seven t e s t p r o d u c t s , o n l y f o u r were a c c e p t a b l e on the b a s i s o f b o t h t h e " i n v i t r o " and t h e " i n v i v o " d a t a . C o r r e l a t i o n o f t h e " i n v i t r o " and t h e " i n v i v o " d a t a r e s u l t e d i n " l e a s t squares" l i n e s w i t h n e g a t i v e s l o p e s .  M. P e r n a r o w s k i , Ph. D. Supervisor  iii TABLE OF CONTENTS Page I . INTRODUCTION  1  I I . LITERATURE SURVEY  5  I I I . THE "IN VITRO" CHARACTERISTICS OF PHENYLBUTAZONE (a) The S o l u b i l i t y  o f Phenylbutazone i n  Buffered Solutions  28  (b) D e t e r m i n a t i o n o f t h e I s o s b e s t i c P o i n t  29  (c) D e t e r m i n a t i o n o f A b s o r p t i v i t y V a l u e  30  IV. THE OPERATING CHARACTERISTICS OF A CONTINUOUS FLOW DISSOLUTION APPARATUS (a) D e s c r i p t i o n  o f t h e Apparatus  35  (b) C a l i b r a t i o n o f t h e R e c o r d e r  36  (c) The E f f e c t o f S t i r r i n g Rate on D i s s o l u t i o n  39  (d) The E f f e c t o f Pumping Rate on D i s s o l u t i o n  42  (e) T e s t P r o c e d u r e  45  (f) Results  46  V. THE "IN VIVO" CHARACTERISTICS OF PHENYLBUTAZONE TABLETS V I . "IN VIVO" - "IN VITRO" CORRELATION  56 61  iv Page V I I . DISCUSSION V I I I . SUMMARY I X . BIBLIOGRAPHY  67 70 71  LIST OF TABLES Page I . The E f f e c t o f S t i r r i n g Rate on D i s s o l u t i o n I I . The E f f e c t o f Pumping Rate on D i s s o l u t i o n  41 43  I I I . D i s s o l u t i o n Data f o r Seven Brands o f 50  Phenylbutazone T a b l e t s ^50%  anc  *  ^9<yfo  V" l a  u e s  f°  r  Seven Brands o f  Phenylbutazone T a b l e t s  52  V. A r e a s under B l o o d Curves f o r Seven Brands of Phenylbutazone T a b l e t s  60  vi LIST OF FIGURES Page 1.  The E f f e c t o f pH on the S o l u b i l i t y o f Phenylbutazone  2 . The I s o s b e s t i c P o i n t o f Phenylbutazone  32 33  3 . C a l i b r a t i o n Curve f o r 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 a t 240 mu  34  4 . Diagram o f Continuous Flow D i s s o l u t i o n •Apparatus  37  5 . C a l i b r a t i o n Curve f o r R e c o r d e r E x t e r n a l t o the S p e c t r o n i c 505 6 . pH Changes a t a Pumping Rate o f 60 ml./min. 7a.  7b.  D i s s o l u t i o n P r o f i l e s f o r Two Brands of Phenylbutazone T a b l e t s  44  47  D i s s o l u t i o n P r o f i l e s f o r Two Brands o f Phenylbutazone T a b l e t s  7c.  33  43  D i s s o l u t i o n P r o f i l e s f o r Three Brands o f Phenylbutazone T a b l e t s  49  V l l  Page 8 . C o n c e n t r a t i o n o f Phenylbutazone  i n Serum  a f t e r A d m i n i s t r a t i o n of Product A t o Subject 1  59  9 . C o r r e l a t i o n o f T^Q^ V a l u e s w i t h " I n V i v o " Data f o r S u b j e c t 1  63  1 0 . C o r r e l a t i o n o f T^Q^ V a l u e s w i t h " I n V i v o " Data f o r S u b j e c t 1 11.  64  C o r r e l a t i o n o f T^Q^ V a l u e s w i t h " I n V i v o " Data f o r S u b j e c t 2  65  1 2 . C o r r e l a t i o n o f T^Q^ V a l u e s w i t h " I n V i v o " Data f o r S u b j e c t 2  66  viii ACKNOWLEDGEMENT The a u t h o r w i s h e s t o express h e r s i n c e r e g r a t i t u d e t o Dr.. M. P e r n a r o w s k i f o r s u g g e s t i n g and s u p e r v i s i n g t h i s s t u d y . The a u t h o r i s i n d e b t e d t o Mr. R.0. S e a r l f o r h i s many h e l p f u l s u g g e s t i o n s t h r o u g h o u t t h e r e s e a r c h . Thanks i s a l s o due t o Mrs. J . N a y l o r 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 l a b o r a t o r y .  I . INTRODUCTION Tablet d i s i n t e g r a t i o n implies  t h a t the s o l i d dosage  form has broken up i n t o s m a l l e r p a r t i c l e s . However, i t does not n e c e s s a r i l y  mean t h a t the a c t i v e i n g r e d i e n t  has been  r e l e a s e d from the p r i m a r y p a r t i c l e s . T h i s was f i r s t out i n the e a r l y 1950's by s e v e r a l and more r e c e n t l y  pointed  r e s e a r c h e r s (23, 28)  by'Levy and Hayes (13) and Yen ( 3 4 ) . By t h e  mid 1 9 5 0 s , Chapman and h i s co-workers ( 5 , 6 ) , i n s e p a r a t e T  studies  on p r o d u c t s c o n t a i n 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 , showed t h a t p h y s i o l o g i c a l c o u l d be p r e d i c t e d  availability  from the d i s i n t e g r a t i o n t i m e s determined  by t h e 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 ( 3 0 ) . However, t h e i r r e s u l t s d i d suggest t h a t the more i m p o r t a n t c r i t e r i o n t o consider i n r e l a t i o n t o a v a i l a b i l i t y i s the release  o f drug  from t h e p r i m a r y drug p a r t i c l e . Even though the c o r r e l a t i o n 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 has r e c e n t l y been shown t o be i n v a l i d ( 1 , 9, 1 3 ) , t h e d i s i n t e g r a t i o n time i s s t i l l an i n d i c a t i o n o f drug r e l e a s e  because, i f the s o l i d dosage form remains  i n t a c t , the s u r f a c e a r e a f o r d i s s o l u t i o n i s l i m i t e d . As shown by t h e Noyes-Whitney drug d i s s o l v e d dissolving  i s dependent  E q u a t i o n ( 1 3 ) , the amount o f on t h e s u r f a c e a r e a o f the  solid. da _' KS ( Cs - C ) ctt "  where a = amount o f drug d i s s o l v e d  i n time t  2 S = surface area of the d i s s o l v i n g  solid  K = s o l u t i o n rate constant of the s o l i d C, - c o n c e n t r a t i o n o f t h e d i s s o l v i n g s o l i d i n t h e medium 1  Cs = c o n c e n t r a t i o n o f t h e d i s s o l v i n g s o l i d i n t h e d i f f u s i o n l a y e r surrounding the solute p a r t i c l e s . Dissolution go  i s t h e p r o c e s s whereby s o l i d p a r t i c l e s  i n t o s o l u t i o n . I t can be c o n s i d e r e d as s p e c i f i c t y p e s o f  heterogeneous r e a c t i o n s  i n which a mass t r a n s f e r i s e f f e c t e d  t h r o u g h t h e n e t r e s u l t o f escape and d e p o s i t i o n molecules a t the solute-solvent of d i s s o l v e d dissolved the  of solute  i n t e r f a c e . From t h i s  p a r t i c l e s , d i f f u s i o n occursscarrying  solute  layer  the  from t h e i n t e r f a c e i n t o t h e main body o f  d i s s o l u t i o n medium. Because t h e r e a c t i o n a t t h e i n t e r f a c e  i s much s l o w e r t h a n t h e c o n v e c t i o n t r a n s p o r t ultimately  process, i t  determines the r a t e of d i s s o l u t i o n ( 3 2 ) . Even though i t i s g e n e r a l l y  recognised to-day  t h a t d i s i n t e g r a t i o n t i m e s do n o t n e c e s s a r i l y  bear a r e l a t i o n -  ship t o the " i n v i v o " a c t i o n of the t a b l e t , the d i s i n t e g r a t i o n time t e s t i s s t i l l t h e o n l y o f f i c i a l " i n v i t r o " check on drug r e l e a s e  from t a b l e t s . I t has been s t a t e d t h a t  this  t e s t i s i n a d e q u a t e and s h o u l d 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 . S i n c e t h e e a r l y 1960's,. s e v e r a l w o r k e r s have d e s i g n e d d i s s o l u t i o n t e s t s r a n g i n g from Levy's beaker method (13) t o c o m p l e t e l y automated systems ( 2 4 ) .  3 The  g r e a t v a r i a t i o n s i n t h e equipment used f o r " i n  v i t r o " d i s s o l u t i o n s t u d i e s can be a t t r i b u t e d t o t h e wide differences  i n t h e p h y s i c a l forms o f t h e t e s t  preparations  as w e l l as t o t h e a t t e m p t s t o d u p l i c a t e " i n v i v o "  conditions.  However, b a s i c a l l y t h e y a l l c o n s i s t o f a v e s s e l f o r t h e d i s s o l u t i o n medium and t h e t e s t p r e p a r a t i o n ,  a means o f  a g i t a t i o n , a s a m p l i n g system and a means o f c o n t r o l l i n g t h e t e m p e r a t u r e o f t h e d i s s o l u t i o n medium. Most o f t h e " i n v i t r o " d i s s o l u t i o n s t u d i e s have been done i n a s t a t i c system, i . e . , t h e d i s s o l u t i o n medium remains unchanged throughout t h e e n t i r e d i s s o l u t i o n r u n . T h i s system may e n c o u n t e r a s a t u r a t i o n problem e s p e c i a l l y w i t h t h e l e s s s o l u b l e drug p r e p a r a t i o n s .  Several  researchers  (7, 22., 33) have used a c o n t i n u o u s f l o w system t o c a r r y out d i s s o l u t i o n s t u d i e s . T h i s t y p e o f system e l i m i n a t e s t h e p o s s i b i l i t y o f s a t u r a t i o n o f t h e medium by t h e d r u g . I t may also simulate " i n v i v o " conditions  more t h a n t h e s t a t i c  system because under " i n v i v o " c o n d i t i o n s j u i c e s are continuously  being secreted  the d i g e s t i v e  and absorbed by t h e  mucosal c e l l s o f t h e g a s t r o - i n t e s t i n a l t r a c t . I n an attempt t o i n v e s t i g a t e t h e p o t e n t i a l s o f t h i s t y p e o f system, an a p p a r a t u s f o r c o n t i n u o u s f l o w was developed w i t h , a g r a d u a l change i n t h e pH o f t h e medium, from t h a t o f g a s t r i c j u i c e t o i n t e s t i n a l j u i c e . T h i s system was i n v e s t i g a t e d and u s i n g a s t a n d a r d p r o d u c t ,  pertinent  4 d i s s o l u t i o n c o n d i t i o n s were e s t a b l i s h e d f o r t h i s s t u d y . Under t h e s e c o n d i t i o n s , seven brands o f c o m m e r i c i a l l y  available  phenylbutazone t a b l e t s were t e s t e d . The " i m v i t r o " d i s s o l u t i o n d a t a o b t a i n e d was t h e n c o r r e l a t e d w i t h " i n v i v o " d a t a for several  subjects.  obtained  5  I I . LITERATURE SURVEY The has  the basic  o f f i c i a l U.S.P. d i s i n t e g r a t i o n a p p a r a t u s ( 3 0 ) p a r t s needed i n a d i s s o l u t i o n t e s t . Workers  have e i t h e r used t h e d i s i n t e g r a t i o n a p p a r a t u s i t s e l f o r modified i t to carry  out d i s i n t e g r a t i o n as w e l l as d i s s o l u t i o n  studies. The  apparatus c o n s i s t s  o f a b a s k e t r a c k assembly  t h a t can be r a i s e d and l o w e r e d a t a c o n s t a n t f r e q u e n c y r a t e o f between t w e n t y - e i g h t t o t h i r t y - t w o  cycles per  minute t h r o u g h a d i s t a n c e o f not more t h a n s i x cm. and n o t l e s s t h a n f i v e cm. The volume o f t h e d i s s o l u t i o n medium i n the thermostatically  controlled vessel  (35°C - 39°C)  i s such t h a t a t . t h e h i g h e s t p o i n t o f t h e upward s t r o k e t h e w i r e mesh remains a t l e a s t 2 . 5 cm. below t h e s u r f a c e o f t h e medium and descends t o n o t l e s s t h a n 2 . 5 cm. from t h e bottom of t h e v e s s e l  on t h e downward s t r o k e .  assembly c o n s i s t s  The b a s k e t r a c k ss;?  of s i x v e r t i c a l l y held  whose l o w e r ends a r e c o v e r e d by a s i e v e  open-ended tubes o f v a r y i n g mesh  s i z e . Each tube i s p r o v i d e d w i t h a s l o t t e d and p e r f o r a t e d c y l i n d r i c a l d i s k o f p l a s t i c . The d i s k j u s t f i t s t h e tube and it  moves up and down w i t h t h e movement o f t h e b a s k e t as i s r a i s e d and l o w e r e d . U s i n g t h i s a p p a r a t u s , S c h r o e t e r and h i s co-workers  (25) rates  d e t e r m i n e d t h e d i s i n t e g r a t i o n t i m e s and d i s s o l u t i o n o f s e v e n t y - s i x l o t s o f compressed t a b l e t s ,  including  6  an a n t i - i n f l a m m a t o r y s t e r o i d , a s u l f o n a m i d e , an 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 o m b i n a t i o n . Without s t o p p i n g t h e a g i t a t i o n o f t h e U.S.P. t a b l e t d i s i n t e g r a t i o n  apparatus,  a l i q u o t s o f t h e d i s s o l u t i o n medium were withdrawn  at different  i n t e r v a l s f o r a n a l y s i s . Time f o r 5 0 % o f t h e drug t o go i n t o solution  (t^o^)  o r  t h e amount o f drug i n s o l u t i o n a t a  s p e c i f i c time was used as t h e c r i t e r i o n f o r t h e r a t e o f dissolution. Disintegration  t i m e s were o b t a i n e d w i t h and  w i t h o u t t h e use o f t h e p l a s t i c  disks.  