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The adsorption of atropine sulfate and selected opium alkaloids and sulfonamides by kaolin Choi, Ho Pang 1975

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THE  ADSORPTION  OF  SELECTED AND  ATROPINE  OPIUM  SULFATE  AND  ALKALOIDS  SULFONAMIDES BY  KAOLIN  by  HO P A N G B . S c ,  UNIVERSITY HONG  A  THESIS THE  of  the  SUBMITTED  IN  REQUIREMENTS  HONG  KONG  PARTIAL FOR  THE  FULFILMENT DEGREE  OF  OF  SCIENCE  Division  of  Pharmaceutical Chemistry  Faculty  of  Pharmaceutical Sciences  the  We a c c e p t required  THE  OF  KONG, 1 9 7 1  M A S T E R OF in  CHOI  this  thesis  as  conforming to  standard  UNIVERSITY  OF  BRITISH  f. O C T O B E R ,  19 7 5  COLUMBIA  the  In p r e s e n t i n g t h i s t h e s i s  in p a r t i a l  an advanced degree at the U n i v e r s i t y the L i b r a r y  s h a l l make i t  freely  f u l f i l m e n t of  the requirements  of B r i t i s h C o l u m b i a , I agree  available for  I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e  of  representatives.  this thesis for  It  copying of t h i s  i s u n d e r s t o o d that c o p y i n g o r  thesis  written permission.  kA&AJ^^l  The U n i v e r s i t y  o f B r i t i s h Columbia  2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5  Date  II  OCA..  /^tSu2^£jL^  or  publication  f i n a n c i a l cgain s h a l l not be a l l o w e d w i t h o u t my  Department of  that  r e f e r e n c e and s t u d y .  f o r s c h o l a r l y purposes may be g r a n t e d by the Head o f my Department by h i s  for  1 ABSTRACT  The  adsorption  promazine  hydrochloride,  atropine  sulfate,  With  exception  of  the  the  interactions  and  sulfonamides,  kaolin  into  Due  codeine  four  of  chlorpromazine these  solubility  test  chloric  solution.  A l l  in  3.0,  water  and  solutions adsorbed  and  adsorption therms Giles  and  not  adsorbed pH  of  the  sulfate,  1.2,  a  could, the  basis  his  the  were  by  this  by  alkaloids  the  basis  of  normal  data dose  5.0  of  been  sulfate, in  and  vitro. three  combined  out  several the  with  were  The be  in  A l l  other  With  the  be  obtained,  i t  was  chlorpromazine  a  data  for  or  Langmuir  adsorption outlined  studies  i s o -  by  for  solution. the  test  drugs  adsorption the  out  acid  cited,  sulfonamides were  varied  exception  chlorpromazine to  carried  represented  system  aqueous  general,  hydro-  Freundlich of  the  1:12.5  Desorption  conditions  medium. of  the  to  of  hydrochloric  instances,  (1960).  In  in  37.0°C.  appears  of  studied  adsorption  studies  either  kaolin.  adsorption  opium  a  of  carried  clay.  adsorption the  most  experimental  adsorbed  and  according  co-workers  drugs  other  However,  c l a s s i f i e d  the  of  in  the  investigated  temperature  equations.  Under were  on  were  adsorbed  at  drugs  graphically  k a o l i n was  pH  were  have  chlor-  morphine  hydrochloride  drugs  problems,  by  in  and  preparations.  sulfonamides acid  kaolin  phosphate,  sulfonamides  antidiarrheal  to  between  of  with  atropine  hydrochloride  reversible estimated  process.  that  hydrochloride,  the  over  and On 90%  atropine  sulfate,  morphine  adsorbed  by  and of  the  a  sulfate,  normal  adsorbent  dose  were  or  codeine  (six  gm.)  allowed  to  phosphate  of  would  be drug  kaolin  i f  the  equilibrate  in  40  ml.  water. The  in  vivo  significance  However,  on  the  chloride  (Wagner,  basis  1966)  decreases  in  of  containing  kaolin  might  be  imply  that  sulfate  plasma  predicted the  into  by  and  in  a  carefully  abstract  data  following  f i n a l  are  opium  of  controlled  represents  the  of  concurrent greater This  may,  an  studies  in  Supervisor  drugs,  administration those  that  therefore, or  atropine kaolin  assumption  is  must  man.  contents  submitted.  known. hydro-  other  containing  such  true  not  than  alkaloids  preparations proof  is  lincomycin  number  data.  of  results for  limited  vitro  antidiarrheal  be  This  vivo  incorporation  the  these  preparations  but  on  in  levels  undesirable based  of  of  of  the  thesis  1  i i i TABLE  OF  CONTENTS  Page  I. II.  III.  INTRODUCTION  1  LITERATURE  4  1.  Kaolin  2.  Theory  3.  Adsorption  4.  In  THE  TEST  1.  Chlorpromazine  2.  Codeine  3. 4. 5. IV.  SURVEY  4 of  Vivo  Adsorption of  Drugs  9 by  Kaolin  15  Studies  22  DRUGS  27 Hydrochloride  27  Phosphate  29  Morphine  Sulfate  31  Atropine  Sulfate  34  Sulfonamides  36  TThe  EXPERIMENTAL  42  1.  Apparatus  42  2.  Chemicals  3.  A n a l y t i c a l Procedures f o r and S t a b i l i t y C h a r a c t e r i s t i c s of the Test Drugs  4.  5.  and  Reagents  44  47  AAdsorpti>onCGhar.ac^eristi'Gsoc5f t M i e T T e s t Drugs Desorption  Characteristics  of  the  65  Test  Drugs V.  RESULTS 1. 2.  AND  67 DISCUSSION  E q u i l i b r i u m Time f o r the Adsorption Process Chlorpromazine Hydrochloride  70  .  70 74  iv P a  3.  5.  e  (a) A d s o r p t i o n C h a r a c t e r i s t i c s i n Aqueous Solution  74  (b) A d s o r p t i o n C h a r a c t e r i s t i c s i n pH 1.2, 3.0, and 5.0 S o l u t i o n s .  80  (c) D e s o r p t i o n C h a r a c t e r i s t i c s o f CPZSHCl  86  (d) A d s o r p t i o n I n t e r a c t i o n between Therapeutical: Doses o f CPZ-HC1 and Kaolin  89  Codeine Phosphate  90  (a) A d s o r p t i o n C h a r a c t e r i s t i c s i n Aqueous Solution  90  (b) A d s o r p t i o n C h a r a c t e r i s t i c s i n pH 1.2, 3.0, and 5.0 S o l u t i o n s  94  (c) D e s o r p t i o n C h a r a c t e r i s t i c s o f CDN-P0  98  4  (d) A d s o r p t i o n I n t e r a c t i o n between TherapeuticaDoses o f CDN-PO. and Kaolin 7 4.  ?  99  Morphine S u l f a t e  100  (a) A d s o r p t i o n C h a r a c t e r i s t i c s i n Aqueous Solution  100  (b) A d s o r p t i o n C h a r a c t e r i s t i c s i n pH 1.2, 3.0, and 5.0 S o l u t i o n s  100  (c) Desorption C h a r a c t e r i s t i c s o f MOP-SO^  106  (d) A d s o r p t i o n I n t e r a c t i o n between TherapeuticaDoses o f M©£-SO. and Kaolin ' 7  106  Atropine Sulfate  110  (a) A d s o r p t i o n C h a r a c t e r i s t i c s i n Aqueous Solution  110  (b) A d s o r p t i o n C h a r a c t e r i s t i c s i n pH 1.2, 3.0, and 5.0 S o l u t i o n s  114  (c) D e s o r p t i o n C h a r a c t e r i s t i c s o f ATP-SC>  118  4  o  V  Page  (d)  6. VI;  The  Adsorption Interaction between Therapeutic Doses of ATP-SO. and Kaolin : . . .  118  Sulfonamides  120  SUMMARY AND  CONCLUSIONS  REFERENCES BIOGRAPHICAL APPENDIXES  122 128  INFORMATION  132 133  vi LIST OF TABLES Table 1  Page The e f f e c t o f time on the amount o f chlorpromazine h y d r o c h l o r i d e adsorbed per gm. o f k a o l i n  71  2  The e f f e c t o f time on the amount o f codeine phosphate adsorbed per gm. o f k a o l i n  72  3  The e f f e c t o f time on the amount o f morphine s u l f a t e adsorbed per gm. o f k a o l i n  72  4  The e f f e c t o f time on the amount o f a t r o p i n e s u l f a t e adsorbed per gm. k a o l i n  73  5  The e f f e c t o f time on the amount o f chlorpromazine h y d r o c h l o r i d e adsorbed per gm. o f k a o l i n  73  6  A d s o r p t i o n data f o r chlorpromazine hydrochlor-df-.; ide by k a o l i n  75  7  A d s o r p t i o n o f chlorpromazine h y d r o c h l o r i d e by k a o l i n a t 37 C  85  E f f e c t o f f i v e - f o l d d i l u t i o n o f chlorpromazine h y d r o c h l o r i d e - k a o l i n suspension w i t h water on chlorpromazine h y d r o c h l o r i d e a d s o r p t i o n ....  88  A d s o r p t i o n data f o r codeine phosphate by k a o l i n  91  A d s o r p t i o n o f codeine phosphate by k a o l i n at 37°C  97  E f f e c t o f f i v e - f o l d d i l u t i o n o f codeine phosphate-kaolin suspension w i t h water on codeine phosphate a d s o r p t i o n  99  8  9 10 •11  12  A d s o r p t i o n data f o r morphine s u l f a t e by k a o l i n  102  13  A d s o r p t i o n o f morphine s u l f a t e by k a o l i n at 37 C  107  E f f e c t o f f i v e - f o l d d i l u t i o n o f morphine s u l f a t e - k a o l i n suspension w i t h water on morphine s u l f a t e a d s o r p t i o n  108  A d s o r p t i o n data f o r a t r o p i n e s u l f a t e by k a o l i n  112  14  15  vii Table  Page  16  Adsorption  o f a t r o p i n e s u l f a t e by k a o l i n a t 37°C  117  17  E f f e c t of f i v e - f o l d d i l u t i o n o f a t r o p i n e s u l f a t e - k a o l i n suspension with water on a t r o p i n e sulfate adsorption  119  viii L I S T OF FIGURES  1  Diagrammatic sketch o f the s t r u c t u r e kaolin  of the  layer  5  2  System o f i s o t h e r m c l a s s i f i c a t i o n  12  3  Chemical structure  of chlorpromazine hydrochloride  27  4  Chemical structure  o f codeine phosphate  30  5  Chemical structure  o f morphine s u l f a t e  32  6  Chemical structure  of atropine sulfate  35  7  Chemical structure  of sulfadiazine  38  8  Chemical structure  of sulfamerazine  39  9  Chemical structure  of sulfamethazine  40  10  Chemical structure  of sulfisoxazole  41  11 12  Constant temperature r e a c t i o n tank Spectral c h a r a c t e r i s t i c s of chlorpromazine hydrochloride  13  Spectral  c h a r a c t e r i s t i c s o f codeine phosphate  14  Spectral  c h a r a c t e r i s t i c s o f morphine s u l f a t e  15  Spectral  c h a r a c t e r i s t i c s o f r.eineekate  of  43 48 ....  52  .....  