These workers found f o r t h e s t e r o i d a h i g h l y s i g n i f i c a n t l i n e a r c o r r e l a t i o n between t h e r a t e o f d i s s o l u t i o n and t h e average  d i s i n t e g r a t i o n time w i t h o u t t h e use o f t h e  p l a s t i c d i s k s . T h i s c o r r e l a t i o n was absent when d i s k s were used. F o r t h e s u l f o n a m i d e t a b l e t s , a s i m i l a r c o r r e l a t i o n was observed when sodium c h l o r i d e was p r e s e n t as an  ingredient.  B o t h t h e a n t i - d i a b e t i c agent and t h e a s p i r i n - p h e n a c e t i n c o m b i n a t i o n showed no s i g n i f i c a n t c o r r e l a t i o n between d i s s o l u t i o n r a t e and d i s i n t e g r a t i o n  time.  The r e s u l t s i n d i c a t e d t h a t t h e r e was an extreme s p e c i f i c i t y i n t h e absence o r presence o f a r e l a t i o n s h i p between r a t e o f d i s s o l u t i o n and d i s i n t e g r a t i o n t i m e s . When a quantitative  r e l a t i o n s h i p existed, the " l e a s t  squares"  l i n e s r e l a t i n g t h e v a r i a b l e s were found t o v a r y w i d e l y depending  upon t h e p a r t i c u l a r drug as w e l l as on t h e o t h e r  a d j u v a n t s i n t h e t a b l e t . The use o f p l a s t i c d i s k s  i n the  7 d i s i n t e g r a t i o n t e s t was observed t o mask r e a l between t h e v a r i o u s l o t s  differences  tested.  M i d d l e t o n and h i s co-workers ( 1 9 ) , u s i n g t h e U.S.P. d i s i n t e g r a t i o n a p p a r a t u s , found 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 t i m e , d i s s o l u t i o n and  physiological  rate  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 . The t a b l e t s were immersed f o r t h i r t y minutes i n s i m u l a t e d g a s t r i c f l u i d and t h e remainder o f t h e time i n simulated i n t e s t i n a l f l u i d . Without stopping the a g i t a t i o n o f t h e a p p a r a t u s , a l i q u o t s o f t h e s i m u l a t e d d i g e s t i v e f.Mi f l u i d s were withdrawn a t v a r i o u s i n t e r v a l s f o r a n a l y s i s . From t h e r e s u l t s , t h e s e workers c o n c l u d e d t h a t t h e d i s i n t e g r a t i o n time p r o v i d e d a v a l i d i n d i c a t i o n o f t h e r a t e a t which r i b o f l a v i n went i n t o s o l u t i o n from t h e s u g a r - c o a t e d t a b l e t s , t h u s e i t h e r d i s i n t e g r a t i o n time o r d i s s o l u t i o n r a t e can p r o v i d e a u s e f u l  estimate 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 o f r i b o f l a v i n from s u g a r - c o a t e d t a b l e t s . However, t h i s r e l a t i o n s h i p may not e x i s t f o r o t h e r drugs. I n t h e i r study o f t h e d i s s o l u t i o n r a t e s o f e i g h t e e n brands o f c o m m e r i c i a l l y a v a i l a b l e t o l b u t a m i d e t a b l e t s i n g a s t r i c f l u i d , Brudney and h i s co-workers (1) found  that  t h e r e Was no c o r r e l a t i o n between d i s s o l u t i o n r a t e s and t h e d i s i n t e g r a t i o n times. Disintegration  time was determined  by t h e o f f i c i a l method o f t h e Food and Drug D i r e c t o r a t e ( 3 ) . D i s s o l u t i o n was determined by t h e method d e s c r i b e d by Levy and  Hayes (13) w i t h m o d i f i c a t i o n s .  S i x l i t r e s o f 0.1 N.HC1  containing  0.2% N a C l was used as t h e d i s s o l u t i o n medium. The  s t i r r i n g r a t e was m a i n t a i n e d a t 250 r.p.m. and t h e temperature O  n  c o n t r o l l e d a t 37 C + 0.5 C. T w e n t y - f i v e m l . samples o f t h e medium were withdrawn t h r o u g h a n y l o n f i l t e r pad a t f i v e minute i n t e r v a l s over a s i x t y minute p e r i o d .  Following  each w i t h d r a w a l , t w e n t y - f i v e ml.' o f f r e s h medium was added t o m a i n t a i n a c o n s t a n t volume. Lu and h i s co-workers (18),  i n t h e i r comparative  , s t u d y o f ' t w e n t y - s i x brands o f c o m m e r i c i a l l y  available  t o l b u t a m i d e t a b l e t s , found t h a t t h e r e was no c o r r e l a t i o n 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 i n g a s t r i c f l u i d as had been r e p o r t e d e a r l i e r ( 1 ) , but t h a t t h e r e was a s t a t i s t i c a l l y s i g n i f i c a n t c o r r e l a t i o n 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 i n i n t e s t i n a l f l u i d . The d i s i n t e g r a t i o n t i m e s were determined by u s i n g t h e Food and Drug D i r e c t o r a t e  method. The d i s s o l u t i o n r a t e s were d e t e r -  mined i n b o t h g a s t r i c and i n t e s t i n a l f l u i d s o f pH 1.5 and 7.5 r e s p e c t i v e l y .  Two and a h a l f l i t r e s o f t h e s o l u t i o n  was h e a t e d t o 37°C i n a t h r e e - l i t r e g l a s s  j a r . The t a b l e t  was p l a c e d a t t h e bottom o f t h e j a r and t h e s o l u t i o n s t i r r e d by a b l a d e s t i r r e r s e t a t one i n c h from t h e bottom o f t h e j a r a t 300 r.p.m. I n two o f t h e l o t s , t h e d i s i n t e g r a t i o n time exceeded t h e Food and Drug D i r e c t o r a t e  l i m i t of sixty  m i n u t e s , whereas t h e o t h e r t w e n t y - f o u r l o t s  disintegrated  w e l l w i t h i n .this l i m i t . D i s s o l u t i o n  r a t e s were  calculated  9  on t h e b a s i s  o f t h e amount i n mg. d i s s o l v e d  the time r e q u i r e d  i n one hour and  t o r e a c h 2 0 $ and 4 0 $ d i s s o l u t i o n i n g a s t r i c  f l u i d and 5 0 $ and 9 0 $ d i s s o l u t i o n i n i n t e s t i n a l f l u i d . The r e s u l t s showed a c o n s i d e r a b l e v a r i a t i o n i n t h e d i s s o l u t i o n r a t e s among t h e d i f f e r e n t brands t e s t e d . These tend t o r e i n f o r c e  findings  t h e o b s e r v a t i o n s o f S c h r o e t e r and h i s  co-workers ( 2 5 ) t h a t t h e e x i s t e n c e o f a r e l a t i o n s h i p between d i s s o l u t i o n and d i s i n t e g r a t i o n time depends on t h e p a r t i c u l a r drug as w e l l as on t h e c o n d i t i o n s the  under which  d i s s o l u t i o n and d i s i n t e g r a t i o n t e s t s a r e c a r r i e d o u t . Among t h e v a r i o u s f a c t o r s t o be c o n s i d e r e d i n t h e  d e s i g n o f a d i s s o l u t i o n t e s t , t h e means and i n t e n s i t y o f a g i t a t i o n a r e v a r i e d most and have been r e p o r t e d t o have a s i g n i f i c a n t e f f e c t on t h e d i s s o l u t i o n  rate.  Hamlin and h i s co-workers (S) used t h r e e d i f f e r e n t methods t o s t u d y c o n s t a n t s u r f a c e p e l l e t s o f two polymorphic forms o f m e t h y l p r e d n i s o l o n e compressed a t h i g h p r e s s u r e . One form had g r e a t e r water s o l u b i l i t y and hence s h o u l d have a greater i n i t i a l d i s s o l u t i o n rate i n water. The  f i r s t method was t h a t o f N e l s o n ( 2 1 ) , a method  i n which f r e e c o n v e c t i o n , d i f f u s i o n c o e f f i c i e n t and concent r a t i o n were s t a t e d t o be t h e r a t e d e t e r m i n i n g f a c t o r s . The only modification  was t h a t i n s t e a d  o f d e t e r m i n i n g weight  l o s s o f the p e l l e t s , the f l u i d surrounding the s t e r o i d p e l l e t s was a s s a y e d s p e c t r o p h o t o m e t r i c a l l y . I n t h e second method, t h e p e l l e t s were h e l d i n a p o l y e t h y l e n e h o l d e r a t  10 the  c e n t e r o f o v a l f o u r f l u i d ounce b o t t l e s  containing  120 m l . o f d e i o n i z e d w a t e r . The b o t t l e s were a t t a c h e d t o t h e machine d e s c r i b e d by Wurble (31). ent  After rotation for  differ-  i n t e r v a l s o f time, the f l u i d surrounding the p e l l e t  was a s s a y e d s p e c t r o p h o t o m e t r i c a l l y .  The dimensions o f t h e  p e l l e t b e f o r e and a f t e r exposure t o t h e d i s s o l u t i o n medium were a l s o determined. The machine was r o t a t e d and  a t 6 r.p.m.  a t 12 r.p.m. The t h i r d method was s i m i l a r t o t h e second  except t h a t t h e machine d e s c r i b e d by Souder and E l l e n b o g e n (29) was used i n s t e a d were r o t a t e d  o f t h e Wurble machine. The b o t t l e s  a t 40 r.p.m. d u r i n g exposure i n a ' c o n s t a n t  temperature b a t h h e l d a t 37°C. I t was found t h a t when t h e i n t e n s i t y o f a g i t a t i o n or t h e v e l o c i t y o f t h e d i s s o l u t i o n medium a c r o s s t h e d i s s o l v i n g s o l i d was o f a l o w o r d e r o f magnitude, a s i g n i f i c a n t difference  i n d i s s o l u t i o n r a t e s was observed f o r b o t h forms  o f t h e s t e r o i d . When t h e speed o f r o t a t i o n o f t h e wheel i n the Wurble machine was i n c r e a s e d from 6 r.p.m. t o 12 r.p.m., the r a t e s o f d i s s o l u t i o n o f t h e two polymorphs became e q u a l . R o t a t i o n a t 40 r.p.m. i n t h e machine d e s c r i b e d by Souder and E l l e n b o g e n showed no o b s e r v a b l e s i g n i f i c a n t d i f f e r e n c e i n the d i s s o l u t i o n r a t e s o f t h e two polymorphs. I n t h e " i n v i v o " studies two  c a r r i e d out by i m p l a n t i n g t h e p e l l e t s i n r a t s , t h e  polymorphs showed s i g n i f i c a n t l y d i f f e r e n t r a t e s o f  weight l o s s . The " i n v i v o " d a t a t e n d t o i n d i c a t e t h a t t h e " i n v i t r o " t e s t i n w h i c h t h e r e was a r e l a t i v e l y l o w i n t e n s i t y  11 of a g i t a t i o n c o r r e l a t e d  best with the " i n v i v o "  results.  Levy ( 1 1 ) , i n h i s study o f t h e e f f e c t s o f a g i t a t i o n on d i s s o l u t i o n , used two methods t h a t v a r i e d g r e a t l y i n a g i t a t i o n i n t e n s i t y - t h e beaker method (13) and t h e o s c i l l a t i n g tube method. I n t h e second method, a p l e x i g l a s s c y l i n d e r w i t h a 100-mesh s t a i n l e s s s t e e l w i r e s c r e e n on the bottom was a t t a c h e d t o t h e b a s i c  u n i t o f t h e U.SI'P.  d i s i n t e g r a t i o n a p p a r a t u s and immersed i n a beaker i n g 300 m l . o f 0.1 N.HC1  contain-  at 37°C With the apparatus i n  m o t i o n , a t a b l e t was dropped i n t o t h e c y l i n d e r and t h e medium sampled a t i n t e r v a l s by a f r i t t e d - g l a s s immersion f i l t e r tube f o r a n a l y s i s . Two p r o p r i e t a r y  brands'of a s p i r i n  were t e s t e d . One c o n t a i n e d a l k a l i n e a d d i t i v e s w h i l e t h e o t h e r d i d n o t . W i t h t h e beaker method, which u t i l i z e d a v e r y l o w a g i t a t i o n r a t e and p e r m i t t e d t h e s o l i d p a r t i c l e s t o remain as an a g g r e g a t e on t h e bottom o f t h e b e a k e r , t h e tablets containing dissolved  a s p i r i n and t h e a l k a l i n e  additives  much more r a p i d l y than t h e p l a i n a s p i r i n t a b l e t s .  T h i s was i n agreement w i t h t h e " i n v i v o " a b s o r p t i o n t e s t s c a r r i e d o u t . The d i s s o l u t i o n h a l f - t i m e  o f one was approx-  i m a t e l y t h r e e t i m e s t h a t o f t h e o t h e r . On t h e o t h e r hand, t h e r e was p r a c t i c a l l y no d i f f e r e n c e  i n the d i s s o l u t i o n  r a t e s o f t h e two t a b l e t f o r m u l a t i o n s when t e s t e d by t h e o s c i l l a t i n g tube method, which i n v o l v e d  r e l a t i v e l y high  a g i t a t i o n i n t e n s i t i e s and caused t h e s o l i d p a r t i c l e s t o be d i s p e r s e d .  