55  derivative  atropine sulfate  58  16  Spectral  characteristics of sulfadiazine  61  17  Spectral  characteristics of sulfamerazine  62  18  Spectral  characteristics of sulfamethazine  63  19 20  Spectral characteristics of sulfisoxazole A d s o r p t i o n i s o t h e r m a t 37°C f o r c h l o r p r o m a z i n e h y d r o c h l o r i d e by k a o l i n susperidediinwwater  21  L a n g m u i r i s o t h e r m a t 37°C f o r c h l o r p r o m a z i n e h. h y d r o c h l o r i d e by k a o l i n suspended i n w a t e r  64 77 78  ix  22  23  24  A d s o r p t i o n isotherm a t 37 C f o r chlorpromazine h y d r o c h l o r i d e by k a o l i n , suspended i n pH 1.2, pH 3.0, and pH 5.0 s o l u t i o n s  82  Langmuir isotherm at 37°C f o r chlorpromazine h y d r o c h l o r i d e by k a o l i n suspended in.pH 3.0 andapHcS. 0 s o l u t i o n s  83  F r e u n d l i c h isotherm a t 37°C f o r chlorpromazine h y d r o c h l o r i d e by k a o l i n suspended i n pH 1.2 solution  84  <J  25 AdAdsorption isotherm a t 37°C f o r codeine phosphate by k a o l i n suspended i n water 26 27  28  29 30 31  92  Langmuir isotherm at 37°C f o r codeine phosphate by k a o l i n suspended i n water  93  A d s o r p t i o n isotherm a t 37°C f o r codeine phosphate by k a o l i n suspended i n pH 1.2, pH and pH 5.0 s o l u t i o n s  95  3.0,  Langmuir i s o t h e r m a t 37°C f o r codeine phosphate by k a o l i n suspended i n pH 3.0 and pH 5.0 solutions  96  A d s o r p t i o n i s o t h e r m a t 37°C f o r morphine s u l f a t e by k a o l i n suspended i n water . . . ^  101  Langmuir isotherm a t 37°C f o r morphine s u l f a t e by k a o l i n suspended i n water  10 3  A d s o r p t i o n isotherm a t 37°C f o r morphine s u l f a t e by k a o l i n suspended i n pH 1.2, pH 3.0, and pH 5.0 s o l u t i o n s  104  32  Langmuir i s o t h e r m a t 37°C f o r morphine s u l f a t e by k a o l i n suspended i n pH 3.0 and pH 5.0 s o l u t e ^ '~ tions 105  33  A d s o r p t i o n isotherm at 37°C f o r a t r o p i n e s u l f a t e by k a o l i n suspended i n water I l l  34  Langmuir isotherm at 37°C f o r a t r o p i n e s u l f a t e by k a o l i n suspended i n water  113  A d s o r p t i o n isotherm a t 37°C f o r a t r o p i n e s u l f a t e by k a o l i n suspended i n pH 1.2, pH 3.0, and pH 5.0 s o l u t i o n s  115  Langmuir isotherm at 37°C f o r a t r o p i n e s u l f a t e by k a o l i n suspended i n pH 1.2 and pH 5,0 -~ - ; •. solutions  116  35k  36  X ACKNOWLEDGEMENTS  I  wish  to  express  Dr.  M.  my  Dr.  T.  Brown  the  original  Dr.  F.  Financial Canadian  M.  for  his  his  and  appreciation  encouragement  and  t o : -  guidence  suggestions  and  criticisms  of  in  chemistry.  manuscript.  Sfo A b b o t t  Lai  for  gratitude  studies.  for  assistance Commonwealth  gratefully  sincere  Pernarowski  during  Miss  is  my  for.his  her  in  counselling  able- typing  the  form  Scholarship  acknowledged.  of  a  and  of  this  organic  manuscript.  scholarship Fellowship  from  the  Administration  1  I.  Kaolin, approximate used  to  value  cause  a to  The and  is  opiate  the  Compendium  gics  gut  thought  provide  a  0  o  with  . 2SiC»  J  to  2  an  ,  has  years.  and  been  Its  depend  protective  used  mixture, in  alkaloid  on  viruses coating  combination  the  i t s which  for  the  acts  It  reduce  tract  antibiotics  cause  the  i l l n e s s .  by  the  is  and  effect  on  the  producing  In  the  principle, in  the  and  p e r i s t a l s i s . '75  the  l i s t s  kaolin-  anticholinerof  the  parasympathetic  blockade,  micro-organisms  that  if  the  effects  combinations  preparations  smooth  and  motility  a  of  decreased  that  a  such  Specialties  claimed  tone  eliminate  ingredients  multi-component  the  directly  spasm w i t h  other  behind  kaolin-anticholinergic,  combinations.  the  to  with  1968 d e s c r i b e s  rationale  Pharmaceuticals  while  Codex  addition  produce  kaolin-opiate,  active  in  Pharmaceutical  to  of  gastrointestinal  these  2  hundred  to  that,  significantly  vidual  two  clay  0. A l  2  bacteria,  morphine  the  antibiotic  is  2H  toxins,  B r i t i s h  kaolin,  several  over  agent  normally  being  The  of  the  and  combination  of  for  s i l i c a t e  mucosa.  Kaolin  muscle  formula  diarrhea  adsorb  intestinal  kaolin  aluminum  therapeutic  diarrhea  drugs.  hydrous  empirical  treat  as  a b i l i t y  a  INTRODUCTION  should  be  are more  of  the  i n d i -  additive, satisfactory  2  antidiarrheal between f a i l s  such  to  drugs  comply  Several adsorption Although  there  drug  as  charcoal  the  in  with vitro  are  and  the  few in  report  diarrheal, Drug  (1975),  cardiac  studies  on  the  and  drugs  tract.  and  and  in  vivo  which  appeared  "additional of  kaolin  antibiotics, attempts  with  respect  vitro  drugs; kaolin  to  morphine  codeine  phosphate,  both  between  kaolin  chlorpromazine  and  being  by  Federal  other  be  gua-  the  Food  Register, is  needed such  as  vitamins".  information  between  sulphate,  from  a n t i -  drugs  and  some  atropine  such  available.  laxative,  alkaloids,  opiate  can  are  products  with  provide  and  and  data  in  kaolin  kaolin-drug  information  interactions  kaolin and  drug  of  adsorbents  of  question  (OTC)  drugs.  absorption  to  antiemetic  that  their  usefulness  over-the-counter  that  interaction  open  vitro  investigation in  The  therefore,  on  alter  many  effect  an  in  which  indicate  and  that  glycosides,  cholinergic;  kaolin  suggest  both  interaction product  literature  attapulgite  interaction  sulfa  the  between  vivo  This  selected  in  other  recommended  to  a  with  emetic,  the  in  studies  Administration  regarding  result  vivo  i s , if  significant  claims.  occur in  any  could  studies  adsorbents  only  The  kaolin  label  absorption,  combinations,  and  and  gastrointestinal  ranteed  However,  interactions  on  between  agents.  kaolin  and  sulfate,  an  kaolin  and  alkaloids;  hydrochloride  as  well  The  anti-  as  latter  3 drug  is  a  t r i c y c l i c  hydroxide  has  been  depressant. shown  is  used  in  this  as  well  as  desorption  processes the  interaction  on  the  tract.  range  vitro  polated  in  studies  important  conducted  the  a model  be  wide  in  as  under  pH  directly  different  to  the  must  be  may an  pH  drug  of in  vivo  in  this  these some  from  study  the  cannot  combinations  f i n a l in  proof  man.  of  gastro-  tract  a  i t  both  effect  Although  study  and  since  the  instances,  The  aluminum  Adsorption  experiments  conditions.  occur. in  out  determining  adsorption  use  compound.  carried  of  by  absorption  gastrointestinal  obtained  indicatedthat,  interaction  interaction  the  values,  information  results vivo  of  were in  i t s  test  absorption  Since  adsorption  decrease  could  intestinal a  study  to  Its  covers  were the be in  extravivo,  potential of  such  an  4  II.  LITERATURE  1.  Kaolin meaning China,  used  r i d g e " , the  The  nomenclature of  i s based  of  kaolin a clay  on  t h a t of  as  "the  2  sent is N.F. and  i n colour.  3  and  2  represent  the m i n e r a l  of  kaolin,  s t r u c t u r e of  Si-0  He  forming Gruner  a  of  the  sheet  (1932),  approximately  adsorbed  the  of of  clay  m i n e r a l was t h a t the  usually  the  white are  composition bases  i f pre-  Kaolinite Kaolin  powdered  elutriation. on  the  kaolinite,  basis the  crystalline  first  category.  s t r u c t u r e c o n s i s t s of  octehedra,  of  major  d e s c r i b e d by  i n a hexagonal  composition  des-  essential-  materials.  minerals  two-layer  Al-(0,0H)  using  by  1953): p l a c e s  i n the  suggested  layer  and  being  They  i s composed  aluminum s i l i c a t e ,  tetrahedra arranged  superposed  now  (1931).  in iron  ob-  kaolin-forming clays  particles  t h e i r . s t r u c t u r e .(Grim,  (1930).  minerals  Kerr  Fu,  first  t h a t c h a r a c t e r i z e s most k a o l i n s . "  Classification  The  of  i m p u r i t i e s or  f r e e d from g r i t t y  of  kaolin  was  i t i s believed that other  i s a native hydrated  mineral  the  The  aluminum s i l i c a t e s  2H 0.Al 0 .2Si0 2  substance  mass w h i c h  word " k a u l i n g " ,  near Jauchau  the  Ross and  rock  Chinese a hill  m a t e r i a l t h a t i s low  or nearly white hydrous  the  name o f  where, c e n t u r i e s ago,  cribed ly  Kaolin  i s a c o r r u p t i o n of  "high  tained.  SURVEY  Pauling a  sheet  network w i t h  the  two  2H 0.Al^O^.2Si0 . 2  X-ray powder p h o t o g r a p h i c  2  a  together Later, techniques,  - 5  described the  unit  taining  £he c e l l  two  obtained  Brindley the  of  only  and  one  in  detail.  lattice  data  by  This  structure  Robinson  (1946)  lattice  2^0. A ^ O ^ . the  diagrammatic  2 S  is  arrays  arrays sketch  of of  using  who  is  layer.  proposed  both was  X-ray  and  and  the  1.  by  unit  i t  consists  According  to  these  blocks  of  kaolinite  silicon-oxygen-tetrahedra  kaolinite  Diagrammatic --structure of layer (Grim,  c e l l  that  structure  and  octahedra. is  1;  Figure  (1936)  electroio  re-defined that  con-  Hendricks  aluminum-oxygen-hydroxyl the  that  monoclinic,  c e l l .  claimed  building of  He  per  t r i c l i n i c  i°2  principal  two-dimensional  Figure  i  more  kaolinite  methods.  two-dimensional A  -  in  2H2O.AI2O2. 2SiC>2 l a y e r s  kaolinite  researchers, are  in.'the  confirmatory  diffraction  of  structure  sketch of the the k a o l i n 1953).  shown  6  In  the silicon-oxygen sheets,  coordinated  with  f o u r oxygen atoms  a regular tetrahedron In  this  sheet,  three  hedron a r e shared fourth lying  the silicon  with  located a t the corners of  the silicon  by three  neighbouring  i n a common p l a n e  with  sheet,  t h e aluminum atom w i t h  corners  planes.  and t e t r a h e d r a l groups,  are  by s i l i c o n  The  2  2-  0  4  Si  . 4+  +2(0H)  4A1  3+  6 (OH)  aluminum-  are located  on t h e s i x  The o x y g e n atoms a n d with  aluminum  two t h i r d s  o f t h e atoms  and aluminum.  charge d i s t r i b u t i o n  6  downward,  I n t h e l a y e r common t o t h e  octahedral shared  The  are coordinated  centres  groups l i e i n two p a r a l l e l planes  atoms between t h e s e  40  In this  groups which  their  o f a regular octahedron.  hydroxyl  i spointed  t h e aluminum atoms  s i x oxygen atoms o r h y d r o x y l  around  tetrahedra.  tetra-  t h e t o p l a y e r o f an a r r a y o f  aluminum-oxygen-hydroxyl octahedra.  with  atom i n t h e c e n t r e .  o f t h e f o u r o x y g e n atoms o f e a c h  oxygen atom o f each t e t r a h e d r o n  oxygen-hydroxyl  atoms a r e  i n t h e l a y e r s i s as f o l l o w s :  12  -  16  +  10  -  12  +  6  ( l a y e r common t o t e t r a h e d r a l and o c t a h e d r a l s h e e t s )  7  and,  therefore,  the  balanced.  However,  balance  charges  broken would  of  bonds give  s i l i c o n  of  pH,  while  to  the  amphoteric  be  positive  at  low  the  the  pH  structure  of  tetrahedral calcium)  and  appearing faces  is  Clarke, is  on  l i k e l y  to  site  of  the  tion  of  ions  This  pH  of  and edge  On  the  that  be  by  to  that  negative.  adsorptive  silica-alumina  aluminum,  negative  at  carries (and  a  may  other  Charges  i t  is  kaolin  in  net  surfaces. of  the  charge  the a  Since  Whatever externally  the  the  as  Samson  and by  charges area  (Armstrong kaolin origin  which  l a t t i c e  extent  negative  the  and  of  the  and  particle and  compensated  the  by  attrac-  surface.  capacity  of  kaolin  is  w i l l Thus  negative)  octahedral  lesser  edges on  values.  Schofield  due  They  charge  the  t e t r a -  w i l l ,  pH.  pH  become  within  the  irrespective  with  higher  even  (to  in  vary  that  units  in  positive  positive  hand,  s i l i c o n  result  overall  the  the  (1953)  charges.  magnesium  than  charge,  suggested  substitutions  cleavage  the  Grim  are  perfect  aluminum layer  aluminum,  1971),  this  octahedral  aluminum and  greater  conditions,  the  positive  layers  units  be  entire  the  of  structural  invariably  nature  low  suggested  edges  the  w i l l  in  increases.  (1953)  certain  disturbed.  the  layer  less  within  unsatisfied  those  at  become  is  to  hedral  w i l l  under  around  rise  pH,  charges  useful  thera-  8  peutically. adsorb is  Barr  bacteria  and  able to adsorb  Kaolin  has,  adsorbent  toxin.  agents  Specifically, dysentery  and  a d s o r p t i o n mechanism  4th  Edition).  fermentation,  (1%)  N.F.  in a  For kaolin  which  the  ability  usual oral  and  the  f o r the  chronic ulcerative  treatment  i s usually  repeated  considered  t o be  innocuous,  may  after  prolonged  result  Therapeutics, Apart  4th  from  several  in vitro  certain  drugs. in a  of  of k a o l i n  the  use  major pre-  treatment  of  colitis  through Therapeutics,  intestinal  (20%)  necessary.  although  toxins.  Kaolin Mixture  (containing as  kaolin  adsorbent  abnormal  g i v e n as  to  and  pectin  tragacanth 6 gm.  of  Kaolin  granuloma of  with  suspension.  kaolin) is the  (Pharmacological Basis  generally stomach of  Edition).  i t s ability  to adsorb  bacteria  and  s t u d i e s h a v e shown t h a t k a o l i n These a d s o r p t i o n i n t e r a c t i o n s  later  and  (Pharmacological Basis of  i s a mixture  be  as  intestinal  i t i s used  d o s e i s 30 m l .  d o s e may  that  a l l , bacteria  extensively  i n the  of k a o l i n  indicates  sweetened, peppermint-flavoured  The  cussed  the  This review  t h e r e f o r e , been used  its  Pectin  reviewed  many, t h o u g h n o t  for toxic  parations. diarrhea,  (1958)  section.  toxins,  adsorbs  will  be  dis-  9  2.  Adsorption, concentration  Theory  as  or The  the  phase,  refers be  to  the  to  adsorption chemical  If  atoms  bonds  less  absorption  or  solution  the  The  adsorption  may  be  called  of  the of  ions  of or  major  the  substance  specific  i t  is  involved  in  implies in  the  the  if  that  weaker  diffuse  i t  concern from  from in  der  Waals  1966),  into  is  the  whereas  van  (Shaw,  to  strong  process  phenomenon  molecules  or  adsorption  forces  distinguish  surfaces  Medium of  phase  the  at  the  adsorbent;  interaction  one  uniformly, to  that  is  the  more  involved  for  system  of  is  nature  are  molecules  or  (1948),  substances  adsorbate.  suggests  more  phenomenon.  of  phase  the  responsible or  Weiser  "Chemisorption"  adsorption"  are  by  medium c o n t a i n i n g  emphasize  process.  forces  phase  the  Definitions  valence  "physical  the  adsorbing  original  adsorbed.  necessary  defined  Adsorption  accumulation  interfaces. adsorbed  of  the  other  termed  the  this  surface thesis  solution  by  a  is solid  adsorbent. Adsorption factors. with  extent  increasing  change is  The  is  less  studied.  from  solution of  if  influenced  adsorption  temperature marked  is  the  but  the  by  many  decreases,in effect  adsorption  of  of  most  different instances,  temperature  gases  by  solids  10  Several  empirical  adsorption  behaviour.  exist  hence,  and,  (1920)  iodine  charcoal  chloroform, which in  is  close  these  tion  and  of  charcoal acetic  fatty and  to  of  commonly  known the  charcoal.  to  about  the  branch  adsorbed  bonds, In system  if  keto,  as  They  unit the or  a  in  hydroxy1  medium,  of  of  for the  on  other  the  groups  solubility  of  iodine  the  that  of  by  from  a  Gortner  acids  from  were  acids,  blood to the strongly  statement (1935)  water  adsorbed  indicating  number  of  that  that  molecules  adsorption  such  a  that  increases  and  is  of  formic  ascended,  the  adsorbate  purified  suggested  is  adsorp-  the  adsorption  hand,  acid  are a  1:2:4.5,  iso-acids  effect the  of  He  normal  of  order  from water  the  rules  caution.  therefore,  organic  On  the  increases  series  these  tetrachloride,  solution  acid.  describe  adsorption  solubility  studied  the  of  in  thirty  as  with  carbon  Linner  that  studies  used  rule.  l i t t l e  area.  to  are  the  homologous  structure  given  as  substances  same e x t e n t  exceptions  suggested,  butyric  of  to  ratio  adsorption  found  has  the  aqueous  Traube's  adsorption in  to  the  chain  per  decreased  that  proposed  be  ratios  (1930)  adsorption  by  the  was,  from  organic as  that  increases  propionic  must  inverse  acids  many  disulphide  It  found  regularly  studied  the  been  solutions  Freundlich  adsorption and  carbon  solution  decreases. series  from  solvents.  from  rules  observed  to  have  However,  these  Lundelius by  rules  is  double  present.  given  adsorbent-adsorbate  relationship  between  degree  11  of  adsorption  at  constant  and  concentration  temperature,  such  of  adsorbate  relationships  is  often  are  examined  called  adsorption  isotherms. Ostwald  and  Izaguirre  researchers  to  isotherms.  They  from  solutions  in  dilute  adsorption  tion  His  which  i n i t i a l  and  workers  (1960)  of  Sub-groups of  the  are  upper  nisms.  The  vertical (ii)  L  cative  at  solid  axis,  and  by  given  high-affinity  by  ions  over  wide  concentra-  five  types  of  adsorption  curvature Giles  and  on  It  was  claimed  to  explain  adsorption  S  curves,  indicative  molecules  "Langmuir" f l a t  on  ions  value  solutes  H on  at  the with  the  with  the classes.  this mechaniof  surface; usually or,  at  particularly ("high  ionic  i n d i times,  strong  a f f i n i t y " ) ,  concentration as  co-  shape  that  surface,  curves the  main the  isotherms  adsorbed  exchanging  on  the  his  isotherms, four  studies.  of  based  (iii)  positive  observed  class,  adsorbed  commence  are  each  adsorbed  which  adsorption  into  (i)  attraction;  often  the  adsorption  curve,  are:  or  of  for  phase  on  f i r s t  the  used  intermolecular  a  based  be  adsorbed  oriented  defined  vapour  curves.  normal  molecules  vertically  for  classes  the  solutions  adsorption  of  the  which  solution  can  of  types  isotherms.  the  system  in  types  the  slope  of  isotherm  later  was  probably  c l a s s i f i c a t i o n  binary  of  described  orientation  curves, of  system  were  other  (1942)  divided  main  six  from  stages  part  two  observed  i n i t i a l  classification  of  are  later  the  general  and  Brunauer  c l a s s i f i c a t i o n  basis  a  described  studies  ranges.  isotherms  attempt  (1922)  in  micelles  low-affinity  ions;  12  (iv) by  C curves solutes  does  types,  Their  into  investigations  the solid  there  are the best  the L2 curves  involving  curves,  more  i s  shown  i n the  from  dilute  i n describing  this  class  isotherms.  Class L  H  c  J •  Is v S  si s •»  C  /  /  5 *t H  a  i J  I  o  u  isotherm  and, according  2 ) , occur  5  c^tfu/fmconcn.  Figure  of solvit in datft  2. System of isotherm c l a s s i f i c a t i o n (Giles et al.1960)  than  diagrammati-  adsorption  S.  given  rapidly  a r e numerous  known  (see Figure  are useful  linear  c l a s s i f i c a t i o n  2. 