12 Levy a t t r i b u t e d t h i s d i f f e r e n c e an aggregate o f d i s i n t e g r a t e d  t o the f a c t that i n  t a b l e t s o l i d s , the a l k a l i n e  components o f t h e b u f f e r e d a s p i r i n t a b l e t caused an i n c r e a s e i n t h e pH o f t h e micro-environment from pH 1 t o about pH 5.6. T h i s i n c r e a s e i n pH r e s u l t e d i n a more r a p i d  dissolution  o f t h e a s p i r i n p a r t i c l e s . T h i s e f f e c t was absent when a s p i r i n and t h e a l k a l i n e components were p h y s i c a l l y s e p a r a t e d by intensive  agitation. The method developed by Levy and Hayes (13) i n  t h e i r s t u d y o f t h e d i s s o l u t i o n r a t e o f p l a i n and b u f f e r e d a s p i r i n t a b l e t s has been used by Levy and o t h e r workers i n d i s s o l u t i o n s t u d i e s w i t h o n l y minor m o d i f i c a t i o n s . d i s s o l u t i o n assembly c o n s i s t e d beaker immersed o o  The  o f a 400-ml. P y r e x G r i f f i n  i n a c o n s t a n t temperature b a t h a d j u s t e d  t o 37 C + 0.1 C. A t h r e e - b l a d e , 5-cm. d i a m e t e r p o l y e t h y l e n e s t i r r e r was a t t a c h e d t o an e l e c t r o n i c a l l y c o n t r o l l e d  stirr-  i n g motor. Two hundred a n d . f i f t y m l . o f 0.1 N.HG1 was p l a c e d i n t h e beaker and allowed, t o e q u i l i b r a t e t o 37°C and t h e a c e t y s a l i c y l i c a c i d t a b l e t was dropped a l o n g t h e s i d e o f the b e a k e r . The p o l y e t h y l e n e s t i r r e r was immersed d i s s o l u t i o n medium t o a depth o f 27 mm. and  i n the  accurately  c e n t e r e d by means o f a g u i d e . The s t i r r i n g r a t e was 59 r.p.m. - j u s t s u f f i c i e n t t o keep t h e s o l u t i o n homogeneous but l o w enough t o a l l o w t h e s o l i d s o f t h e d i s i n t e g r a t e d  tablet to  remain as an aggregate a t the c e n t r e o f t h e bottom o f t h e beaker w i t h i n an a r e a o f one o r two s q . cm. Seven m l . samples  13 were t a k e n a t f i v e , t e n , twenty and t h i r t y minutes by means o f a f r i t t e d - g l a s s immersion f i l t e r tube o f medium  porosity.  S i x brands o f p l a i n a c e t y s a l i c y l i c a c i d t a b l e t s , one b r a n d o f t h e b u f f e r e d drug, and one brand o f c a l c i u m  acetysalicy-  l a t e carbamide complex p r o d u c t were t e s t e d . S i x t a b l e t s were s u b j e c t e d t o t h e d i s s o l u t i o n t e s t ; a n o t h e r s i x t o d i s i n t e g r a t i o n t e s t i n 0.1  N'.HCl by t h e U.S.P. method.  The r e s u l t s showed t h a t t h e r e was a g r e a t  differ-  ence i n the' s o l u t i o n r a t e s o f t h e v a r i o u s brands o f p l a i n t a b l e t s . The t a b l e t w i t h t h e c a l c i u m s a l t d i s s o l v e d  at a  f a s t e r r a t e t h a n a l l t h e o t h e r p r o d u c t s t e s t e d . T h i s was e x p e c t e d due t o t h e g r e a t e r s o l u t i o n o f t h e s a l t i n aqueous medium. They found t h a t t h e d i s s o l u t i o n curve d i d not  p r o g r e s s a r i t h m e t i c a l l y and t h a t i t would t a k e much  l o n g e r f o r t h e second h a l f o f t h e drug t o go i n t o The r a p i d l y d i s s o l v i n g p r o d u c t s e x h i b i t e d r a t i o n t i m e s t h a n t h e more s l o w l y  solution.  longer d i s i n t e g -  d i s s o l v i n g products. I t  was c o n c l u d e d t h a t t h e d i s i n t e g r a t i o n time which i s o f t e n a l l u d e d t o as an i n d e x o f drug a v a i l a b i l i t y i s no c r i t e r i o n o f a v a i l a b i l i t y o r r a t e o f s o l u t i o n . When d i s i n t e g r a t i o n times are abnormally long,  t h e r a t e o f s o l u t i o n and absorp-  t i o n o f a drug w i l l be s e r i o u s l y a f f e c t e d time i s j u s t t h e time r e q u i r e d  since  disintegration  by. t h e t a b l e t t o f a l l  i n t o r e a s o n a b l y s m a l l p a r t i c l e s and not t h e t i m e f o r t h e drug t o go i n t o s o l u t i o n . .  apart  required  14 U s i n g t h e method j u s t d e s c r i b e d ( 1 3 ) , Levy and h i s co-workers (17) c o r r e l a t e d  the e f f e c t of s t i r r i n g  rates  w i t h t h e i n t e s t i n a l a b s o r p t i o n o f t h r e e d i f f e r e n t dosage forms o f a s p i r i n . These dosage forms d i f f e r e d markedly i n drug a b s o r p t i o n r a t e as w e l l as i n t h e p r i n c i p a l mechanism involved  i n the release  o f drug t o t h e d i s s o l u t i o n medium.  One was a r a p i d l y d i s i n t e g r a t i n g t a b l e t c o n t a i n i n g  aspirin  as m i c r o - e n c a p s u l a t e d p a r t i c l e s , a n o t h e r was a r a p i d l y d i s i n t e g r a t i n g " p l a i n " a s p i r i n t a b l e t and t h e t h i r d was a rapidly disintegrating tablet containing alkaline additives. Different  a s p i r i n and  s t i r r i n g rates  i n a clock-  wise d i r e c t i o n u s i n g the p r e c i s i o n s t i r r i n g apparatus of Levy and T a n s k i (15) were used w i t h 0.1 N.HC1 as t h e d i s s o l u t i o n medium. The  r e s u l t i n g comparison o f d i s s o l u t i o n a t 60 r.p.m.  w i t h plasma l e v e l s o b t a i n e d by " i n v i v o " s t u d i e s the  showed t h a t  " i n v i t r o " d i s s o l u t i o n from t h e m i c r o - e n c a p s u l a t e d  p a r t i c l e s was t o o r a p i d r e l a t i v e t o t h e o t h e r dosage forms. Dissolution  from t h e p l a i n t a b l e t s was found t o be v e r y  much more s e n s i t i v e t h a n from t h e m i c r o - e n c a p s u l a t e d p a r t i c l e s which release  drug by a d i f f u s i o n p r o c e s s . A t 50 r.p.m.,  i t was found t h a t t h e r a t i o o f " i n v i v o " a b s o r p t i o n  rates  from t h e p l a i n t a b l e t s and t h e m i c r o - e n c a p s u l a t e d p a r t i c l e s was e q u a l t o t h e r a t i o o f t h e d i s s o l u t i o n r a t e s . A t 30 r.p.m., the more r a p i d l y absorbed p l a i n t a b l e t s were found t o d i s s o l v e  15  more s l o w l y t h a n t h e much more s l o w l y absorbed micro-encaps u l a t e d p a r t i c l e s . I n t h i s study, i t was o b s e r v e d t h a t a change o f o n l y 20$ i n s t i r r i n g r a t e s made a d i f f e r e n c e between s u c c e s s f u l c o r r e l a t i o n o r f a i l u r e w i t h " i n v i v o " d a t a . Changes i n t h e c o m p o s i t i o n was s u b s e q u e n t l y  o f t h e d i s s o l u t i o n medium  r e p o r t e d t o have s i m i l a r  Besides  effects.  s t i r r i n g r a t e , Levy and h i s co-workers (16)  found t h a t c e r t a i n f o r m u l a t i o n f a c t o r s have an e f f e c t on t h e d i s s o l u t i o n r a t e o f t h e a c t i v e i n g r e d i e n t . U s i n g t h e method d e s c r i b e d ( 1 3 ) , t h e s e workers observed t h a t t h e d i s s o l u t i o n r a t e o f s a l i c y l i c a c i d i n compressed t a b l e t s i n c r e a s e d w i t h decreasing granule  s i z e but t h i s i n c r e a s e was n o t s t r i c t l y  p r o p o r t i o n a l t o t h e i n c r e a s e i n t h e apparent s u r f a c e  area  of t h e g r a n u l e s . The i n c r e a s e i n d i s s o l u t i o n r a t e from t h e t a b l e t s c o n t a i n i n g 20 - 40 mesh and 40 - 60 mesh  granules  was not as g r e a t as t h e i n c r e a s e i n t h e apparent s u r f a c e a r e a s i n c e t h e d i s i n t e g r a t e d t a b l e t p a r t i c l e s remain a g g r e g a t e d on t h e beaker bottom due t o t h e l o w i n t e n s i t y o f a g i t a t i o n . The much g r e a t e r d i s s o l u t i o n o f t h e t a b l e t s w i t h 60 - 30 mesh g r a n u l e s was due t o t h e f a c t t h a t t h e s e  granules  were s m a l l enough t o be d i s p e r s e d somewhat i n t h e medium d e s p i t e the low i n t e n s i t y o f a g i t a t i o n , thus p e r m i t t i n g the moving s o l v e n t t o come i n c o n t a c t w i t h a g r e a t e r p o r t i o n o f t h e p o t e n t i a l l y a v a i l a b l e s u r f a c e . An i n c r e a s e o f s t a r c h content  i n t h e t a b l e t s from 5 - 20$ r e s u l t e d i n an i n c r e a s e  16  i n t h e d i s s o l u t i o n r a t e o f s a l i c y l i c a c i d , p r o b a b l y because of more r a p i d and thorough d i s i n t e g r a t i o n o f t h e g r a n u l e s . Dissolution  r a t e s were a l s o found t o i n c r e a s e w i t h an  increase i n the precompression pressure of the t a b l e t s . This may be due t o t h e f r a c t u r i n g o f t h e drug p a r t i c l e s a t t h e higher s l u g g i n g pressure, thus y i e l d i n g smaller primary p a r t i c l e s . F r a g m e n t a t i o n o f t h e more h i g h l y  compressed  g r a n u l e s d u r i n g subsequent t a b l e t i n g may a l s o o c c u r . F i n a l l y , the  s o f t e r granules obtained a t the lower precompression  p r e s s u r e s a r e more l i k e l y t o undergo bonding d u r i n g t a b l e t i n g and t h u s y i e l d l a r g e r  granules.  I n t h e i r study o f t h e e f f e c t s o f l u b r i c a n t s on d i s s o l u t i o n rates  o f t a b l e t s , Levy and Gumtow (12) used t h e  beaker method (13) and t h e r o t a t i n g d i s k method ( 1 4 ) . These w o r k e r s found t h a t magnesium s t e a r a t e ,  a hydrophobic  lubri-  cant, decreased a p p r e c i a b l y the d i s s o l u t i o n rate o f s a l i c y l i c a c i d t a b l e t s compressed from g r a n u l e s o f t h e pure drug w h i l e sodium l a u r y l s u l f a t e , a h y d r o p h i l i c  l u b r i c a n t , had t h e  o p p o s i t e e f f e c t . T h i s enhancing e f f e c t o f sodium l a u r y l s u l f a t e was even g r e a t e r w i t h t a b l e t s made from g r a n u l e s t h a t c o n t a i n e d s a l i c y l i c a c i d and s t a r c h . E x p e r i m e n t s w i t h nondisintegrating  disks of s a l i c y l i c acid indicated  the more commonly used hydrophobic l u b r i c a n t s stearate, the  aluminum s t e a r a t e ,  that  (magnesium  s t e a r i c a c i d , t a l c ) decreased  e f f e c t i v e d r u g - s o l v e n t i n t e r f a c i a l a r e a and t h e r e b y  d e c r e a s e d t h e r a t e o f d i s s o l u t i o n o f t h e drug, w h i l e  1  water-soluble lubricants sulfate)  (sodium o l e a t e ,  7  sodium l a u r y l  d i d not have t h i s e f f e c t . The d i s s o l u t i o n  rate  enhancing e f f e c t o f sodium l a u r y l s u l f a t e was not due t o any  modification  o f t h e m i c r o - e n v i r o n m e n t a l pH o r s o l u b i l i z -  a t i o n by m i c e l l e s , but r a t h e r  t o the better  penetration of  the  s o l v e n t i n t o t h e t a b l e t s and t h e i r component g r a n u l e s  and  t h e r e s u l t i n g g r e a t e r a v a i l a b i l i t y o f drug Levy and S a h l i  surface.  ( 1 4 ) , i n t h e i r comparative study  of 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 s a l i c y l i c a c i d and  i t s aluminum s a l t , c o r r e l a t e d  excretion  the u r i n a r y  salicylate  w i t h t h e d i s s o l u t i o n r a t e o b t a i n e d by t h e r o t a t -  i n g d i s k method. The compressed t a b l e t s were mounted on P l e x i g l a s h o l d e r s w i t h p a r a f f i n wax so t h a t  o n l y one s u r f a c e  of t h e t a b l e t was exposed. The h o l d e r was c o n n e c t e d t o an electronically controlled precision hundred m l . q u a n t i t y  s t i r r i n g motor. A two  o f t h e d i s s o l u t i o n medium was p l a c e d  i n a 5 0 0 - m l . t h r e e - n e c k round-bottom f l a s k , w h i c h was immersed i n a c o n s t a n t t e m p e r a t u r e b a t h a d j u s t e d t o 37°C. A f t e r temperature e q u i l i b r a t i o n , the t a b l e t attached t o the h o l d e r was immersed i n t o t h e d i s s o l u t i o n medium t o a depth o f one i n c h , w i t h t h e s t i r r e r t u r n e d on a t 5 5 5 r.p.m. Aliquots  o f f i v e o r t e n m l . were removed from t h e f l a s k a t  a p p r o p r i a t e i n t e r v a l s o f t i m e f o r a n a l y s i s . A s i m i l a r volume o f medium was added t o m a i n t a i n a c o n s t a n t volume. The t a b l e t was weighed b e f o r e and a f t e r t h e d i s s o l u t i o n r u n as a check on t h e a s s a y . The c o n d i t i o n s  o f t h e experiment was such  that  18 the  c o n c e n t r a t i o n o f drug i n t h e medium was m a i n t a i n e d a t  a small f r a c t i o n of i t s t o t a l  solubility.  I n 0.1 N.HC1, t h e d i s s o l u t i o n r a t e o f a c e t y s a l i c y l i c a c i d was found t o be 65.1 mg./hr.cm. and t h a t o f aluminum acetysalicylate  i n terms o f s a l i c y l i c a c i d was 8.88 mg./hr.cm.  Similar differences  were found when a l k a l i n e medium was u s e d .  