'Although  the L curves  equations  partition"),  penetrate  i n Figure  authors,  Two  which  the solvent.  cally  of  ("constant  to the  majority solution.  of  adsorption  13  (a) the  The  Freundlich  spite  of  the  originator nally  solution  equation  equation  fact  that  (McBain,  derived  pressure.  It  f i r s t  to  this  describe i t  adsorption  generally  Freundlich eminent  1932).  However,  states  or  is  It  is  been  isotherms  adsorption  researcher  an  adsorption  has  the  to  as  isotherm,  was  not  in  i t s  empirical  equation  o r i g i -  of  solid  low  found  in  referred  gas  by  applicable low  to  at the  concentration  L  type  range.  that:  k  m  =  C  1  /  r( VE q . li>)  n  "x" where  is  brium The  amount  concentration  latter  This  the  linear  can  that  Freundlich  by  from  the  K h a l i l  and  often  "k"  per  gram  and  "1/n"  called  transformed,  the  by  of  adsorbent  are  empirical  adsorption  use  of  at  e q u i l i constants.  exponent.  logarithms,  into  form:  intercept  acid  is  be  log such  "C",  constant  equation  adsorbed  if  |  =  log  x/m  is  values  are  equal  (1930)  \  plotted to  with  s i l i c a t e ,  magnesium o x i d e ,  the  blood  found  k  =  charcoal 2.606  that  the  and  (Eq. slope  adsorption  equation  on  C,  the  Freundlich  hydrochloride  log  k  that  by  cyclimine  versus  log  "k",  solution  (1973)  +  and  demonstrated  Moustafa  C  "1/n"  aqueous  and  log  2)  and  respectively.  can 1/n  of  be =  acetic represented -0.425.  adsorption, of  oxyphen-  various  adsorbents  (magnesium  calcium  carbonate,  aluminum  t r i -  hydroxide,  14  kaolin,  and  bismuth  oxycarbonate)  obeys  the  Freundlich  adsorption  isotherm. (b)  The  (1916).  The  adsorption tions.  dent  of  gas  the  the  equation It  on  "a"  or  f i t s  the  the  adsorbate  L2  was  used  to  was  based  an  are  thereof  on  of  two  solution  assump-  range,  molecule  are  the  major  short  adjacent  produced  Langmuir  describe on  atom or  by  is  indepen-  sites.  monomolecular.  adsorption  isotherm  and  "C"  have  monolayer that  abc  is  to  involved  surface linear  of  the  the  same m e a n i n g  capacity  layer  forces  (Eq.  3)  1+bC  monomolecular  in  of  type  =  gram  the  derived  forces  films  one  the  that  solid  lack  adsorbed  was  states:  "x/m"  is  a  adsorption  x m where  which  adsorptive  adsorption  Secondly,  well.  a  F i r s t l y ,  hence,  equation  derivation  of  and,  The  second  of  1  and  as  in  represents  adsorbent  can  the  adsorb  complete.  "b"  is  in  the  adsorbate  binding  adsorbent.  This  Eq.  a  1,  amount when  constant  equation  of  the related  molecules  can  be  to  written  form:  -  = —i—  x m  +  —  ab  ( a  E  g  .  4) ^  •• C " If  2. m  is  plotted  from  slope  this  adsorption  and  against  intercept isotherm  "c",  values. are  "a"  and  "b"  Examples  numerous.  of  Evcim  can  be  calculated  systems and  Barr  obeying (1955)  15  reported  that  quinine  from  described showed  trihexethyl  adsorption  aqueous  by  that  the  the the  solutions  Langmuir  chloride,  and  antacids  are  of  The  two  equations  in the  explaining present  most  of  Early  the  values  recommended  the  as  Fantus  (1916)  of  to  1.5  for  were  adsorption  kaolin,  1.75 earth  but  time  administration  of  use  an  f u l l e r ' s that  given  of  clays  and  can  Gross  atropine bromide  found  to  isotherms  of of  dogs death pure  of  Drugs  clays was  in  be  (1965)  sulphate,  by  various  be  adequate  encountered  in  weighing was  general,  to  f i r s t  observed  many  of  earth,  found  strychnine  later  alkaloid.  25  Kaolin  in  alkaloidal  (1916)  by  explored  property  f u l l e r ' s  Felter  grains to  and  agents  this  antidote  and  of  investigations  therapeutic  s i l i c a t e ,  Blaug  and  type.  Adsorption  a b i l i t y  ago.  different  methantheline  just  adsorb":.certain :medicinal years  six  atropine,  investigation.  3.  The  by  isotherms  Langmuir  of  strychnine,  equation.  adsorption  the  of  the  clays. an  than  Lloyd  aluminum  poisoning. that  sulfate to  potential  the  that  magnesium However,  administration  adsorbed  30 p o u n d s  (1916)  on  caused  observed  death  after  -  16  (1920)  Jensen fuller's  earth  released  slowly and  reported  retained  emesis  of  hyoscyamine-clay,  function  as  are  continuously  and  passing  of  rice  factory  used  found  that  clay  could  be  co-workers  adsorption  only  5 mg.  in  pH  4.5  at  37°G  combinations  (1945)  acetate  that  this  therapeutic  i s always  so  dilute  produce  adsorbate  preparation  Using  o f an  B  by with  The  various  The  Later,  i n vitro  fuller's  for  Keresztesy  was  unsatistests,  adsorbed  on  Melnick  experiments  earth  the  and on t h e  and k a o l i n .  They  q u a n t i t i e s of the  clays  mixtures  extent  extract  rat curative"  of the vitamin  conducted  buffer.  f o r s i x hours.  of  i n  materials  of the vitamin.  by t h e a n i m a l .  of thiamine  active  can a l s o  earth  standard.  absorbed  longer  as t h e i n t e r n a t i o n a l s t a n d a r d  one-half  of vitamin  mixed  of clays  fuller's  showed  as a r e f e r e n c e  advantages  of s e n s i t i v e t i s s u e . "  to the synthesis  (1937)  they  his  A  aggregates  was  quinine-clay  i n the form of ions  property  effects.  oh  incidents  the  drug-clay  s o l u t i o n , which  irritation  prior  Sampson  these  colloid  supplied  p o l i s h was  vitamin and  from which  adsorptive  undesirable  discussed  opium a l k a l o i d - c l a y , and  into true  to prevent The  also  " i n a c t i v e depot m a t e r i a l , remaining  body,  as  He  In h i s opinion,  the  value  adsorbed  and r e s u l t e d i n r e d u c e d  irritation.  combinations.  ipecacuanha  i t s e f f i c a c y as an a m o e b i c i d e ,  i n vivo,  of  that  were e q u i l i b r a t e d  of adsorption  was  found  to  17  increase level,  with  increasing quantity  k a o l i n adsorbed  fuller's  earth  in  more  to  Barr  salt,  200  ml.  added.  The  minutes  at  t u r e was fluid  of  and  the  of  At  the  present  vitamin  d r u g s has  container 24±1°C.  was  At  The  was  obtained five  by  gm  solution. of  adsorption  been i n v e s t i g a t e d  the  The  amount o f  the  could  authors  a  power o f  different  represented that  f o r the  clay  for  the  minutes, clear  mix-  by  the  that by  for  different  monolayer capacity values  of  kaolin for  the  every  Langmuir  the  isotherm adsorptive  concentrations. strychnine,  atropine,  and  quinine  b a s e s w e r e c a l c u l a t e d t o be  10.4  and  4.6  per  adsorbent,  at  a l l the  adsorption  at  clay  isotherms  procedure with  comparison of  gram o f  the  supernatant  adsorbed  adsorbents  mg.  was  thirty  for adsorption  found  clays.  transferred  the  concentrations  I t was be  the  described  claimed  s u i t a b l e way  thirty  Data  of  shaken  alkaloid  alkaloidal  combination.  provided  of  a l i q u o t s of  repeating  obtained  equation.  end  the  six different  gm.  and  of  form of  s o l u t i o n was  0.5  closed  adsorption  a l l i n the  s o l u t i o n by  difference.  different  alkaloid-clay isotherms  quinine,  to which  c e n t t i f u g e d and  analyzed.  mg.,  0.5  whereas  from  p o t e n t i a l hazard  alkaloidal  container  c a l c u l a t e d by  The  vitamin  s t u d i e d the  from aqueous  was  least  the  (1955)  atropine,  hundred ml. a  years,  clay.  depth.  strychnine,  One  the  b e t w e e n k a o l i n and  E v c i m and  sulfate  of  r e m o v e d a l l 5 mg.  I n more r e c e n t interactions  54%  of  10.3  mg.,  respectively.  18  Sorby  and  Plein  15  phenothiazine  by  kaolin,  that of  talc  (1961)  derivatives and  norit  a l l  the  adsorption  those  for  dibasic  Langmuir  equation.  capacity  of  mg.  per  kaolin  gm.  of  been  troches.  On  with  Batuyios  Brecht  and  that,  type  They is  the  20 and  mg.  2.5 of  found  bacterial  25°C,  gm.  on  their  of  solution  showed  with  the  talc,  exception  follow  data,  the  hydrochloride  the  monolayer is - 8 . 5 3  that  the  the  activity.  cetylpyridinium  data  was  also  (which  They  chloride  was  exhibited  Langmuir  from  micelles  the by  with  suspension that  to  The  have  50 m l . failed the  Langmuir  the  i r r e v e r s i b i l i t y  known  adsorbed  clays.  concentrations  typical  demonstrated.  suggested was  of  The  chloride)  resulting  a  the  and  high  deviation  formation  molecules.  compressed  chloride  for  yield  this  into  germicides  cetylpyridinium  proposed  chloride  investigated  these  not  kaolin  kaolin  (1957)  did  to  benzalkonium and  chloride  cetylpyridinium that  talc  that  process of  and  but  chloride  adsorption  mixed  at  related  benzalkonium  of  aqueous  results  obtained,  adsorbed  between  adsorption  benzalkonium  isotherm.  Their  chlorpromazine  chloride  They  equation  isotherms  incorporated  found  adsorption  unbuffered  20°C.  basis  the  adsorbent.  interaction  of  at  the  for  adsorption  Langmuir  from  compounds  Cetylpyridinium have  investigated  of  authors  adsorbed of  to  water show  20 m g .  irreversibly  a n t i -  of by  kaolin.  19 Similarly, adsorption  capacity  not  changed  HC1  or  (from  4.5  A  to  chloride  lower  than  and  tion.  chloride of  the  the  authors  pH  be  It  6.5  the  of  better  more  of  the  also  from  drug  2.5  increase  species)  in  to  high  be  drug  to concentra-  of  the  properties  adsorption  dihydrochloride buffer.  