S i m i l a r l y , " i n v i v o " s t u d i e s showed t h a t u r i n a r y excretion  from s u b j e c t s t a k i n g aluminum a c e t y s a l i c y l a t e  m a r k e d l y l e s s t h a n t h a t from s u b j e c t s t a k i n g the  salicylate was  the a c i d . Since  a b s o r p t i o n o f s a l i c y l a t e s i s r a t e - l i m i t e d by t h e i r  d i s s o l u t i o n r a t e i n g a s t r o - i n t e s t i n a l f l u i d s , t h e s e workers c o n c l u d e d t h a t t h e l e s s r a p i d a b s o r p t i o n and subsequent excretion  o f aluminum a c e t y s a l i c y l a t e was p r o b a b l y due t o  i t s slow d i s s o l u t i o n . R e c e n t l y , S e a r l and P e r n a r o w s k i (26)  evaluated'cthe  d i s i n t e g r a t i o n t i m e s and d i s s o l u t i o n r a t e s o f t w e n t y - t h r e e brands o f p h e n y l b u t a z o n e t a b l e t s . The " i n v i v o "  character-  i s t i c s o f t h r e e brands were compared w i t h t h a t o b s e r v e d f o r a c l i n i c a l l y a c c e p t a b l e p r o d u c t by a comparison o f t h e l e v e l s o f t h e drug i n t h e b l o o d a f t e r o r a l a d m i n i s t r a t i o n .  Disinteg-  r a t i o n t i m e s were d e t e r m i n e d by u s i n g t h e Erweka t a b l e t d i s i n t e g r a t i o n a p p a r a t u s . The procedure i s i n a i s s u e d by t h e Food and Drug D i r e c t o r a t e  publication  (4). S i x tablets  were p l a c e d i n t h e a p p a r a t u s and t h e mean d i s i n t e g r a t i o n times c a l c u l a t e d .  Dissolution  r a t e s were d e t e r m i n e d by an  19 a p p a r a t u s s i m i l a r t o t h a t o f Levy and Hayes ( 1 3 ) . Two and a h a l f l i t r e s of simulated i n t e s t i n a l  fluid in a  three-litre  g l a s s j a r was a l l o w e d t o e q u i l i b r a t e i n a c o n s t a n t tempera t u r e water b a t h s e t a t 37°C + 1°C. One t a b l e t was p l a c e d i n a c y l i n d r i c a l w i r e basket (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 ) which was a t t a c h e d below t h e i m p e l l e r o f a s t i r r ing  s h a f t ( t h r e e - b l a d e , T e f l o n - c o a t e d p r o p e l l e r , 5 cm. i n  d i a m e t e r ) . The s h a f t which was connected t o a F i s h e r S t e d i Speed s t i r r e r was i n s e r t e d t o a depth o f t e n cm. below t h e s u r f a c e o f t h e l i q u i d and r o t a t e d a t e x a c t l y 100 r.p.m. i n a c l o c k w i s e d i r e c t i o n . Ten m l . a l i q u o t s were t a k e n a t f i f t e e n - m i n u t e i n t e r v a l s f o r the. f i r s t hour, a t t h i r t y - m i n u t e i n t e r v a l s f o r t h e second hour and h o u r l y t h e r e a f t e r f o r seven h o u r s . R e s u l t s showed t h a t n i n e o f t h e t w e n t y - t h r e e p r o d u c t s had d i s i n t e g r a t i o n t i m e s o f more t h a n t h i r t y  minutes.  Twelve p r o d u c t s (some w i t h d i s i n t e g r a t i o n t i m e s g r e a t e r than t h i r t y minutes and some w i t h d i s i n t e g r a t i o n t i m e s l e s s than t h i r t y minutes) were s e l e c t e d f o r more e x t e n s i v e s t u d y . Of t h e s e t w e l v e p r o d u c t s , t h r e e were found t o have a d i s i n t e g r a t i o n time o f more t h a n t h i r t y minutes w i t h a range o f more t h a n t h i r t y m i n u t e s . From t h e d i s i n t e g r a t i o n time d a t a , i t would appear t h a t t h e drug i n t h e s e t a b l e t s may n o t he a v a i l a b l e t o t h e p a t i e n t . D i s s o l u t i o n s t u d i e s showed t h a t f o u r o f t h e t w e l v e p r o d u c t s had T C Q ^ v a l u e o f more t h a n  20 120 minutes but most o f t>he t w e n t y - t h r e e p r o d u c t s d i s i n t e g r a t e d and r e l e a s e d t h e i r phenylbutazone  c o n t e n t t o the medium  q u i c k l y . A s t a n d a r d T^Q^ v a l u e o f 120 minutes was t h e s e workers  chosen by  on the b a s i s o f the d a t a a v a i l a b l e . I t was  not p o s s i b l e t o c o r r e l a t e the " i n v i v o " d a t a t o t h a t o b t a i n e d " i n v i t r o " . F o r t h e t a b l e t s examined, the b e s t c o r r e l a t i o n was  s t i l l t o t a b l e t d i s i n t e g r a t i o n t i m e . However, maximum  d i s i n t e g r a t i o n t i m e s would be more m e a n i n g f u l than mean d i s i n t e g r a t i o n times. Nash and Marcus (20) used a p e r i o d i c s o l v e n t exchange method t o s t u d y d-amphetamine s u l f a t e " s u s t a i n e d r e l e a s e " c a p s u l e s and t r i p e l e n n a m i n e h y d r o c h l o r i d e " s u s t a i n e d r e l e a s e " t a b l e t s . The t e s t sample was  put i n t o 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  disk  f i l t e r bed and g e n t l y a g i t a t e d i n 400 ml. o f s i m u l a t e d g a s t r i c j u i c e . F i n e r p o r o s i t y f i l t e r s prevent proper drainage of the f l u i d w h i l e c o a r s e r types l e a k d u r i n g sampling p e r i o d s . P o s i t i v e a i r p r e s s u r e was m a i n t a i n e d between s a m p l i n g p e r i o d s to  prevent l e a k a g e . A f t e r t h i r t y minutes, 200 ml. was  drawn  o f f by vacuum t h r o u g h the f i l t e r bed i n t o the s u c t i o n f l a s k and c o l l e c t e d i n a 250 ml. beaker. A . f o u r - i n c h s t a n d a r d two-way s t o p c o r k f u s e d i n t o the bottom o f the s u c t i o n f l a s k facilitated of  the removal o f f l u i d samples d u r i n g t h e c o u r s e  each r u n w i t h o u t u p s e t t i n g the p o s i t i v e p r e s s u r e a t t h e  bottom o f the f i l t e r bed. An a d d i t i o n a l 200 ml. p o r t i o n o f s i m u l a t e d g a s t r i c f l u i d was added t o the f u n n e l t o r e p l a c e  21 t h e withdrawn volume. F u r t h e r samples were withdrawn a t one and a h a l f , two, t h r e e , f i v e , seven and t w e n t y - f o u r  hour  i n t e r v a l s , each time w i t h replacement o f t h e f l u i d . Norby (22) developed a c o n t i n u o u s  s o l v e n t exchange  system t o s t u d y t h e r e l e a s e p a t t e r n o f " s u s t a i n e d r e l e a s e " t a b l e t s . One u n i t o f t h e drug was p l a c e d i n a beaker c o n t a i n i n g t e n m l . o f d i s s o l u t i o n medium a t 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 t e m p e r a t u r e . T h i s s o l u t i o n was kept a t a c o n s t a n t l e v e l w i t h t h e r e s e r v o i r o f f r e s h medium t o ensure a c o n s t a n t volume i n t h e d i s s o l u t i o n v e s s e l . The medium from t h e d i s s o l u t i o n v e s s e l f l o w e d t h r o u g h t u b i n g which had a c o t t o n  filter  a t t h e open end i n t o a c o l l e c t i n g v e s s e l a t a r a t e (0-10  ml./min.) c o n t r o l l e d by a magnetic v a l v e . There'  was an automatic  mechanism c o n t r o l l i n g t h i s v a l v e which  c o n t r o l l e d t h e f l o w r a t e t h r o u g h t h e system t o g i v e a r e p r o d u c i b l e t e s t . The opening and c l o s i n g o f t h e v a l v e was c o n t r o l l e d by an e l e c t r o n i c a l l y d r i v e n mechanical, d e v i c e . The  s t i r r e r was power d r i v e n . A s c r e e n around t h e p r o p e l l e r  p r o t e c t e d t h e t e s t ' p r e p a r a t i o n from coming i n c o n t a c t  with  the b l a d e s . The s t i r r e r was moving f a s t enough so t h a t t h e drug was moving f r e e l y and d i d not s t i c k t o t h e s i d e s o r the bottom o f t h e d i s s o l u t i o n v e s s e l . C o n c e n t r a t i o n  of the  medium was d e t e r m i n e d e i t h e r by a n a l y s i n g a f r a c t i o n o f t h e c o l l e c t e d medium o r by a c o n t i n u o u s photometer.  r e c o r d i n g on a s p e c t r o -  22 I n t h e i r study o f the e f f e c t o f compression pressure on d i s s o l u t i o n , Ganderton and h i s co-workers (7) used two ° methods t o t e s t compressed t a b l e t s o f p h e n i n d i o n e o f d i f f e r ent  formulations, a l l containing  100 mg. c r y s t a l l i n e l a c t o s e  w i t h 15 mg. of. p o t a t o s t a r c h d i s p e r s e d w i t h i n t h e g r a n u l e s , o v e r a p r e s s u r e range o f 60 - 2500 Kg.cm.  on a s i n g l e  punch machine. I n t h e f i r s t method, t h e d i s s o l u t i o n was a 2 - l i t r e beaker ( c o n t a i n i n g  vessel  1.5 l i t r e s o f d i s s o l u t i o n  medium) immersed i n a water b a t h . The medium was s t i r r e d by a p e r s p e x paddle 11 cm. i n d i a m e t e r , h e l d 0.5 cm. above the bottom o f t h e v e s s e l and r o t a t i n g a t 56 r.p.m. The two b l a d e s o f t h e paddle were 2.5 cm. deep and p i t c h e d  a t 45°  t o promote a x i a l m i x i n g . Two d i a m e t r i c a l l y opposed b a f f l e s 1.3 cm. wide  were f i x e d i n t h e v e s s e l . The t e s t  tablet  was p l a c e d i n a cube o f lOOsmesh s t a i n l e s s s t e e l gauze o f s i d e s 1.5 cm., r i g i d l y suspended i n t h e b a t h 4 cm. from t h e p a d d l e a x i s and 2 cm. below t h e s u r f a c e o f t h e l i q u i d . The t e s t was performed i n 0.001 N.NaOH a t 3 7 ° C F i v e m l . samples were withdrawn t h r o u g h a f i l t e r tube a t s u i t a b l e i n t e r v a l s over a p e r i o d  o f one hour, d i l u t e d and a s s a y e d . The second  method was a c o n t i n u o u s d i s s o l u t i o n p r o c e s s , u s i n g a c y l i n d r i c a l perspex c e l l 5.1 cm. i n d i a m e t e r . A 100-mesh, concave, s t a i n l e s s s t e e l gauze was f i x e d a c r o s s t h e c e l l and t h e t a b l e t h e l d l i g h t l y a t t h e c e n t r e w i t h a v e r t i c a l p i n . Water b u f f e r e d a t pH 7 was a d m i t t e d t h r o u g h t h e c e n t r e o f t h e c e l l  23 base and d i r e c t e d  r a d i a l l y on t h e gauze below t h e t a b l e t .  When t h e t a b l e t was w e t t e d , t h e r e t a i n i n g p i n was removed and  t h e l i q u i d i s s u i n g from t h e t o p o f t h e c e l l was c o l l e c t e d o  and  a s s a y e d . The t e s t was c a r r i e d out a t pH 7 and 20 G t o  a l l o w t h e d i r e c t a s s a y o f the emerging s o l u t i o n w i t h o u t further and  d i l u t i o n . The f i r s t l i t r e o f s o l u t i o n was c o l l e c t e d  a s s a y e d . The t e s t l a s t e d a p p r o x i m a t e l y e l e v e n m i n u t e s ,  g i v i n g a mean l i q u i d v e l o c i t y i n t h e c e l l o f 0.075 cm./sec. Disintegration  t e s t s were c a r r i e d out u s i n g t h e method  d e s c r i b e d i n t h e B r i t i s h Pharmacopeia  1963.  From t h e r e s u l t s , i t was found t h a t t h e speed o f disintegration progressively  d e c r e a s e d as t h e compression  p r e s s u r e i n c r e a s e d . The d i s s o l u t i o n r a t e s f e l l s t e e p l y a t the l o w compression p r e s s u r e s and t h e n r i s e t o form a peak at p r e s s u r e s which v a r i e d w i t h f o r m u l a t i o n from 500 t o 800  Kg. cm.  . The r a t e t h e n decreased t o g i v e an extended  h i g h p r e s s u r e r e g i o n i n which d i s s o l u t i o n r a t e was independent  o f b o t h p r e s s u r e and f o r m u l a t i o n .  A l t h o u g h v e r y weak  and  e a s i l y p e n e t r a t e d by t h e d i s s o l u t i o n medium, t a b l e t s  produced a t v e r y low p r e s s u r e s d i d not break up  extensively  d u r i n g t h e t e s t . L i t t l e f r a g m e n t a t i o n had o c c u r r e d so t h a t p a r t i c l e l o s s and d i s s o l u t i o n r a t e were l o w . At h i g h e r pressures, penetration s t i l l release  o c c u r r e d q u i c k l y and s t r e s s  and t h e l o s s o f s m a l l a i r b u b b l e s caused much more  d i s r u p t i o n . The van d e r Waals f o r c e s  holding the t a b l e t  t o g e t h e r i n t h e d r y s t a t e were i n e f f e c t u a l i n t h e presence o f a l i q u i d o f h i g h d i e l e c t r i c c o n s t a n t and p e n e t r a t i o n by the d i s s o l u t i o n medium caused t h e t a b l e t t o break up. W i t h f u r t h e r i n c r e a s e i n p r e s s u r e , rebonding  of the material  o c c u r r e d and a s t r o n g e r and denser t a b l e t was formed, which was l e s s e a s i l y p e n e t r a t e d .  