adsorption (which  higher  pH.  of  sodium  physical  that  is is  con-  between  leads  effects  and  amine at  but,  hydrochloride  phosphate in  0.01N  found  sites  the  his  0.01N  concentrations  fluphenazine pH  in  of  minimal was  and  hydrochloride  high to  the  competition  observed  unprotonated  adsorbed  is  that  due  pH  hydrochloride  from water*at  at  on  and  effect  adsorption  be  and  this  The  promazine  may  was  than  claimed that  formation  low  solubility  hydrochloride  from  for  0.05N in  Sorby  water,  promazine  that  adsorption  hydrochloride  adsorbent.  higher  to  increased  low  was  adsorption by  adsorption  concluded  ions at  at  with  promazine  adsorption  than  authors  adsorption  on  promazine  the  The  water  the  d i s t i l l e d  solution,  higher  promazine  The  promazine  but  on  quinine  effect  i n i t i a t e d  solution.  the  alkaloids.  elucidate  in  and  washed  l i t t l e  of  that  Variations  these  adsorption  chloride  from  had  k a o l i n was The  f i r s t  U.S.P.XV.  for  to  found  strychnine  was  7.0)  kaolin  solution  that  centration.  decreased  on  chloride  concentration  sodium  Fluid  attempt  (1957)  for  clay  investigated  sodium  sodium  the  of  (1966b).  0.10N  kaolin  Gastric  drugs  k a o l i n was  sodium  Arnista  approximately  of  0.1ON  of  capacity  co-workers  and  after  preliminary  mechanism  and  even  Simulated  adsorptive  by  Barr  due  is The to  believed  of  20  In a  similar  adsorption in  the  data  isotherm.  adsorption  data  i s due  surfaces layer  on  the  flat-layer mg.,  Since  a t pH  the  of  the  surfaces  c h a r g e on of  pH  and  the  claimed  by  kaolin  that  with of  flat-layer the  broken  to  the  first  of mg.  of  Armstrong of  also  crystal  increased  contended  that  charge  the  on  8.89  the  and  on  the  on  and  this  (1)  the  ( i i ) the  21.0  flat-  broken 5.0,  mg.  gm.  the  and of  remains  kaolin.  negative  be  section  like  on  atropine  independent of  increase  with  edges d i d 5.0,  from  to  1.44  pH.  pH Ridout  increase mg.  at  9.7.  Clarke  with  that  -  (see  drug  will  s e r i e s of  violet,  from  broken edges changes  broken  a t pH  their  in  adsorption  s u l f a t e per surface  when  plotted  c a l c u l a t e d t h a t , a t pH  k a o l i n a t pH  increase  edge o f  planes,  edges w i l l  gin*  and  proposed  These are  surface  per  was  occurs  different  a cationic  mg.  that  were o b t a i n e d  i n c r e a s i n g pH  adsorption  adsorption  two  flat-layer  the  kaolin,  of  5.0  step  He  atropine  that  0.9  In  on  9.7.  pH  broken edges adsorb  adsorption  the  that  7.2,  He  the  Kaolin),  on  , a  curves  cleavage  and  to negative  pH  and  14  kaolin particles.  positive  sulfate  page  presence  particles.  irrespective  from  7.2  r e s p e c t i v e l y , of  the  while  on  (1968b) o b s e r v e d  s u l f a t e at  Similarly,  the  surfaces  edges of  0.9  to  Ridout  for atropine  manner d e s c r i b e d  Langmuir  step  study,  studies  on  adsorption  (1971) r e p o r t e d  a basic  substance,  i n c r e a s i n g pH. i n density  kaolin with  that  of  increase  by  However, the  the  they  negative  i n pH  is  21  too at  small  to  account  higher  pH  values.  centrations values  the  ions.  unbalanced  exchange cations kaolin  of  supported  crystal  The  ion  ion  mechanism.  adsorption was  However,  that pH  to  the  aproximately anions have  at  are a  pH  0.4  in  of  capacity 5.0,  the  of  at  kaolin.  adsorbed  on  the  area  anionic  compared  to  rise  in  is  authors  are  through  species,  by  (1972).  pH  It  with  an  5.0,  decreased small  after  rapidly. -  explained  charged  the  more  was  increased  adsorbed  positively  a  species  Armstrong  The  the  adsorption.  surfaces  kaolin  The  adsorption  approximately  the  amount  in  cationic  adsorption  for  positively  corresponding  an  and  of  small  a  conclusion  kaolin  mg./gm.  very  a  on  created  increase  that  Clarke  extent  of  aluminum  valency  charge  medium of  charged  by  higher  This  pre-  l a t t i c e .  therefore,  the  a maximum v a l u e  adsorption even  the  the  of  pH  compensated  for  negative  con-  high  possibly  ion  benzoic'acid,  also'studied  in  the  of  surface  kaolin  that  adsorption  achieve  the  therefore,  exchange  to  in  violet.  concentration  the  cations  a c c o m p a n i e d by  negatively  increase  which  is  increased  adsorption  observation  suggested,  observed  that  crystal  that  kaolin  This,  the  the  kaolin',  which  for  in  c a l c i u m and  increasing  a whole.  violet  on  The  was  an  as  the  authors,  adsorbed an  such  by  magnesium  in  situation  ion  the  charge sodium  increase  required  pre-adsorbed  monovalent  as  on  magnesium,  negative  particle  charged  hydroxide  These  resulted  favourable  for  of  marked  believed  replacement  cations  sodium  the  They  sodium  promoted  adsorbed by  of  for  broken  negatively  edges,  charged  22  cleavage  surfaces.  limited. the  anionic species  fore, due  Degree of  the  initial  to the  decrease  Therefore,  extent  ionization  measurements showed  of  acid  benzoic  increase  production  a p h y s i c a l change  is  supported  by  kaolin  pH  i s a t pH  which  adsorption  anionic  that  the  i s positive  This  value  are  The  authors  adsorbed  on  to  the  adsorption zero  later authors,  sites.  p o i n t of  at  values  pH  This  charge  the  low  There-  probably-  c h a r g e on  from  edge of  the  pH  at  therefore,  broken edges of  the  changes  i n c r e a s i n g w i t h pH  suggested, the  is The  coincides with  c a p a c i t y changes  w i t h pH.  species  i n the  at which the  which  5.0.  sign)  decreasing  finding  value  particles,  pH  be  that i t i s  i s adsorbed.  capacity, according  c a u s e d by  i s , the  which  i n adsorption with  is  (that  adsorption would  o f more a n i o n i c s p e c i e s .  i n adsorption  the  of  to  that  the  kaolin  particle.  4.  Melnick in  vitro  by  kaolin.  of  the  was on the  They then  A  m i l k was  5.0  on mg.  the  f o r 24  average,  individuals  18%  (1945)  showed t h a t ,  to  i n v e s t i g a t e the  thiamine  to each of  hours, the  were g i v e n  hydrochloride five  analyzed, test 100  dose. gm.  of  and  subjects. found  In a kaolin  to  second in  under  adsorbed  physiological availability  dose of  of  Studies  h y d r o c h l o r i d e was  proceeded  administered  collected the  h i s co-workers  conditions, thiamine  adsorbent  vitamin. in  and  In Vivo  influence of  the  dissolved Urine contain, experiment,  aqueous  23  suspension dissolved found  followed i n milk.  t o be  absorption decreased kaolin  degradation  3 8.2  (1922)  found  that  The c o r r e s p o n d i n g  ly.  i n their  This  symptoms fed  slightly  researchers, adsorbed  was  a n d 1 0 0 mg.  xerophthalmia  the rats died data  diet,  were  developed  21.2 d a y s ,  p e r day.  i n an a v e r a g e o f 54.1  i n pigeons.  Mixture  with  lincomycin, chloride  avitaminosis  a n d 5 0 0 mg.  symptoms  suggested  of vitamin  accelerated  were of  appeared i n  s u r v i v a l time  The a u t h o r  no  respective-  was  f o r t h e c o n t r o l s was  t h e amount  and, t h e r e f o r e ,  Wagner  data  of  days.  received  Three pigeons  rice  Avitaminosis  respectively.  k a o l i n decreased  i n an average  46.3 d a y s a n d 59.8 d a y s ,  The c o r r e s p o n d i n g  avitaminosis  onto the  f o r the c o n t r o l s , which  n o t as obvious  per bird  absorption  due t o  k a o l i n p e r day on s i x  a v e r a g e o f 15.6 d a y s a n d t h e a v e r a g e  rats,  enhanced  investigated the e f f e c t of a diet consist-  a c c e l e r a t i o n i n the development of  21 d a y s . and  t o these  a diet consisting of decorticated  kaolin an  This  was  gastrointestinal.tract.  days and t h a t  kaolin  hydrochloride  24 h o u r e x c r e t i o n v a l u e  of the vitamin  of decorticated rice He  of thiamine  The a v e r a g e  was, a c c o r d i n g  i n the  rats.  mg.  24% o f t h e t e s t d o s e .  Messerli ing  b y 5.0  14.2  days  that, i n  available for  the development of  symptoms. (1966)  studied  the influence of Kaopectate  Pectin N.F.XIII) given  on t h e serum and u r i n e  i n the form of L i n c o c i n  monohydrate)  The L i n c o c i n c a p s u l e s  capsules,  i n eight  ( 0 . 5 gm.)  and 3 f l .  (lincomycin adult  (Kaolin  l e v e l s of hydro-  subjects.  oz. of  Kaopectate  24  were g i v e n  t o each subject  (a)  one L i n c o c i n  (b)  Kaopectate  capsule; of the  (c)  capsule  taken  taken  same t i m e .  taken  curve  from  48 h o u r s  i n the urine  a,  b, c, and d, r e s p e c t i v e l y .  and t h e c a p s u l e  0 t o 12 h o u r s  A decrease  o f k a o l i n was  excretion  k a o l i n on d r u g  the i n vivo  Forrest Aludrox  hydroxides, to  adsorb  The  determined the  drug  Aludrox an  absorption.  hydrochloride  amounts  excreted  f o r treatments  a n d 30 m l . o f A l u d r o x . the urinary  studies studies  of  both  on t h e e f f e c t with  other.•:  the effect of  Aluminum and  of Aludrox,  daily  excretion  and compared t o t h a t  a v e r a g e o f 27%.  were  studied  hydrochloride  48-hour u r i n a r y  decreased  under the  phenomenon c a n  were g i v e n i n three level  magnesium  were  i n separate  Ten male m e n t a l p a t i e n t s  ofachlorpromazine  at  drugs.  