P a r t i c l e l o s s and d i s s o l u t i o n  r a t e were, t h e r e f o r e , d e p r e s s e d . U l t i m a t e l y , h i g h s t r e n g t h and l o w p e n e t r a t i o n p r e v e n t e d  break-up o f t h e t a b l e t , and  d i s s o l u t i o n o c c u r r e d o n l y from t h e s u r f a c e o f t h e t a b l e t and was t h e r f o r e independent o f any f o r m u l a t i o n v a r i a b l e s . At l o w p r e s s u r e , t h e d i s s o l u t i o n r a t e o f t a b l e t s i n c r e a s e d as t h e f i l l e r  s i z e or the granule  s i z e d e c r e a s e d . These  r e s u l t s i n d i c a t e d t h a t these f a c t o r s g r e a t l y a f f e c t t h e s i z e o f t h e p a r t i c l e s l i b e r a t e d by p e n e t r a t i o n and break-up. I n t h e case o f t h e f i l l e r ,  decrease i n s i z e i n c r e a s e d t h e  homogeneity o f t h e o r i g i n a l mix, opposing t h e f o r m a t i o n o f l a r g e agglomerates o f p h e n i n d i o n e .  Decrease i n g r a n u l e  size  modified the d i s p o s i t i o n of the external s t a r c h , a f a c t o r which has been shown t o g r e a t l y a f f e c t p e n e t r a t i o n and break-up o f the t a b l e t . S m a l l e r g r a n u l e s would a l l o w i t s more e f f e c t i v e d i s t r i b u t i o n as a h y d r o p h i l i c o r a n t i b o n d i n g l a y e r . Both t h e s e e f f e c t s w i l l d i s a p p e a r a t h i g h  pressures  of compaction when break-up i s depressed and s o l u t i o n occurs o n l y from t h e s u r f a c e o f t h e t a b l e t .  2  A c o n t i n u o u s f l o w system was d e s i g n e d by Woo ( 3 3 ) t o study e l e v e n brands o f c o m m e r i c i a l l y a v a i l a b l e  tolbut-  amide t a b l e t s . The d i s s o l u t i o n v e s s e l was a t w o - l i t r e  aspir  a t o r b o t t l e . The r u b b e r s t o p p e r a t t h e bottom o u t l e t o f t h e b o t t l e c a r r i e d a short piece of glass tubing that  was  connected on t h e i n s i d e o f t h e d i s s o l u t i o n v e s s e l  to a  p i e c e o f r u b b e r t u b i n g . A p i e c e o f v e r y f i n e gauze t h a t c o v e r e d t h e open end o f t h e r u b b e r t u b i n g a c t e d as t h e f i l t e r f o r t h e o u t f l o w i n g medium. The g l a s s  tube t h a t  proje  ed out o f t h e v e s s e l was connected t o a T - g l a s s t u b e , one arm  o f which was j o i n e d t o an a i r s u p p l y , w h i l e t h e o t h e r  arm  l e d t o a 500-ml. s u c t i o n  f l a s k v i a r u b b e r t u b i n g . The  rubber stopper a t the top of the d i s s o l u t i o n v e s s e l  carried  a thermometer and an i n l e t tube from a r e s e r v o i r o f s i m u l a t e d g a s t r i c f l u i d . The d i s s o l u t i o n v e s s e l was s e t on a p y r o - m a g n e t s t i r , t h a t kept t h e medium i n t h e v e s s e l a t a t e m p e r a t u r e o f 37°G + 0 . 5 ° C , and caused t h e magnetic s t i r r e r i n the d i s s o l u t i o n vessel  t o s t i r t h e medium a t  v a r y i n g speeds. The d i s s o l u t i o n v e s s e l was f i l l e d w i t h one and  a h a l f l i t r e s of simulated g a s t r i c f l u i d . A f t e r the o  medium had e q u i l i b r a t e d t o 3 7 C, a t e s t t a b l e t  of.tolbut-  amide ( 5 0 0 mg.) was dropped i n t o t h e d i s s o l u t i o n The  s t i r r e r was t u r n e d on t o g i v e a v i g o r o u s  vessel.  stirring  i n t e n s i t y . A f t e r an i n i t i a l t e n m i n u t e s , t h e clamp on t h e  26  tube t o t h e s u c t i o n  f l a s k was p a r t i a l l y unscrewed t o a l l o w  a f l o w r a t e o f 500 ml./30 m i n u t e s , when s u c t i o n was  applied.  At t h e same t i m e , t h e i n f l o w r a t e from t h e r e s e r v o i r was a d j u s t e d t o d e l i v e r 500 ml./30 m i n u t e s , by p a r t i a l l y unscrewi n g t h e clamp on t h e d e l i v e r y t u b e . T h i s ensured t h a t t h e volume, i n t h e d i s s o l u t i o n v e s s e l was kept c o n s t a n t . D u r i n g the  changing o f t h e s u c t i o n  f l a s k s ( a f t e r each  thirty-minute  i n t e r v a l ) b o t h t h e i n f l o w and o u t f l o w tubes were clamped o f f by a second clamp. As t h e f l u i d f l o w e d t h r o u g h t h e f i n e gauze f i l t e r ,  p a r t i c l e s o f t h e t e s t t a b l e t c o l l e c t e d on t h e  f i l t e r and caused i t t o be c l o g g e d up, t h u s s l o w i n g t h e o u t f l o w r a t e . T h i s was overcome by t u r n i n g occassionally the  on t h e a i r s u p p l y  t o blow t h e p a r t i c l e s o f f t h e gauze back i n t o  d i s s o l u t i o n medium. The d i s s o l u t i o n t e s t was c a r r i e d  on f o r a p e r i o d of three l i t r e s . each p o r t i o n  o f t h r e e h o u r s , c o l l e c t i n g i n t o t a l a volume I n d i v i d u a l a n a l y s e s were c a r r i e d out on  o f d i s s o l u t i o n medium c o l l e c t e d .  Disintegration  t e s t s were c a r r i e d out on t h e s e t o l b u t a m i d e t a b l e t s u s i n g the o f f i c i a l  U.S.P. d i s i n t e g r a t i o n a p p a r a t u s (30). The  disintegration studies of t h e p l a s t i c  were c a r r i e d out w i t h o u t t h e use  disks.  The v a r i o u s brands o f t o l b u t a m i d e t a b l e t s to f o l l o w a s i m i l a r pattern  seemed  of d i s s o l u t i o n . I n the i n i t i a l  t e n m i n u t e s , most o f t h e t a b l e t s broke up i n t o v e r y f i n e p a r t i c l e s o r f l a k e s . The r e l e a s e  of the active  ingredient  increased gradually t i l l  a maximum was reached i n t h e f i r s t  h a l f hour. The l e v e l remained c o n s t a n t f o r about an hour and t h e n g r a d u a l l y decreased due t o a d i l u t i o n p r o c e s s by t h e incoming s o l v e n t , thus g i v i n g a p l a t e a u - l i k e  curve.  Even though t h e d i s s o l u t i o n p a t t e r n was s i m i l a r f o r t h e d i f f e r e n t brands, t h e t o t a l . a m o u n t o f t h e a c t i v e  ingredient,  r e l e a s e d i n t h r e e l i t r e s o f s o l u t i o n ranged from 60 mg. t o 270 mg. No c o r r e l a t i o n w i t h t h e d i s i n t e g r a t i o n t i m e s c o u l d be found, c o n f i r m i n g an e a r l i e r r e p o r t by Brudney and h i s co-workers  (1). However, t h e d i s s o l u t i o n t e s t was c a r r i e d  out on o n l y one t a b l e t o f each p r o d u c t , so d e f i n i t e c o n c l u s i o n s about t h e t a b l e t q u a l i t y c o u l d n o t be made. The d i s s o l u t i o n t e s t d e s c r i b e d was v e r y time consuming and r e q u i r e d c o n s t a n t s u p e r v i s i o n . Moreover,  the f i l t e r i n g  system was not t o o e f f i c i e n t and t e n d t o b l o g up towards the end o f t h e d i s s o l u t i o n r u n and hence would be inadequate f o r longer d i s s o l u t i o n runs.  28 I I I . THE "IN VITRO" CHARACTERISTICS OF PHENYLBUTAZONE The drug b e i n g i n v e s t i g a t e d i s phenylbutazone and i s used f o r t h e r e l i e f o f j o i n t p a i n caused by rheumatoid a r t h r i t i s , gout, b u r s i t i s and o t h e r r e l a t e d Phenylbutazone  disorders.  (1,2-Diphenyl-4-butyl-3,4 Pyrazolidinedione),  a weak o r g a n i c a c i d o f pKa 4 . 4 ,  i s very s l i g h t l y soluble i n  w a t e r ( l e s s t h a n 0 . 7 mg./ml. a t 25°C) but f r e e l y s o l u b l e i n a l c o h o l (50 mg./ml.), a c e t o n e , e t h e r and e t h y l a c e t a t e . P h e n y l b u t a z o n e powder t e n d s t o agglomerate and f l o a t on t h e s u r f a c e o f an aqueous medium. A t t e m p t s a t r e c r y s t a l l i z a t i o n y i e l d e d l o n g n e e d l e s t h a t f l o a t on t h e s u r f a c e o f aqueous s o l u t i o n s . Hence, B u t a z o l i d i n (Geigy) t a b l e t s (which have been r e p o r t e d t o g i v e good c l i n i c a l response ( 2 , 2 7 ) )  were chosen as a s t a n d a r d f o r t h i s  investigation. (a) The 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 i n B u f f e r e d S o l u t i o n s I t i s necessary, during the d i s s o l u t i o n t e s t , t o change from an a c i d i c medium o f pH 1.2 t o a pH 6 . 2 . S i n c e the s o l u b i l i t y o f phenylbutazone i s a f f e c t e d by t h e p.H o f t h e d i s s o l v i n g medium, s o l u b i l i t y s t u d i e s were c a r r i e d out i n b u f f e r s o f d i f f e r e n t pH v a l u e s . Procedure - Using the Smith, K l i n e & French d i s i n t e g r a t i o n a p p a r a t u s ( 2 9 ) , phenylbutazone powder i s put i n t o each o f s i x ' b o t t l e s c o n t a i n i n g 50 m l . o f b u f f e r (two samples o f each b u f f e r a r e u s e d ) . The b o t t l e s a r e suspended  i n a w a t e r b a t h m a i n t a i n e d a t 37°C and r o t a t e d so as t o provide  good m i x i n g f o r a p e r i o d o f t w e n t y - f o u r h o u r s . A t  the end .of t h i s p e r i o d , t h e s o l u t i o n s a r e f i l t e r e d q u i c k l y , d i l u t e d i f n e c e s s a r y w i t h the b u f f e r and a s s a y e d  spectro-  photometrically. R e s u l t s - The s o l u b i l i t y curve ( F i g u r e 1 ) , drawn from t h e d a t a o b t a i n e d ,  showed t h a t t h e s o l u b i l i t y o f  phenylbutazone i s v e r y low i n b u f f e r s o f l o w pH v a l u e s . However, once t h e pH v a l u e reached 6, t h e s o l u b i l i t y increased  greatly.  (b) D e t e r m i n a t i o n o f t h e I s o s b e s t i c P o i n t The i s o s b e s t i c p o i n t o f a s o l u t i o n i s t h e wavel e n g t h a t which changes i n t h e pH o f t h e s o l u t i o n do not a f f e c t t h e absorbancy (As) r e a d i n g  of the s o l u t i o n . Since  the c o n d i t i o n s o f t h i s d i s s o l u t i o n t e s t i n v o l v e a change from an a c i d i c t o a b a s i c medium, t h e w a v e l e n g t h a t which absorbancy r e a d i n g s isosbestic  a r e t o be r e c o r d e d must be a t t h e  point. P r o c e d u r e - Weigh a c c u r a t e l y 100 mg. o f p h e n y l -  butazone powder and d i s s o l v e ^ i n 100 m l . o f 95%  ethanol.  Ten m l . a l i q u o t s o f t h i s s o l u t i o n a r e d i l u t e d a c c u r a t e l y t o 1000 m l . w i t h b u f f e r s o f v a r i o u s pH v a l u e s  (ranging  from pH 1.2 t o pH 7.5)'. The spectrum o f t h e s e s o l u t i o n s a r e r e c o r d e d on a r e c o r d i n g s p e c t r o p h o t o m e t e r 505,  (Spectronic  Bausch and Lomb). From t h e s p e c t r a o f t h e s o l u t i o n s ,  30 an i s o s b e s t i c p o i n t was observed a t between 238 mu and 245 mu. The absorbancy o f t h e s e s o l u t i o n s a r e then r e a d on a Beckman DU s p e c t r o p h o t o m e t e r from 238 mu t o 245 mu w i t h each s o l u t i o n b l a n k e d a g a i n s t t h e r e s p e c t i v e b u f f e r . A p l o t o f t h e absorbancy r e a d i n g s f o r the s o l u t i o n s showed t h a t t h e wavelength that i s c l o s e s t t o being the i s o s b e s t i c - point f o r phenylbutazone i s 240 mu ( F i g u r e 2 ) . T h i s p o i n t was chosen as t h e w a v e l e n g t h a t which a l l subsequent absorbancy r e a d i n g s were r e c o r d e d . (c) D e t e r m i n a t i o n o f t h e A b s o r p t i v i t y V a l u e The a b s o r p t i v i t y ( a ) i s a c o n s t a n t f o r a p a r t i c u l a r s  s o l u t e i n a p a r t i c u l a r solvent a t a c e r t a i n wavelength. A c c o r d i n g t o B e e r ' s Law, i t i s t h e s l o p e o f t h e l i n e  relating  the absorbancy o f a s o l u t i o n and i t s c o n c e n t r a t i o n . As = a b c s  where As i s t h e absorbancy o f t h e s o l u t i o n a  s  i s the a b s o r p t i v i t y  b i s t h e c e l l l e n g t h i n cm. c i s t h e c o n c e n t r a t i o n i n gm./L. Procedure -.Weigh a c c u r a t e l y 100 mg.  phenylbutazone  poxtfder and d i s s o l v e i n 100 m l . o f 95% e t h a n o l . D i l u t e a l i q u o t s o f f i v e t o twenty ml. t o 1000 m l . w i t h 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. The absorbancy o f each s o l u t i o n i s r e a d on a Beckman DU s p e c t r o p h o t o m e t e r a t 240 mu, u s i n g 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. as a b l a n k .  31 R e s u l t s - The and a s t r a i g h t l i n e was calculated (Figure 3).  