the .majorconstituents  experiments.  doses.  of  and h i s co-workers(1970)  chlorpromazine  taken  r e f l e c t e d by  few i n v i v o  the adsorption  absorption  on c h l o r p r o m a z i n e  administration  i n availability  a c t i o n . However,. : i n v i v o  indicate that  of the  data.  There have been r e l a t i v e l y  affect  after  were 1.0:0.71:0.69:0.20  i n the presence  serum and u r i n a r y  oz. of water;  administration  and t h e r a t i o s o f average  in  adsorbents  3 fl.  The r a t i o s o f t h e a v e r a g e a r e a s  1.0:0.83:0.53:0.09  of  manner:  with  two h o u r s  (d) K a o p e c t a t e  serum c o n c e n t r a t i o n  lincomycin  orally  two h o u r s b e f o r e  Kaopectate  the capsule;  i n the following  shown  i n vitro 400 - 1200  divided  of the drug  was  following administration Their  excretion  r e s u l t showed  of  that  of chlorpromazine  by  mg.  25  Sorby  (1965)  attapulgite  and  Each  test  of mg.  of  six  promazine of  the  mg.  activated  and  activated  in  40 m l .  over  authors on  noted  of  In  a  mixture, promazine  that,  drug  those  in  in  with  did  amount  0.1N  in  with  solution, 45 m l .  affect  charcoal, of  drug  hydrochloric the  by  mg. 50  aqueous with  100 The  the  total  on  found  period  desorption  from  50  suspension.  not  collection vitro  turn,  hydrochloride  urine;  desorbed  f i r s t  study,  administration (each  the in  the  35%.  The  experiments  based  acid,  and  58.1%  attapulgite  f l .  oz.  Sorby  and  of .2.5  Liu  f l .  contained  (1966a)  oz.  4 gm.  of  and  excretion  levels  observed  following  administration  alone.  also  36-hour  absence  of  This  decreased urinary  found  an  were  delayed of  large  the  drug  collection  antidiarrheal  of to  compared  dose  promazine of  appearing  76% o f  preparation  as  peak  50 m g .  comparatively amount  that,  antidiarrheal  attapulgite),  urinary  attapulgite  the  total  24 h r .  was  similar  hydrochloride  in  f i r s t  the  absorption.  respectively.  following  the  the  washing  the  charcoal  to  the  in  activated  aqueous  aqueous  attapulgite  excreted  reduced  repeated  22.7%  that  in  attapulgite  charcoal  of  urine  500 mg.  45 m l .  promazine  amount  drug  in  of  promazine  treated,  of  indicated  hand,  was  on  50 mg.  result  other  subjects  with  effect  charcoal  hydrochloride  drug  suspension,  investigated'the  that  in  observed  administration.  26  Tsuchiya activated  and  the  adsorption  was  changed  adsorption  aspirin,  of  found  aspirin 1 to  of  the  high  pH  a  low  environment,  reversed  the  the  competitive  contents  played  In  an  in  vivo  under  in  vitro  was  human  found  or  a more  study,  that  the  60.8%,  drugs  were  23.1%, given  totally  along  with of  recovered 6.5%,  alone.  of  basis  these  the the  drugs  adsorb of  a  passed  intestine, of  the  intestinal pH  that drug, above  effect. would, were  from  urine of  were that  given  drugs.  salicylamide,  respectively,  slightly,  unless  aspirin, the  would  decrease  slightly  the  a  aspirin  normal  than  of  pH  de-  the  charcoal  one  slightly the  of  role  the  enhanced  increased  effect  as  and  as to  conditions,  change  adsorption  be  amount  amounts  and  that,  important  conditions  subjects  On  of  phenyl-  decreased  salicylamide would  might  the  pH  and  vitro  was  similar  vivo  displacing  phenylpropanolamine to  in  adsorption  in  salicylamide  significantly,  phenylpropanolamine  the  A  environment,  and  to  under  charcoal  suggested pH  the  salicylamide,  phenylpropanolamine. authors  stomach,  on  of  studied  that,  8.2.  adsorption  from  be  on  They  from  the  results,  (19 72)  charcoal  propanolamine.  creased  Levy  It  and  decreased when  the  27  III  The  drug  investigation  substances on  the  Chlorpromazine  name  white,  i s  l i s t e d  odorless,  used of  i s  a white  of  Chlorpromazine and not  more  H, ClN„S.HCl, 19 2 n  molecular  powder.  weight,  C - ^ H ^ C l ^ S . H C l ,  Hydrochloride than  the  calculated  B.P.  i s  of  reference  slightly  Its  chemical  phenothiazine based  equal  contains  equivalent with  this  kaolin.  or  2-Chloro-10(3-(dimethylamino)propyl)  formula  i n  Hydrochloride  crystalline  molecular  17  were  properties  hydrochloride  and i t s  C  DRUGS  herein  adsprptive  monohydrochloride  99.0%  TEST  Chorpromazine  1.  creamy  THE  .  not  to  the  a  355.33.  less  101.0% to  on  than  of dried  substance.  CH CH CH N(CH ) 2  Figure  3.  2  2  3  2  Chemical structure of chlorpromazine hydrochloride.  28  The of  a  drug  substance  5% a q u e o u s  soluble ether  in  and  is  solution  alcohol  and  benzene.  very  is  in  soluble  between  4 and  chloroform  Chlorpromazine  but  197?C ' ( B r i t i s h  Pharmacopoeia,  mate  value  It  at  254 t o  by  nonaqueous  for  the  method was  of  analysis, to  is  described  drug  to  were  this  light.  in  by  researchers  found  through  formation  the  that  Chlorpromazine  d e t a i l  of  a  free  the  treatment  be  lessens used  toxic  to  and  Sciences,  motor treat  senile 14th  and  next  activity selected psychosis  Edition).  (British of  in  has  is  energy  analyzed  1973)  value  but,  at  oxidized  Discher  254  nm.,  This  when  for  this  (1964).  These  zero-order  kinetics  intermediate.  c l a s s i f i e d  as  a  Pharmacopoeia, tension, It  major 1973).  agitation,  can,  schizophrenia,  (Remington's  approxi-  radiant  pathways  psychotics. of  an  solution.  easily  anxiety,  cases  and  between  section.  followed  is  in  spectrophotometry  in  radical  hydrochloride  It and  is  degradation  antiemetic  in  the  Felmeister  and  used  in  drug  photodegradation  tranquillizer is  of  freely  melts  substance  a  pH  insoluble  absorptivity  amount  The is  Pharmacopoeia,  hydrochloride The  outlined  the  i t s  is  It  a maximum of  investigation, on  5.  1973)  powdered  (British  based  determine  Chlorpromazine exposed  absorbs The  titrimetry  purposes  used  9.2.  255 n a n o m e t e r s .  of  method  of  water.  hydrochloride  194° and pK^  in  therefore, mania,  Pharmaceutical  and  29  The action  drug  on  systems  exerts  the  central  throughout  Therapeutics,  4th  75  of  to  the  800 mg.  drug  is  intramuscular  codeine,  known  body  as  drug an  as  is  less the  than  solution soluble phate  or  25  organ  Basis  the  to  on  its"  of  diagnosis, daily.  50 m g .  When  are  given  by  Phosphate  the  The  is  - 4 ,  406.38.  H  2 4  Codeine l  g  H  is  ° 7  P  '  as  3  s  H  2  0  '  7  from  codeine.  fine,  Phosphate  N0 P,  alkaloid  extracted  crystalline N  salt  5-epoxy-3-methoxy-  0.5%  marketed  i 8  c  phosphate  phenanthrene  alkaloid  a white  of  C  hemihydrate  approximately  as  formula  98.0% of  dried The  6th  to  on  through  as  administered  8 - D_ehyd.ro  phosphate  crystals  equal  be  occuring  7,  contains  molecular  can  is  N-methylmorphinan-6-ol.  a  Depending  Codeine  naturally  chemically  shaped  well  (Pharmacological  antiemetic,  phosphate  Codeine  as  effects  injection.  a  opium which  system  Edition).  2.  of  pharmacological  nervous  the  the  used  Codeine  i t s  i  white,  needle-  powder. t  S  m  B.P.  calculated  o  l  e  c  Based u  l  a  with  weight  r  contains  on  not  reference  to  substance. drug is  in  melts  Edition)  is  freely  4.6.  It  alcohol at  and  is  but  235°C.  soluble very more (The  absorbs  in  water.  soluble so  in  in  hot  boiling  Condensed  The  pH  of  water,  alcohol.  Chemical  a maximum o f r a d i a n t  a  2%  slightly The  phos-  Dictionary,  energy  at  285  30  nanometers.  The  titrimetry poses  of  analysis tion.  powdered  (British  this was  This  substance  Pharmacopoeia,  investigation, used  to  method  a  determine  of  analysis  is  analyzed  1973)  but,  by  nonaqueous  for.the  pur-  spectrophotometry  method  the  in  is  amount  of  described  drug in  the  of  solu-  next  section.  Figure  Codeine Mital  phosphate  (1969)  reported  Compound  Codeine  exposure  to  Codeine suppress are of  one-sixth the  dose  (5  and  to  the B.P.  was  can  be  used  treat  those  of  morphine  to  10 m g .  be  purposes.  the  to of  accelerated  base  Opium,  as  an  diarrhea.  administered  of  exposed  of  light. the  drug  both  by  analgesic,  to  in  moisture.  to  must  when  decomposition  and  base  antitussive  that  phosphate  cough,  discolors  Tablets,  light  Chemical structure codeine phosphate  4.  and, to  every  Its  analgesic  therefore, suppress four  instead  of  pain.  hours) pure  15  is  to  properties 60 mg.  A  lower  used  codeine  for  phosphate,  31  is  normally  diarrheal morphine  used  in  the  properties and  are,  of  treatment  of  this  are  therefore,  3.  Morphine naturally as  7,  14%  sulfate  occuring  of  is  the  powder.  It  weight, is  98.0%  to  and  7  l  n  or  V  2.  H  than  SO., 4  has  of  known  of  the  chemically  a  contains  salt or  is  as  bitter  formula  of  B.P.  equivalent  calculated  2.  The  Sulfate  the  salt  alkaloid  masses  a molecular  more  those  6-dihydroxy-N-methylmorphinan.  cubical  758.8.Morphine  to  a n t i -  Sulfate  opium which  and  The  below.  pentahydrate  alkaloid.  odorless on  not  ( C H N O j l / iy J l  is  based  equal  from  anhydrous  crystals  the  5-epoxy-3,  obtained  acicular  Morphine  is  similar  discussed  phenanthrene  8-Dehydro-4,  Morphine  drug  diarrhea.  with  from  9  marketed  a white taste.  reference  molecular .H SC> . 5 H 0  2  2  not  101.0%  white,  crystalline  (C^H^NO^)  of  as  The  contains  to  4  less  2  than  of  to  the  dried  substance. Morphine aqueous water,  solution slightly  insoluble melts of  at  about  250°C at  when  4.8.  in  in It  alcohol  and  with  in  water. is  the  Pharmacopoeia,  more  ether.  The  decomposition  pH  of  the  may  be  analyzed  1973)  but  The  freely  but  285 n a n o m e t e r s .  substance  analyzed  soluble  about  soluble  energy  powdered  be  is  is  chloroform  occurs  (British may  in  radiant  spectra The  sulfate  A  of  soluble so  in  in  hot  absorbs  solution  by  alcohol,  a  maximum shift  is  titrimetry  containing  measuring  of  increased.  nonaqueous  solutions  hot  sulfate  bathochromic  by  an  anhydrous  and  aqueous  spectrophotometrically  pH  the  drug  absorbance  32  values given  at in  285 n a n o m e t e r s . the  next  sulfate  aqueous  solution  changes  produce  (Merck the  Index,  may no  of  5.  Chemical morphine  discolors turn  loss  Eighth  s t a b i l i t y  in  brown  Edition).  N-oxide,  fixed  pH,  and The  i t  h a l f - l i f e  of  the  estimated  to  be  and  Yeh  the  pseudomorphine  a  storage.  in  parts  at  on  aqueous  nine  methylamine.  exposure  in  decomposes,  be  on  morphine  morphine  morphine  structure su'lf ate.  potency  that  of  analytical  procedures  are  section.  Figure  Morphine  Detailed  a  trace  and  to  increase  Lach  presence  of  one  which  degradation  rate  increases  degradation days.  reaction  at  pH  is  such toxicity studied  They  oxygen,  base  first-order  Ampuled  in  (1961)  solution.  (oxymorphine),  pseudo  light.  However,  of  follows  10  no  of 'I  reported to  part  of  believed with  pH,  kinetics. 5.0  and  form  95°C  to but, The was  33  Morphine B.P.  dosage  salt.  sulfate  for  Morphine  tion,  the  which  administered, Opium  has  dysentry  form  is  is  in  dilute  to  four  Such  a  dose  from  2.3  Morphine intestine of  i s ,  side  for  of  contraction  most  usual  the  usually  delayed  longer  the  used  drug  dosage opium  10.0 ml.  of  one  XVIII).  codeine  of  and  retard  The in i t s  small  nonpropulsive but  Because  in  the  thus  decreases  waves.  resulting  is  the  (Pharmacological  absorbed  contents  morphine  turn,  mg.  tone  decreased.  stay  intestinal  in  0.26  spasm  completely  which,  to  simplified  therefore,  of  Pharmacopoeia  resting  more  feces  to  5.0  is  p e r i s t a l t i c  Respiratory  powdered  The  propulsive  administra-  diarrhea  commonly  Edition).  markedly  colon,  sulfate  morphine.  therefore,  the  is  States  to  In  the  drug.  of  0.45% of  dose  0.13  The  of  repeated  overdose  The  tend  of  an  pain.  20 m g .  the  treatment  contents  viscosity  to  the  periodic  4th  if  to  of  effect.  contains  from  causes  are  addicted death  (United  increases  and  contractions bowel  The  mg.  Therapeutics,  rhythmic  used  daily  4.5  after  chief  contains  to  and,  cause  alcohol.  times  euphoria  may  which  relief 10  centuries.  paregoric  the  from  become  been  for is  may  the  for  used  purpose  causes  patient  depression,  and  this  is  or  type  from  of  propulsive of  this,  intestine. the  Water  chyme  and  increased. even  passage  of  considerable advance  Basis  abolished contents  the i s ,  dessication  through  the  of  colon.  is  34  The  amplitude  ion  of  the  i s  on the  produce  i s  nonpropulsive usually  greatly  defecation  drug  the  colon  sphincter the  of  central  i s  Codeine  nervous  motility  of  produces the  and large  an  alkaloid  other  which  members  racemic is  sulfate  of  mixture  marketed  powder.  It  molecular  i s  of  i s  dl-tropyl  colorless  i s  odorless  weight,  C  H  N  U.S.P. of  contains  S 0  H  not  ( 2.7 23 °3 ^ 2 ' 2 C  H  The of  H  N  drug  an aqueous  glycerin  194°C.  H  solution  and i n  for  the  i n  effect  from  s a l t  Atropa  family.  t o t a l ,  s  or  The as  a molecular e  q  u  a  l  i s  l  c  u  l  a  t  t  very about Its  the  o  69  atropine,  alkaloid  hydrated  a white,  4.85.  L.  e  t  ^  o  n  t  n  soluble 5.4.  melting  It  e  taste.  point  water. freely i s  a  The  of  anhydrous  i s  i s  crystalline  Atropine  in  and  sulfate  Sulfate  98.5% a n d n o t m o r e t h a n  than a  on  belladonna The  tropate.  of  formula  i s  alcohol.  similar  on  c  substance  of  effects,  bitter  i  4'  anal  stimuli  action  and has a very  less S 0  the  Sulfate--;  crystals  based  ^ 17 23°3 ^2' 2 4" 2°'  normal  the monohydrate  Solanaceae  as  the the  of  contract-  intestines.  Atropine  obtained  the  tone  These  a qualitatively  small  The  due t o  system.  rhythmic  constipation.  4.  Atropine  whereas  ignored  morphine-induced  of  enhanced.  increased  reflex  type  101.0%  basis. The  pH  soluble  between  190°  in and  35  CH NCH  CH-OOC  3  ^  525  sulfate  nanometers  reineckate  absorbs  Details  i n solutions  in  o f h i g h e r pH.  d e g r a d a t i o n was c a t a l y z e d  kinetics. at  40°C.  a t a fixed  of radiant  i n dilute  t o form a energy a t  This analytical sulfate  used  proce-  i n this  section.  sulfate sufuric  However, K o n d r i t z e r  of hydrolysis  that,  i n acetone  reinec-  was s t a b l e acid  solution but  o f ammonia, sodium b i c a r b o n a t e , a n d  but the rate  and  1952).  atropine  aqueous  the alkaloidal  a maximum  that degradation of atropine  solutions  from  are given i n the next  (1921) c l a i m e d t h a t  sodium carbonate. found  t o form  t o analyze the atropine  18 h o u r s w h e n d i s s o l v e d  degraded  2  of atropine  c a n be d i s s o l v e d  (Colby andBear,  investigation. Dott  structure  can be p r e c i p i t a t e d  s o l u t i o n which  dure was used  for  6. C h e m i c a l sulfate-  b y ammonium  4  2  This precipitate  colored  2  2  Atropine  kate.  .H S0 .H 0  H C—CH  Figure  solution  CH  w a s much l e s s Their  (1957)  d i d o c c u r i na c i d i c than that  investigation  by both hydrogen  pH, i t f o l l o w e d  T h e pH o f maximum s t a b i l i t y The h a l f - l i f e  and Z v i r b l i s  medium  observed  showed  that  andhydroxyl ions  pseudo  first-order  was found  t o b e 3.6 4  of the degradation reaction  a t this  2 pH a n d t e m p e r a t u r e w a s 1.8 8 x 1 0 v a l u e was found  t o b e 0.16 y e a r s .  years.  A t pH 7.0,  the  36  Atropine It  has  with in  been  shown  the  stomach,  orally  however,  that  produce  incorporated such  in  the  such  subjects  to  1.0  Register,  is  exhibit  large  unwanted  into  mg.)  side  Donnagel  Specialties,  preparations  gastrointestinal  several  patients  motor  activity  following*, f u l l sub|||i'ta'neously  quantities  drugs  that  preparations. Enterogel  w i l l ,  is  so  are  the  small  minimal  often  Examples  (Compendium  However,  usually  tract  reduced  Such  1975).  is  some  effects.  of  and  motility.  administered  1975).  one  (and  intestines  antidiarrheal  are  Pharmaceutical drug  and  sulfate  products  normal  (0.6  (Federal  gastrointestinal  disease)  small  doses  Atropine  on  reduces  gastrointestinal  therapeutic or  sulfate  of  of  amount  that  (Federal  i t s  of effect  Register,  1975) .  5. The  word of  These  were  for  the  recent the  ly  the  the  sulfonamides  drugs  are  of  inexpensive,  f i r s t  used  as  but,  easy  effective  bacterial  more  effective,  infections .  is  a  generic  para-aminobenzenesulfonamide  treatment years,  Sulfonamides  "sulfonamide"  derivatives drugs  The  in- those they to  have  in  man.  antibiotics  have  instances the  administer,  where  advantage and  for  (sulfanilamide).  chemotherapeutic  infections  effective  name  of  rarely  the  In  agents more  replaced latter  being causing  r e l a t i v e super-  37  Sulfonamides In  general,  they  mechanism of tion 4th  of  the  has if  been  these  of  of  the  be  used  four  of  for  f i n a l  bacillary in  the  mixtures  the of  to  used  of  to  bacteriasuppress  lumen. in  this  investigation  kaolin.  diarrhea,  the  eradica-  Therapeutics,  dysentry)  bowel  is  defense  treatment  containing  infection  administered  containing  the  the  sulfonamides  into  effect,  Basis  for  activity.  patient  one  However,  or  along  more  with  of  a  kaolin,  Sulfadiazine This  white  drug  occurs  as  white,  crystals  or  as  darkens  on  exposure  slowly formula  of  calculated  name  of  B.P.  contains  with  in  alcohol  and  in  aqueous  The  melting  dissolved  in  maximum o f  this  reference  Sulfadiazine  is  in  solutions  point  of  the  hydrochloric radiant  powder.  to  It  light.  drug, not to  almost  and  yellowish  white, is  or  stable  Based  on  a  pinkishin  air  but  molecular  2-(4-aminobenzenesulf onamide)-pyrimidine ,  4  chemical  soluble  a white  C-^QH^QN 02S ,  Sulfadiazine  a  been  organisms  symptoms  may  antimicrobial  responsible  example,  incorporated  preparation  the  have  the  of  (Pharmacological  (for  of  range  bacteriostatic  being  harmful  one  drugs  (a)  They  diarrhea  growth  one  host  a  infection  Edition).  Only  a wide  exert  the  the  induced  have  has less  the  insoluble  a l k a l i  drug acid  energy  than  dried  acetone, of  a molecular  at  is  of  250.3.  C-^QH^QN 02S, 4  substance. in  water, in  hydroxides 252° t o  solution, 243  99.0% of  soluble  from  weight  sparingly  dilute and  carbonates.  