absorbancy r e a d i n g s were p l o t t e d o b t a i n e d . The  absorptivity  was  from the s l o p e of t h i s l i n e and found t o be  41.5  32  240  243  246  0  Wavelength  (mu)  F i g u r e 2 . The I s o s b e s t i c P o i n t o f Phenylbutazone  34  0.80  0.60  %  0.40 As= a b c s  a  q  - As = 41.5  0.20  5  10  15  20  C o n c e n t r a t i o n (mg./L.) F i g u r e 3. C a l i b r a t i o n Curve f o r 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 a t 240  mu  35  IV. THE OPERATING CHARACTERISTICS OF A CONTINUOUS FLOW DISSOLUTION APPARATUS (a) D e s c r i p t i o n o f t h e A p p a r a t u s The d i s s o l u t i o n v e s s e l (a o n e - l i t r e t h r e e - n e c k round-bottom f l a s k ) i s immersed i n a c o n s t a n t temperature o o w a t e r b a t h a t 37 C t 0 . 5 C. D i p p i n g i n t o t h e c e n t r a l neck of the f l a s k i s the shaft o f a F i s h e r Stedi-Speed a d j u s t a b l e stirrer  (Model 12) w i t h a f o u r - b l a d e i m p e l l e r b l a d e (3 cm.  i n d i a m e t e r ) and a c y l i n d r i c a l w i r e b a s k e t a t i t s bottom. The b a s k e t which i s A cm. l o n g and 2 . 5 cm. i n d i a m e t e r i s made from 10-mesh s t a i n l e s s s t e e l w i r e c l o t h . A g l a s s tube which a c t s a s t h e i n l e t tube f o r t h e d i s s o l u t i o n medium d i p s t h r o u g h t h e r i g h t s i d e neck i n t o the d i s s o l u t i o n v e s s e l t o a depth o f 10 cm. Connected t o t h i s tube i s a two-way s t o p c o r k , one arm o f w h i c h i s connected to a r e s e r v o i r of simulated g a s t r i c j u i c e  (2 gm. NaCl + 7 m l .  HCl i n 1 0 0 0 m l . d i s t i l l e d w a t e r , pH 1 . 2 ) w h i l e t h e o t h e r arm i s joined t o a r e s e r v o i r of simulated i n t e s t i n a l  juice  ( 6 . 8 gm. K H P 0 ^ + 1 . 5 2 gm. NaOH i n 1000 m l . d i s t i l l e d w a t e r , 2  pH 7 . 5 ) . B o t h r e s e r v o i r s o f d i s s o l u t i o n medium a r e p l a c e d on h e a t e r s t o keep t h e s o l u t i o n a t 37°C  0.5°C  An i n v e r t e d s i n t e r e d g l a s s f u n n e l (30 m l . c a p a c i t y ) of coarse p o r o s i t y dips i n t o the l e f t  s i d e arm o f t h e d i s s o l -  u t i o n v e s s e l . I t i s j o i n e d t o a s h o r t l e n g t h o f g l a s s tube  c a r r y i n g a s i n t e r e d t i p (coarse p o r o s i t y ) , that dips i n t o t h e d i s s o l u t i o n v e s s e l t o a depth o f '5.0 cm. A combination g l a s s electrode (not i l l u s t r a t e d i n F i g u r e 4) l e a d i n g from a r e c o r d i n g p o t e n t i o m e t e r  (Potent-  i o g r a p h E336A) and a s h o r t p i e c e o f g l a s s t u b e , which a c t s as t h e o u t l e t t u b e , d i p i n t o the broad end o f t h e s i n t e r e d g l a s s f u n n e l . The o u t l e t tube i s j o i n e d by Tygon t u b i n g t o an a d j u s t a b l e pump (Cole Palmer A-769) from which t u b i n g leads t o a flow c e l l  (1 cm. i n l e n g t h )  i n a recording  spectro-  photometer ( S p e c t r o n i c 505, Bausch & Lomb). A r e c o r d e r ( V a r i c o r d Model 43) i s a t t a c h e d t o t h e s p e c t r o p h o t o m e t e r f o r a d i r e c t recording o f the concentration o f the s o l u t i o n p a s s i n g t h r o u g h t h e f l o w c e l l . From t h e f l o w c e l l , t h e s o l u t i o n i s d e l i v e r e d i n t o a t w e l v e - l i t r e covered g l a s s v e s s e l , that a c t s as t h e c o l l e c t i n g v e s s e l . (b) C a l i b r a t i o n o f t h e R e c o r d e r Procedure - The r e c o r d e r i s s e t on t h e 25 and mV range. I t i s zeroed w i t h g a s t r i c j u i c e i n t h e sample c e l l and a i r as t h e b l a n k . S o l u t i o n s o f known c o n c e n t r a t i o n o f p h e n y l butazone a r e r e a d i n t h e sample c e l l o f t h e s p e c t r o p h o t o m e t e r a t 240 mu and t h e c h a r t r e a d i n g s  on t h e r e c o r d e r s c a l e a r e  recorded. From t h e known c o n c e n t r a t i o n s and t h e c h a r t on t h e r e c o r d e r s c a l e , a graph i s p l o t t e d ( F i g u r e 5 ) .  readings  gure 4. Diagram o f Continuous Flow D i s s o l u t i o n Apparatus  ISPECTRONIC 5 Q 5 •  DISCHARGE  t C O L E PALMER A-769 ADOUSTABLE PUMP  t  VARICORD M O D E L FISHER S T E D I * S P E E D STIRRER TO STIRRING SUCTION / S H A F T GLASS TUBE  T  £  S  T  F  U  J  |  D  x  TWO WAY STOPCOCK  T E S T FLUID H  FILTERING D E V I C E F O R CONTINUOUS FLOW SINTERED G L A S S FUNNEL (COARSE 3 0 mi.) S I N T E R E D TIP (COARSE)  GLASS TUBE  ONE L I T E R FLASK BASKET  38  150  to •H  Ti crj CD  100  ca •p u crj X!  o  10 C o n c e n t r a t i o n (mg.  20 phenylbutazone/L^)  F i g u r e 5. C a l i b r a t i o n Curve f o r R e c o r d e r E x t e r n a l t o the Spectronic  505  (c) The The researchers  E f f e c t of S t i r r i n g  Rate on D i s s o l u t i o n  s t i r r i n g r a t e has been r e p o r t e d by many (8, 11, 17)  t o have a c o n s i d e r a b l e  d i s s o l u t i o n r a t e . Levy (11) has  e f f e c t on  the  s t a t e d t h a t too i n t e n s i v e  an a g i t a t i o n r a t e i s t o be a v o i d e d s i n c e X - r a y photographs have shown t h a t t a b l e t p a r t i c l e s t e n d t o remain as  an  a g g r e g a t e on the stomach s u r f a c e . T h i s i m p l i e s t h a t  the  m i x i n g p r o c e s s i n the stomach i s v e r y low. However, i n the s m a l l i n t e s t i n e , the p a r t i c l e s appeared t o be v e r y w e l l dispersed  i n d i c a t i n g t h a t the m i x i n g i n t h i s r e g i o n i s q u i t e  vigorous. S i n c e phenylbutazone i s n e a r l y i n s o l u b l e i n s o l u t i o n s of pH 1.2  but v e r y s o l u b l e i n s o l u t i o n s of pH  i t would appear t h a t the a b s o r p t i o n  7.5,  of phenylbutazone o c c u r s  m a i n l y under the b a s i c c o n d i t i o n s o f the s m a l l i n t e s t i n e . Hence, a s t i r r i n g r a t e t h a t causes the drug p a r t i c l e s t o w e l l d i s p e r s e d throughout the medium may  be  be d e s i r a b l e i n  the d i s s o l u t i o n t e s t under s t u d y . C o n s e q u e n t l y , s t i r r i n g r a t e s of 65, 100  and  115  r.p.m. i n the f o r w a r d d i r e c t i o n were i n v e s t i g a t e d u s i n g  the  d e s i g n e d d i s s o l u t i o n a p p a r a t u s and t e s t p r o c e d u r e . These s t i r r i n g r a t e s were i n v e s t i g a t e d w i t h the s t i r r e r a t  differ-  ent depths i n the d i s s o l u t i o n medium, u s i n g B u t a z o l i d i n t a b l e t s as the t e s t p r e p a r a t i o n , and a t a c o n s t a n t r a t e of 60 ml./minute. Each r a t e was  pumping  tested i n duplicate.  40 Results runs are t a b u l a t e d  - The d a t a o b t a i n e d from t h e d i s s o l u t i o n i n T a b l e I . I t can be seen t h a t when t h e  s t i r r i n g i s n o t enough t o move t h e p a r t i c l e s , t h e r e l e a s e r a t e o f t h e drug i s l o w even though t h e s o l u t i o n i n t h e d i s s o l u t i o n v e s s e l appears t o be homogeneous. The l o w r e l e a s e r a t e i s due t o t h e f a c t t h a t t h e t a b l e t p a r t i c l e s remain as an aggregate on t h e d i s s o l u t i o n v e s s e l bottom, t h u s p r e s e n t ing  a l i m i t e d s u r f a c e a r e a t o t h e d i s s o l u t i o n medium. When t h e b a s k e t i s 6 Cm. from t h e v e s s e l  bottom,  the s t i r r i n g i s i n s u f f i c i e n t even a t t h e h i g h s t i r r i n g  rate  of 115 r.p.m. A t 3.5 cm. from t h e bottom o f the v e s s e l , t h e s t i r r i n g i s adequate except a t t h e lox^est r a t e o f 65 r.p.m., when about h a l f o f t h e t a b l e t p a r t i c l e s remain a g g r e g a t e d on t h e v e s s e l bottom. The o t h e r two s t i r r i n g r a t e s  caused  the p a r t i c l e s t o move t h r o u g h t h e medium, t h e h i g h e r r a t e of 115 r.p.m. g i v i n g a more v i g o r o u s movement. At a depth of 1 cm. from t h e v e s s e l bottom, t h e s t i r r i n g e f f e c t i s q u i t e v i g o r o u s even a t t h e r a t e o f 65 r.p.m. To a v o i d  this  s t i r r i n g e f f e c t , t h i s depth was n o t chosen f o r p r o d u c t testing. The depth f i n a l l y chosen was 3.5 cm. w i t h a s t i r r ing  r a t e of! 100 r.p.m. r a t h e r t h a n 115 r.p.m. The former  r a t e produced t h e d e s i r e d s t i r r i n g e f f e c t . At t h i s speed, t h e p a r t i c l e s move s l o w l y t h r o u g h t h e medium.  41 Table I . The E f f e c t of S t i r r i n g Rate on D i s s o l u t i o n  S t i r r i n g rate  Depth of basket  Mg. phenylbutazone  (forward d i r e c t i o n )  from v e s s e l bottom  i n s o l u t i o n i n 3 hours  65 r.p.m.  100 r.p.m.  115 r.p.m.  1 cm.  .87.5 mg.  3*5 cm.  62.1 mg.  6 cm.  55.4 mg.  1 cm.  83.1 mg.  3.5 cm.  83.5 mg.  6 cm.  75.0 mg.  1 cm.  90.0 mg.  3.5 cm.  85.0 mg.  6 cm.  78.5 mg.  42  (d) The E f f e c t o f Pumping Rate on D i s s o l u t i o n Three pumping r a t e s were s t u d i e d f o r t h e i r e f f e c t on d i s s o l u t i o n r a t e . The d i s s o l u t i o n t e s t was c a r r i e d out w i t h B u t a z o l i d i n t a b l e t s as t h e t e s t p r e p a r a t i o n and w i t h the b a s k e t a t 3.5 cm. f r o n r the v e s s e l bottom s t i r r i n g a t a r a t e o f 100 r.p.m. The pumping r a t e s s t u d i e d were 50 ml./min., 60 ml./min. and 70 ml./min. R a t e s l o w e r t h a n 50 ml./min. were n o t s t u d i e d due t o i n s t r u m e n t a l the more c o n c e n t r a t e d  l i m i t a t i o n s i n reading  solutions.  R e s u l t s - The data o b t a i n e d  are tabulated i n  T a b l e I I . T h i s d a t a shows t h a t t h e r e i s no s i g n i f i c a n t  differ-  ence i n t h e r e l e a s e o f t h e drug i n t h e t h r e e - h o u r p e r i o d . The  pH changes i n t h e medium a r e a f f e c t e d by t h e  pumping r a t e t o a s l i g h t e x t e n t . H i g h e r pumping r a t e s gave a much f a s t e r pH change from a c i d i c t o b a s i c pH. A t t h e pumping r a t e o f 60 ml./min., the sharp r i s e i n pH from about pH o f 2 t o pH o f 6 . 2 o c c u r r e d w i t h i n t w e n t y - f i v e  minutes  ( F i g u r e 6 ) , w h i l e a t a pumping r a t e o f 70 ml./min., i t o c c u r r e d w i t h i n twenty m i n u t e s . However, a t 70 ml./min., the f i n a l volume o f s o l v e n t i s too g r e a t t o be h a n d l e d e a s i l y . At 50 ml./min., t h e pH change o c c u r r e d  i n thirty  minutes but a t t h i s r a t e , t h e s o l u t i o n i s becoming t o o s a t u r a t e d t o be r e a d on t h e s p e c t r o p h o t o m e t e r . A pumping r a t e o f 60 ml'./min. was t h e r e f o r e , f i n a l l y chosen f o r t h e dissolution  test.  43 T a b l e I I . The E f f e c t o f Pumping Rate on D i s s o l u t i o n  Mg.  Pumping  1 hour  2 hours  3 hours  1.  4.0  mg,  56.0  mg,  86.5  mg.  2.  3.9  mg.  51.0  mg.  86.4  mg.  1.  9.0  mg.  68.4  mg.  89.6  mg.  2.  8.3  mg.  62.6  mg.  86.4  mg,  1.  5.9  mg.  62.2  mg.  86.5  mg.  2.  6.7  mg.  63.0  mg.  88.2  mg.  rate  50 ml./min.  60 ml./min.  70 ml./min.  o f phenylbutazone i n s o l u t i o n  45' (e) T e s t Procedure W i t h t h e a p p a r a t u s s e t up as d e s c r i b e d and as shown i n F i g u r e 4, t h e d i s s o l u t i o n v e s s e l ( c o n t a i n i n g one l i t r e o f simulated g a s t r i c juice) i s allowed to e q u i l i b r a t e i n a c o n s t a n t temperature water b a t h a t 37°C + 0.5°C The e n t i r e system i s f l u s h e d out w i t h s i m u l a t e d g a s t r i c j u i c e t o remove air  from t h e system. The r e c o r d e r i s z e r o e d w i t h s i m u l a t e d  g a s t r i c j u i c e i n t h e sample f l o w c e l l and a i r as t h e b l a n k . A s i n g l e phenylbutazone t a b l e t (100 mg.) i s put i n t o t h e w i r e b a s k e t below t h e i m p e l l e r b l a d e and t h e whole a p p a r a t u s i s s e t infemotion. The s t i r r i n g r a t e i s 100 r.p.m. i n a f o r w a r d ( c l o c k w i s e ) d i r e c t i o n a t a depth o f 3.5 cm. from t h e bottom o f t h e d i s s o l u t i o n v e s s e l . W i t h t h e i n l e t tube from t h e r e s e r v o i r o f s i m u l a t e d g a s t r i c j u i c e opened, the  pump i s t u r n e d on t o d e l i v e r 60 ml./min.  entire  through t h e  system. A f t e r the i n i t i a l t h i r t y minutes, simulated i n t e s t -  i n a l j u i c e i s a l l o w e d i n t o t h e system. A t t h i s p o i n t , t h e p o t e n t i o m e t e r i s s w i t c h e d on t o r e c o r d pH changes as t h e medium i s g r a d u a l l y changed from an a c i d i c medium t o a b a s i c one. A l i q u o t s from t h e c o l l e c t i n g v e s s e l a r e t a k e n a t h o u r l y i n t e r v a l s f o r a n a l y s i s on a Beckman DU s p e c t r o p h o t o meter a t 240 mu, w i t 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 as t h e b l a n k . As t h e s o l u t i o n from t h e d i s s o l u t i o n v e s s e l passes  46 t h r o u g h the f l o w c e l l i n the s p e c t r o p h o t o m e t e r s e t a t 240  mu,  the V a r i c o r d r e c o r d s the c o n c e n t r a t i o n . T h i s g i v e s a c o n t i n uous r e c o r d i n g of the c o n c e n t r a t i o n of t h e s o l u t i o n as dissolution The  occurs. d i s s o l u t i o n r u n i s c a r r i e d on f o r t h r e e t o  s i x hours depending on the d i s s o l u t i o n r a t e of the !  indivi-  d u a l p r o d u c t s . At the end o f each r u n , the e n t i r e system i s f l u s h e d out w i t h 95% e t h a n o l and  water.  U s i n g t h i s t e s t p r o c e d u r e , seven brands of commeri c i a l l y a v a i l a b l e phenylbutazone t a b l e t s (100 t e s t e d i n t r i p l i c a t e . F o u r of the p r o d u c t s t a b l e t s ( P r o d u c t s A, E, W,  were  sugar-coated  X) w h i l e the o t h e r t h r e e  e n t e r i c c o a t e d t a b l e t s ( P r o d u c t s AA, was  are  mg.)  CC,  DD^).  are  Each  product  tested i n t r i p l i c a t e . (f)  Results  An average c o n t i n u o u s o b t a i n e d f o r each product  concentration plot  was  from the curves drawn out on  the  r e c o r d e r . T h i s p l o t gave the d i s s o l u t i o n p r o f i l e of the product  and a l s o a l l o w s the c a l c u l a t i o n of the t o t a l amount  o f drug r e l e a s e d i n any p e r i o d of time ( F i g u r e s 7 a , The  h o u r l y a n a l y s i s on the Beckman DU  b, c ) .  spectrophotometer  a l s o gave the amount of drug r e l e a s e d a t each h o u r l y t h u s p r o v i d i n g a check on the amount r e g i s t e r e d by recorder  interval,  the  (Table I I I ) . From the data on the p r o d u c t s  o b t a i n e d by the  two  47  L8  CC  LO  I-H  e o  •H  •P cd U  •P  c  © o o o  20  1  2 Time (hours)  F i g u r e 7b. D i s s o l u t i o n P r o f i l e s f o r Two Brands o f Phenylbutazone T a b l e t s  50  T a b l e I I I . D i s s o l u t i o n Data f o r Seven Brands o f Phenylbutazone T a b l e t s  Mg. o f p h e n y l b u t a z o n e i n s o l u t i o n Product  A  E  AA  CC  1 hour  2 hours  3 hours  1.  5.2  mg.  62.5  mg.  86.5  mg.  2.  5.2  mg.  61.9  mg.  88.0  mg.  3.  5.2  mg.  65.9  mg.  93.5  mg.  1.  1.2  mg.  52.5  mg.  86.5  mg.  2.  1.8  mg.  50.4  mg.  81.8  mg.  3.  1.5  mg.  48.0  mg.  79.2  mg.  1.  0.8  mg.  43.2  mg.  85.3  mg.  2.  0 . 8 mg.  43.2  mg.  86.5  mg.  3.  1.2  mg.  51-5  mg.  89.6  mg.  1.  1.4  mg.  91.4  mg.  96.2  mg.  2.  1.7  mg.  95.7  mg.  100.0  3.  1.7  mg.  90.7  mg.  95.8  mg. mg.  51 T a b l e I I I (Continued)  Mg. Product  X  W  DD  X  o f phenylbutazone i n s o l u t i o n  3 hours  4 hours  5 hours  6 hours  1.  7.4  23.6  mg.  55.8  mg.  75.7  mg.  2.  16.2  mg.  55.3  mg.  78.7  mg.  93.0  mg.  3.  23.8  mg.  50.8  mg.  75.0  mg.  92.2  mg.  1.  36.0  mg.  55.2  mg.  7 0 . 6 mg.  86.3  mg.  2.  36.2  mg.  55.0  mg.  7 0 . 3 mg.  86.0  mg.  3.  36.3  mg.  55.3  mg.  7 0 . 5 mg.  86.2  mg.  1.  5.4  mg.  27.0  mg.  94.0  mg.  101.5  2.  4.5  mg.  22.5  mg.  91.7  mg.  99.0  mg.  3.  4.5  mg.  22.3  mg.  90.9  mg.  93.0  mg.  mg.  mg.  52 Table IV. 5 0 % T  a n d  T  9 0 % V a l u e s f o r Seven Brands of  Phenylbutazone T a b l e t s  Product  T  $ 0  $ value  T  90% value  A  100 minutes  180 minutes  E  120 minutes  215 minutes  W  225 minutes  735 minutes.  X  255 minutes  735 minutes  AA  125 minutes  185 minutes  CC  80 minutes  120 minutes  DD-L  225 minutes  300 minutes  53  methods, time f o r 5 0 $ o f the drug (T5Q$) and 9 0 $ o f the drug ( T ^ ^ ) t o go i n t o s o l u t i o n was 0  c a l c u l a t e d and  tabulated  i n Table IV. The f o u r brands o f s u g a r - c o a t e d t a b l e t s showed l i t t l e d i s s o l u t i o n i n s i m u l a t e d g a s t r i c f l u i d . However, once t h e medium reached a pH of 6 . 2 , the c o n c e n t r a t i o n the a c t i v e i n g r e d i e n t occurred i n twenty-five 60  increased  of  g r e a t l y . T h i s change i n pH  minutes a t t h e pumping r a t e of  ml./minute. P r o d u c t s A and E (which d i s i n t e g r a t e d  within  f i f t e e n minutes o f the s t a r t o f the experiment)  showed  s i m i l a r d i s s o l u t i o n p a t t e r n s . The c o n c e n t r a t i o n  of a c t i v e  ingredient  continued to increase  gradually  once the medium  reached a pH o f 6. A peak was reached i n about one and a h a l f h o u r s . The curve t h e n g r a d u a l l y  d e c l i n e d due t o a  d i l u t i o n p r o c e s s by the incoming s o l v e n t . P r o d u c t E s l i g h t l y less active ingredient  released  from the t a b l e t t h a n d i d  P r o d u c t A. The o t h e r two s u g a r - c o a t e d p r o d u c t s showed d i f f e r ent d i s s o l u t i o n p r o f i l e s due t o the l a c k o f d i s i n t e g r a t i o n . P r o d u c t W d i d not d i s i n t e g r a t e a t a l l even a t t h e end o f s i x h o u r s . D i s s o l u t i o n by t h i s p r o d u c t was v e r y low and s t a y e d a t t h e same l e v e l throughout t h e e n t i r e d i s s o l u t i o n r u n . The a c t i v e i n g r e d i e n t surface  seemed t o d i s s o l v e out from the  of t h e t a b l e t , which was  s m a l l e r but s t i l l  intact  5k a t t h e end o f t h e d i s s o l u t i o n r u n . P r o d u c t W showed v e r y l i t t l e • t a b l e t v a r i a t i o n . P r o d u c t X was found t o v a r y from one t a b l e t t o a n o t h e r i n t h e same l o t . A f t e r t h e . t a b l e t c o a t i n g came o f f a f t e r t h r e e h o u r s , l a r g e p a r t i c l e s c o u l d be'seen coming o f f and,,at t h i s p o i n t , t h e c o n c e n t r a t i o n o f t h e a c t i v e i n g r e d i e n t r e g i s t e r e d on t h e r e c o r d e r was seen t o i n c r e a s e s u d d e n l y b u t not g r e a t l y . The c o n c e n t r a t i o n l e v e l remained a p p r o x i m a t e l y t h e same f o r about an hour, then decreased v e r y s l i g h t l y f o r the r e s t of the time. The d i s s o l u t i o n r a t e o f P r o d u c t s ¥ and X was so low t h a t t h e d i s s o l u t i o n - r u n had t o be c a r r i e d on f o r s i x hours i n s t e a d o f t h r e e h o u r s . P r o d u c t s A and E r e l e a s e d about 90% o f t h e a c t i v e i n g r e d i e n t i n t h r e e hours w h i l e i t t o o k P r o d u c t s W and X s i x hours t o r e l e a s e t h e same amount of a c t i v e i n g r e d i e n t . The t h r e e e n t e r i c c o a t e d P r o d u c t s AA, CC and DD-^ remained i n t a c t t i l l t h e d i s s o l u t i o n medium reached a pH of 7. P r o d u c t s AA and CC broke up v e r y q u i c k l y i n t o s m a l l p a r t i c l e s . P r o d u c t DD^ d i d not s t a r t t o d i s i n t e g r a t e  until  about t h r e e and a h a l f hours a f t e r t h e s t a r t o f t h e d i s s o l u tion run. P r o d u c t CC gave a much f a s t e r d i s s o l u t i o n r a t e t h a n P r o d u c t AA, w i t h a' c o n c e n t r a t i o n peak much h i g h e r t h a n t h o s e o f t h e o t h e r t e s t p r o d u c t s and, even e a r l i e r t h a n t h e s u g a r - c o a t e d p r o d u c t s . T h i s was p r o b a b l y due t o i t s  55 a l m o s t immediate d i s i n t e g r a t i o n i n the a l k a l i n e medium i n t o v e r y f i n e p a r t i c l e s . The was  d i s s o l u t i o n p r o f i l e f o r P r o d u c t AA  s i m i l a r t o those f o r the  s u g a r - c o a t e d P r o d u c t s A and  E,  except f o r a d e l a y of about t w e n t y - f i v e minutes i n i t s peak due  t o the  enteric coating.  o f P r o d u c t CC was  The  f a l l i n the d i s s o l u t i o n curve  v e r y sharp w h i l e t h a t of P r o d u c t AA  much more g r a d u a l . P r o d u c t DD]_  released i t s active  was  ingred-  i e n t r a p i d l y a f t e r d i s i n t e g r a t i o n o c c u r r e d , g i v i n g a peak second o n l y t o P r o d u c t C C . Henee, i t would appear t h a t d i s i n t e g r a t i o n time of the t a b l e t had d i s s o l u t i o n of the t a b l e t when the excessively  an e f f e c t on  the  d i s i n t e g r a t i o n time  was  long.  A T^Q^  v a l u e of 120  minutes would seem t o be  r e a s o n a b l e l i m i t of acceptance of the p r o d u c t s t h a t be  the  s a i d t o be  f o u r of the  e f f e c t i v e " i n vivo". This implies  p r o d u c t s t e s t e d , A, E , AA and  T h i s " i n v i t r o " e s t i m a t i o n can be  CC are  a  could  that  only  acceptable.  s u p p o r t e d by the " i n v i v o "  data that  showed the t h r e e P r d d u c t s E , AA and  CC were a t  l e a s t 75$  as e f f e c t i v e as P r o d u c t A (a p r o d u c t t e s t e d  and  found t o g i v e good c l i n i c a l r e s p o n s e ) . Product. AA would be a border-line results.  case by b o t h the " i n v i v o " and  the " i n v i t r o "  56 V. THE " I N VIVO" CHARACTERISTICS OF PHENYLBUTAZONE TABLETS Burns and h i s co-workers (2) c l a i m e d t h a t due t o the a f f i n i t y o f phenylbutazone f o r plasma p r o t e i n s as compared t o t i s s u e p r o t e i n s , a g r e a t p o r t i o n o f a d m i n i s t e r e d phenylbutazone i s found i n t h e plasma. They r e p o r t e d t h a t peak plasma l e v e l s were r e a c h e d i n about two hours a f t e r o r a l a d m i n i s t r a t i o n , i n d i c a t i n g t h a t t h e drug was r a p i d l y absorbed from t h e g a s t r o i n t e s t i n a l t r a c t . Plasma l e v e l s d i d n o t i n c r e a s e p r o p o r t i o n a t e l y w i t h i n c r e a s i n g doses o f the drug but t e n d to. r e a c h a l i m i t i n g c o n c e n t r a t i o n , which v a r i e d c o n s i d e r a b l y among s u b j e c t s . On r e p e a t e d  daily  dosage, t h e drug.accumulated i n t h e body w i t h a p r o g r e s s i v e i n c r e a s e i n t h e plasma c o n c e n t r a t i o n u n t i l a p l a t e a u was reached on t h e t h i r d o r f o u r t h day. I n a c o m p a r a t i v e study o f c o m m e r i c i a l l y a v a i l a b l e brands o f phenylbutazone t a b l e t s , S e a r l and P e r n a r o w s k i  (26)  d e t e r m i n e d serum l e v e l s a f t e r a d m i n i s t r a t i o n o f t h e products; t o human s u b j e c t s . The  seven p r o d u c t s were a d m i n i s t e r e d t o n i n e  s u b j e c t s as shown i n T a b l e V. Each s u b j e c t was g i v e n two t a b l e t s , that i s approximately  200 mg. o f p h e n y l b u t a z o n e .  I n g e n e r a l , t h e product was g i v e n t o t h e s u b j e c t s h o r t l y a f t e r b r e a k f a s t . Three t o f i v e samples o f b l o o d were t a k e n over a 4 3 - h o u r are shown.  p e r i o d b u t o n l y t h e r e s u l t s t o 30 hours  57  D e t e r m i n a t i o n o f Phenylbutazone i n Serum F i f t e e n m l . o f b l o o d a r e withdrawn by means o f a d r y s t e r i l e s y r i n g e and needle from a l a r g e v e i n i n t h e bend o f t h e elbow. The b l o o d i s a l l o w e d t o c l o t , t h e n c e n t r i f u g e d and t h e serum i s removed. Two m l . o f serum a r e t r a n s f e r r e d t o a 50-ml. glass-stoppered c e n t r i f u g e tube. F i v e m l . o f 3 N.HC1- s o l u t i o n and 2 0 . 0 m l . o f heptane a r e added and t h e tube i s shaken f o r t h i r t y minutes i n an a u t o m a t i c shaker and c e n t r i f u g e d a t 1 2 0 0 r.p.m. f o r f i v e m i n u t e s . F i f t e e n , m l . o f heptane a r e withdrawn and t r a n s f e r r e d t o a 2.00-ml. b o t t l e . F i v e m l . o f 2 . 5 N.NaOH s o l u t i o n a r e added and s w i r l e d g e n t l y . The s o l u t i o n i s t h e n shaken f o r f i v e minutes and poured i n t o a 5 0 - m l . c e n t r i f u g e tube and c e n t r i f u g e d a t 1 2 0 0 r.p.m. f o r t h r e e m i n u t e s . The absorbancy o f t h e sodium h y d r o x i d e s o l u t i o n i s r e a d a t 2 6 5 mu. The a b s o r p t i v i t y o f phenylbutazone a t 2 6 5 mu i n 2 . 5 N.NaOH is 65.2. I t may be n e c e s s a r y t o d i l u t e t h e sodium h y d r o x i d e s o l u t i o n o r t o d e c r e a s e t h e amount o f serum t a k e n f o r a n a l y s i s i f t h e c o n c e n t r a t i o n o f p h e n y l b u t a z o n e i n t h e serum exceeds 3 0 mg. p e r l i t r e . A b l o o d sample t a k e n b e f o r e t h e a d m i n i s t r a t i o n o f t h e drug s e r v e s as a c o n t r o l o r " b l o o d - b l a n k " . T h i s sample when t r e a t e d as d e s c r i b e d above, a b s o r b s some u l t r a v i o l e t r a d i a n t energy a t 2 6 5 mu. C o n s e q u e n t l y , a l l subsequent a s s a y v a l u e s must be a d j u s t e d t o compensate f o r t h i s " b l o o d - b l a n k " .  58 Results Peak plasma l e v e l s were o b t a i n e d i n f i v e r a t h e r t h a n i n two hours as had been r e p o r t e d by Burns and h i s co-workers ( 2 ) . A t y p i c a l b l o o d curve i s shown i n F i g u r e A f t e r the peak r e g i o n , the serum drug l e v e l  8.  decreased  q u i t e g r a d u a l l y . The a r e a s under the b l o o d c u r v e s were determined  by a p l a n i m e t e r and are t a b u l a t e d i n T a b l e  V.  U s i n g P r o d u c t A as a chosen s t a n d a r d , o n l y t h r e e o t h e r p r o d u c t s , E, AA and CC appeared t o be a t l e a s t  75%  as e f f e c t i v e as P r o d u c t A, and t h u s c o n s i d e r e d a c c e p t a b l e . Since data f o r subjects 3 - 9  was  i n c o m p l e t e , i t was  p o s s i b l e t o use i t f o r a comparison.  not  However, a v a i l a b l e  d a t a from t h e s e s u b j e c t s t e n d t o i n d i c a t e t h a t response  to  the p r o d u c t s f o l l o w the same t r e n d as i n s u b j e c t s 1 and  2.  10  20 Time (hours)  F i g u r e 8. C o n c e n t r a t i o n o f Phenylbutazone of Product A t o Subject 1  i n Serum a f t e r A d m i n i s t r a t i o n  u!  60 T a b l e V. A r e a s under B l o o d Curves f o r Seven Brands o f Phenylbutazone T a b l e t s  ^sProduct  A  Sub j e c t N v  E  W  X  CC  AA  DD]_  1  18.57  14.8  1.82  13.3  12.42  15.33  6.55  2  20.55  15.2  4.61  7.0  15.51  22.84  11.21  3  24.1  26.4  8.9  17.0  4  —  —  —  —  5  —  —  —  —  —  —  —  7  —  —  —  —  8  —  —  —  —  9  —  —  —  —  6  .  —  8.62  10.48  —  —  •  —  —  —  —  —  23.34  —  •  —  —  11.48  —  —  —  3.79  —  4.65  61 V I  «  "IN VIVO" - "IN VITRO" CORRELATION  " I n v i t r o " r e s u l t s o n l y serve t o reduce t h e number o f samples c o n s i d e r e d  suitable f o r " i n vivo" testing.  However, t h e y a r e s i g n i f i c a n t when t h e y can be q u a n t i t a t i v e l y c o r r e l a t e d w i t h " i n v i v o " d a t a . Even though t h e " i n v i v o " d a t a a v a i l a b l e i s not complete f o r a l l t e s t p r o d u c t s ,  an  attempt was made t o c o r r e l a t e t h i s d a t a w i t h t h e T^Q^ and the T^Q^ v a l u e s  obtained  by t h e " i n v i t r o " t e s t p r o c e d u r e .  C o r r e l a t i o n was attempted o n l y f o r t h e two s u b j e c t s w i t h complete " i n v i v o " d a t a , s i n c e d a t a f o r P r o d u c t A was not a v a i l a b l e f o r t h e o t h e r s u b j e c t s . However, t h e response shown by t h e s e s u b j e c t s seem t o f o l l o w t h e same t r e n d as t h a t o f s u b j e c t s 1 and 2. I t can be assumed, t h e r e f o r e , the same type o f c o r r e l a t i o n c o u l d be o b t a i n e d  that  f o r these  s u b j e c t s , t a k i n g i n t o account t h e p o s s i b l e d i f f e r e n c e s i n the m e t a b o l i s m o f t h e drug i n t h e s e  subjects.  By t h e use o f l i n e a r r e g r e s s i o n , t h e l i n e o f " l e a s t s q u a r e s " drawn f o r each s e t o f d a t a f o r s u b j e c t s 1 and 2 ( F i g u r e s 9, 10, 11, 12). The p o i n t s f o r s u b j e c t 2 seem t o f i t b e t t e r on t h e l i n e o f " l e a s t s q u a r e s " drawn t h a n those f o r s u b j e c t 1. One o f t h e r e a s o n s f o r t h e d e v i a t i o n s from t h e " l e a s t squares" l i n e c o u l d be t h a t some o f t h e " i n v i v o " b l o o d c u r v e s were drawn from t h e inadequate d a t a . T a b l e t v a r i a b i l i t y  ( e s p e c i a l l y f o r P r o d u c t X)  c o u l d a l s o have c o n t r i b u t e d t o t h e d e v i a t i o n s .  62 The l i n e s o f " l e a s t squares"  had n e g a t i v e  slopes  i n d i c a t i n g an i n v e r s e r e l a t i o n s h i p between t h e " i n v i v o " and the " i n v i t r o " d a t a . The s l o p e s o f t h e s e l i n e s ranged from -0.042, t o -0.075  5  w i t h the s l o p e s o f the T^Q^ l i n e s  greater  t h a n t h e T^Q^ l i n e s o f b o t h s u b j e c t s . The s l o p e s o f the l i n e s f o r s u b j e c t 2 were g r e a t e r t h a n those o f s u b j e c t 1. T h i s was e x p e c t e d s i n c e s u b j e c t 2 showed g r e a t e r response t o t h e drug t h a n s u b j e c t 1. The d i f f e r e n c e between the s l o p e s o f the' T^Q$ l i n e and the T^Q$ l i n e o f s u b j e c t 1 was t w i c e t h a t o f s u b j e c t 2.  64  66  67 VII. The completely  DISCUSSION  d i s s o l u t i o n procedure d e s c r i b e d h e r e i n i s  automatic.  No r o u t i n e a n a l y s i s o f t h e medium i s  r e q u i r e d , because a complete r e c o r d i n g o f t h e amount o f t h e a c t i v e i n g r e d i e n t r e l e a s e d from t h e t a b l e t t h r o u g h o u t t h e d i s s o l u t i o n process  i s o b t a i n e d on t h e r e c o r d e r .  of t h e t o t a l a r e a under t h e r e c o r d e d  Determination  curve w i l l g i v e t h e  t o t a l amount o f drug r e l e a s e d . At t h e same t i m e , a complete r e c o r d i n g o f t h e pH changes i n t h e d i s s o l u t i o n medium can be o b t a i n e d on a r e c o r d i n g p o t e n t i o m e t e r .  This recording  e n a b l e s one t o see how t h e d i s s o l u t i o n p r o c e s s  i s affected  by t h e c h a n g i n g pH o f t h e d i s s o l u t i o n medium. A s i n g l e a n a l y s i s o f t h e c o l l e c t e d medium w i l l a l s o g i v e t h e t o t a l amount o f drug r e l e a s e d i n a p e r i o d o f time but i t w i l l n o t g i v e the d i s s o l u t i o n time f o r a speci f i e d amount o f drug t o go i n t o s o l u t i o n . F u r t h e r ,  this  f i n a l a n a l y s i s does n o t g i v e t h e d i s s o l u t i o n p r o f i l e w h i c h can be seen t o v a r y from product  t o product.  Even though the a p p a r a t u s set-up  seems t o i n v o l v e  many components, t h e b a s i c p a r t s r e q u i r e d f o r t h e c o n t i n u o u s f l o w system a r e t h e r e s e r v o i r s o f d i s s o l u t i o n medium, t h e d i s s o l u t i o n v e s s e l , t h e pump and t h e c o l l e c t i n g v e s s e l . The recording potentiometer  and the s p e c t r o p h o t o m e t e r w i t h i t s  a t t a c h e d r e c o r d e r a r e a c c e s s o r i e s t h a t f u r n i s h more i n f o r m a t i o n and a v o i d manual a n a l y s i s o f t h e medium. These  68 a c c e s s o r i e s are not n e c e s s a r y i f one i s i n t e r e s t e d i n the t o t a l amount o f drug r e l e a s e d i n a c e r t a i n p e r i o d o f t i m e . The b a s i c p a r t s of t h i s d i s s o l u t i o n a p p a r a t u s are r e l a t i v e l y easy t o o b t a i n and assemble and p r o v i d e a good r e p r o d u c i b l e method o f c h e c k i n g on p r o d u c t The  quality.  i n v e r s e r e l a t i o n s h i p e s t a b l i s h e d between the  " i n v i v o " and t h e " i n v i t r o " d a t a o b t a i n e d by t h i s  test  procedure tends t o i n d i c a t e t h a t t h i s procedure may  possibly  be used i n the p r e d i c t i o n o f the " i n v i v o " a v a i l a b i l i t y o f the a c t i v e i n g r e d i e n t from the s o l i d dosage form. A  T^Q%  v a l u e o f 120 minutes as t h e l i m i t o f acceptance f o r the p r o d u c t s seems r e a s o n a b l e on the b a s i s o f b o t h the " i n v i v o " and t h e " i n v i t r o " d a t a . From the " l e a s t s q u a r e s " l i n e s , i t would seem t h a t p r o d u c t s w i t h a T^ % 0  v a l u e o f more than f i v e  hours would not be absorbed i n t o the b l o o d stream a t a l l . From b o t h the " i n v i v o " and the " i n v i t r o " d a t a , o n l y f o u r of the seven p r o d u c t s t e s t e d , namely A, E, and CC, can be a c c e p t e d as p r o d u c t s t h a t w i l l be  AA  effective  when a d m i n i s t e r e d t o p a t i e n t s . P r o d u c t s W and X g i v e such low serum l e v e l s and l o n g T^Q^ v a l u e s t h a t one can  conclude  t h a t these p r o d u c t s a r e u n s a t i s f a c t o r y and s h o u l d not be a d m i n i s t e r e d t o p a t i e n t s . P r o d u c t DD^  with s l i g h t l y higher  serum l e v e l s i s s t i l l u n s a t i s f a c t o r y . The poor " i n v i v o " r e l e a s e from t h e s e p r o d u c t s i s most p r o b a b l y due t o poor f o r m u l a t i o n , w h i c h . i s r e v e a l e d by t h e i r poor  disintegration.  c h a r a c t e r i s t i c s . P r o d u c t W and X do not d i s i n t e g r a t e w h i l t h e d i s i n t e g r a t i o n time of P r o d u c t DD-j_ i s a b n o r m a l l y l o n g  70  V I I I . SUMMARY In t h i s i n v e s t i g a t i o n , a completely automatic c o n t i n u o u s f l o w d i s s o l u t i o n procedure was developed and tested. Pertinent and  conditions  o f d i s s o l u t i o n were  chosen t o t e s t seven brands o f c o m m e r i c i a l l y  phenylbutazone t a b l e t s . " I n v i v o " out  studies  studied available  were c a r r i e d  on t h e s e p r o d u c t s by d e t e r m i n i n g serum l e v e l s a f t e r  the a d m i n i s t r a t i o n  of the products t o nine  subjects.  From t h e " i n v i t r o " d a t a o b t a i n e d by t h e t e s t d i s s o l u t i o n p r o c e d u r e , a T^Q$  v a  l  u e  °f 120 minutes was  chosen as t h e l i m i t o f acceptance f o r t h e t e s t p r o d u c t s . Of t h e seven t e s t p r o d u c t s , o n l y f o u r were a c c e p t a b l e on the b a s i s  o f b o t h t h e " i n v i v o " and t h e " i n v i t r o " Correlation  data r e s u l t e d  data.  o f t h e " i n v i v o " and t h e " i n v i t r o "  i n " l e a s t squares" l i n e s w i t h n e g a t i v e  slopes. This c o r r e l a t i o n indicated the p o s s i b i l i t y of u s i n g t h i s " i n v i t r o " d i s s o l u t i o n procedure i n the p r e d i c t i o n of t h e " i n v i v o " a v a i l a b i l i t y o f phenylbutazone from t h e s o l i d dosage form.  71 IX.  BIBLIOGRAPHY  1. Brudney, N., S t e w a r t , D.J. and E u s t a c e , B.T. : Canad. Med. A s s . J . , 90 : 980 (1964). 2. B u r n s , J . J . , Rose, R.K., Chenkin, T., Goldman', A., S c h u l e r t , A., and B r o d i e , B.B. : J . Pharmacol. Exp. Ther., 109 : 346 (1953). 3 . Canada, Dept. o f N a t i o n a l H e a l t h and W e l f a r e , Food and Drug D i r e c t o r a t e : The d e t e r m i n a t i o n o f t h e d i s i n t e g r a t i o n time o f t a b l e t s , Ottawa, 1965. 4.  Canada Food and Drugs Act, and R e g u l a t i o n s : Food and Drugs a c t and r e g u l a t i o n s , l o o s e - l e a f o f f i c e c o n s o l i d a t i o n , Sec.0.015, The Queen's P r i n t e r , Ottawa, 1954.  5 . Chapman, D.G., C r i s a f i o , R. and Campbell, J.A. : J . Pharm. S c i . , 43 : 297 (1954). 6 . Idem : J . Pharm. S c i . , 45 : 374 (1956). 7 . Ganderton, D., H a d g r a f t , J.W., R i s p i n , W.T. A.G. : Pharm. A c t a H e l v . , 42 : 152 (1967).  and Thompson,  8. Hamlin, W.E., N e l s o n , E., B a l l a r d , B.E. and Wagner, J.G. : J . Pharm. S c i . , 51 : 432 (1962). 9 . Levy, G. : J . Pharm. 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