256°C.  sulfadiazine  nanometers.  mineral  When absorbs  acids  38  2  H  N  \  //  Figure  Sulf adiazihe-.is from  the  body.  containing  drug  dose  For dose gm.  of  for  example,  (b)  Specialties, 15 m l .  product  repeat  the  of  four  of  is  every  treatment  4 gm.  every  absorbed  kaolin,  this  i n i t i a l l y ,  rapidly been  every  "  N H  Chemical structure of sulfadiazine  has  in  for  7.  It  Pharmaceutical the  2  S 0  readily  incorporated into  1975) the  one  into  K e c t i l  which  to  systemic  sulfadiazine  is  preparations  contains  suspension.  six  excreted  (Compendium  of  750 mg.  The  tablespoonful  four of  and  of  recommended  (approximately  15  ml.)  hours. infections,  recommended,  an  i n i t i a l  followed  by  oral one  hours,  Sulfamerazine Sulfamerazine  crystals  or  as  occurs  a white  as  white  powder.  or  Its  faintly  chemical  yellowish name  2-(4-aminobenzenesulfonamido)-4-methylpyrimidine on  a molecular  is  264.31.  not  more  formula  of  Sulfamerazine  than  100.5%  of  c  T_I I2 4°2 H  U.S.P.  N  S  '  its  contains  C ^ H ^ I ^ G ^ S ,  is and,  molecular not  less  calculated  white  on  based weight  than the  99.0%  and  dried  basis. It dilute and from  is  very  mineral  sodium  slightly acids  and  hydroxides.  234° t o  238°C.  soluble in The  When  in  water,  solutions melting  dissolved  of  point in  readily  potassium, of  the  soluble  ammonium,  drug  hydrochloric  in  is  acid  solution,  39  Figure  sulfamerazine  absorbs  For  treatment  the  administered that  i s ,  as  a  properties is  more  dose  of  levels  for  with  to  those and  can  be  to  three  Its  slowly  When  243  is  and  used  However,  by  one  i t  Therefore,  one-half  alone,  followed  usually  pharmacological  excreted. with  nanometers.  sulfamethazine,  sulfadiazine.  obtained  gm.,  at  sulfamerazine  mixture. of  of  energy  sulfadiazine  more  sulfadiazine.  two  radiant  infection,  sulfonamide  absorbed  blood  is  a maximum o f  similar  rapidly  recommended  Chemical structure sulfamerazine.  combination  triple  are  comparable  oral  in  8.  the  the  dose  i n i t i a l  gm.  every  yellowish  white  eight  hours. (c)  Sulfamethazine Sulfamethazine  powder  which  name  is  and,  based  weight 99.0% the  may  darken  is and  dried  on  on  a molecular  a white  exposure  Sulfamethazine  not  than  more  to  to  light.  100.5%  of  C  chemical  6-dimethylpyrimidine  C ^ H ^ N ^ O  U.S.P.  of  Its  S t i t s  molecular  - c o n t a i n s ..ndt  less  ;  ]^2 14 4°2 ' H  N  S  c  a  l  c  u  l  a  t  e  d  .than o  n  basis. very  soluble  in  alcohol,  chloric  acid  197° t o drug  formula  278.33.  is  the  as  2-(4-aminobenzenesulfonamido)-4,  It  from  occurs  slightly  soluble  solution. 200°C.  absorbs  soluble  The  When  in  in  water  acetone,  melting  dissolved  a maximum r a d i a n t  and  point in  and  of  in  in  ether,  1:12.5  at  hydro-  sulfamethazine  hydrochloric  energy  slightly  243  acid  is  solution,  nanometers.  40  Sulfamethazine with  sulfadiazine  perties except  are  i t  sulfonamide Edition).  per  kg. of  is  to  the  When  body  one  those least  used  every  is  odorless,  and  excreted  in  of  oral  pro-  sulfamerazine  drug  Basis  i n i t i a l  recommended,  six  the  t r i p l e  Therapeutics,  dose  followed  by  of a  0.1  gm.  maintenance  hours.  9.  Chemical structure sulfamethazine  occurs  crystalline  molecular  formula  267.31. more  of  101.0%  a white  i i  c  Its  to  of  slighty  chemical  4-dimethylisoxazole H  i 3  Sulfisoxazole  than  as  powder.  benzenesulfonamido)-3,  not  an  combination  pharmacological  sulfadiazine  rapidly  alone,  in  Sulfisoxazole Sulfisoxazole  to  of  Its  (Pharmacological  weight  gm.  administered  sulfamerazine.  Figure  (d)  usually  suspension  4th  dose  and  similar  that  of  is  of  N  3 ° 3  S  U.S.P.  '  name and,  molecular contains  C^H^N^O^S,  yellowish,  not  is  based  on  weight  less  calculated  5-(4-amino-  is  than  on  a  the  equal  99.0% dried  basis. It  is  alcohol, of  the  very  and  dilute  substance  hydrochloric of  in  slightly  radiant  acid  energy  is  soluble  hydrochloric  from  194° t o  solution, at  in  220  water,  soluble  acid.  The  199°C.  sulfisoxazole  nanometers.  When  in  boiling  melting dissolved  absorbs  a  point in  maximum  and  41  3  H^C Figure  tion  Rudy  and  w i l l  occur  in  equal  is  refluxed  is  stable  Senkowski  parts  i f of  a  five  Its  diazine than Basis  of  i t s  of  Edition).  of six  following of  sulfisoxazole times  a  day.  is  acid  solution  substance  105°C. and  in  excreted  of  sulfa-  the  body  is  less  (Pharmacological of  administration  recommended,  the  that  Because  An  by  to  sulfonamide  sulfadiazine.  decomposidissolved  powdered  equal  distribution  4th  that  at  is  Therapeutics,  twice  the  absorbed  activity  slight  sulfisoxazole  stored  latter  is  to  when  that  of  hydrochloric  the  doses,  four  0.IN  for  concentration,  gm.  of  However,  rapidly  volume  plasma  four  and  hour..."  is  observed  reported  2% s o l u t i o n  antibacterial  but  that  (19 73)  days  Sulfisoxazole body.  Chemical structure sulfisoxazole  ethanol  for..:one  for  10.  this, of  i n i t i a l followed  i t s  equivalent dose by  of one  gm.  42  • IV.  EXPERIMENTAL  1.  (a)  Constant A  Temperature  diagram  shown  in  driven eight The 50  heads  constant  be  four  loaded  with  in  with  or  black  x  side  The  in  and  adsorption  experiments  are,  the  dark.  temperature  of  0.5°C  of  the  desired  value  glass 30  a  motor-  tank  a  is  shaft.  at  either bottles 39  is  f i l l e d  totally internal  tank  hard  is  paper  carried  top.  out  maintained  E51  r.p.m.  bottles  with  The  Haake  with  reaction  tumbler  with  is  that  rotates  cm.  tank  a  such  therefore,  the  with  is  reaction  the  f i t t e d  A l l  The  or  of  central  plastic  of a  x  the  heads  tank  equipped  tumbler  part  30 c m .  paper  of  tubes  contained cm.  consists  250 m l .  tank.  reaction  Company),  adjacent  rotating  water 59  apparatus  centrifuge  The  of  temperature  either  two  the  Tank  Colman  tubes  in  capacity.  covered  on  between  placed  dimensions  The  (Barber  centrifuge  immersed  (b)  -  Reaction  11.  tumbler  ml.  when  the  Figure  spacing  can  to  of  Apparatus  in  within  thermoregulator.  Spectrophotometers Beckman Bausch  Model and  (c)  Accumet  (d)  Damon/IEC  (e)  Centrifuge  DU  Lomb  Spectrophotometer Spectronic  220 pH m e t e r , B20-A  505 R e c o r d i n g  Spectrophotometer  Fisher  Centrifuge  Tubes  Fisher,  50 m l . ,  Fisher,  250 m l . ,  28.6  x  1 0 3 . 5 mm. p o l y c a r b o n a t e  polyethylene  wide  mouth  tubes  bottles  F i g u r e 11.  Constant temperature tank.  reaction  44  (f)  Reaction  (g)  Thomas  Bottles,  Hoover  Company,  Capillary  (h)  Wang  or  were  Temperature  procedure Wang  Laboratory,  ing-  100-2-ST3  (General  series,  between  Codeine BDH  (Canada)  U.S.P.  XVIII  substance Morphine  (Canada)  this  drug.  performed  u s -  Library,  This  Montreal,  The drug Ontario.  Identification  Procedures  XVIII  were  between  (M0P-S0 ). 4  235° t o  by  Ontario  Identification  It  melted  the U.S.P.  drug.  was o b t a i n e d It  complied  D and E  for  from  with this  237°C.  The m e l t i n g  The drug  substance was  Quebec.  B and C f o r this 4  L t d . , Toronto,  U.S.P.  Tewksbury,  and was i d e n t i f i e d  (CDN-P0 ).  was 250°C.  I n c . ,  Programme  L t d . , Toronto,  Sulfate  compounds.  (GPZ-HC1).  Limited,  Procedures  and melted  substance  the  Poulenc  Phosphate  Melting  l a  analysis  this  and Reagents  Hydrochloride"  1 9 3 ° a n d 195°C  Identificaton  i n  Lab. Inc.)  Chemicals  Chlorpromazine from  Wang  A . H . Thomas  reported  the U.S.P.  for Class  square  programme  Apparatus,  points  using  A l l least  obtained  (c)  Point  Massachusetts.  2.  (b)  Nalge  A l l melting  determined  600 C a l c u l a t o r ,  520/600  (a)  Melting  Philadelphia.  investigation Range  250 m l . , 8-250  point  was purchased  of the f r o m BDH  and was i d e n t i f i e d  by  Procedures  for  A and E  XVIII  45  Atropine was  Sulfate,  purchased  After  Reagent  from  drying  at  Grade  BDH (Canada)  120°C  The substance  U.S.P.XVIII  Identification  This  4  L t d . , Toronto,  for three  190°-194°C.  (ATP-S0 ).  hours,  i t  complied with Procedures  drug Ontario.  melted  at  the  A and D f o r  this  drug. Sulfadiazine, from  Reagent  BDH C h e m i c a l s  between U.S.P.  255° t o XVIII  Grade.  The drug  L t d . , Poole,  257°C  was  England.  and complied with  Identification  Procedure  purchased  It  melted  the  B for this  drug  substance. Sulfamerazine. Ltd.,  Toronto,  This  drug  Ontario  was purchased  and was i d e n t i f i e d  U.S.P.XVIII  Identification  The  point  melting  Sulfamethazine. Ltd., U.S.P. The  Toronto, XVIII  melting  and  Roche  this  This  Procedure substance  drug  Ontario  point  drug  This  drug  was purchased  C for this  drug.  Kaolin  N.F.  substance  This  from  Mallinckrodt  Chemical Works,  was  through  BDH(Canada)  by t h e substance.  was 196°-197°C.  Quebec.  the U.S.P.  drug.  B for this  this  cedure  screened  Procedure  of  complied with  by t h e  was 233°-235°C.  and was i d e n t i f i e d  L t d . , Montreal,  BDH(Canada)  B for this  was purchased  Identification  Sulfisoxazole. La  of  from  It  XVIII  from  melted  at  Louis,  a 250-mesh sieve  -  193°-196°C  Identification  was purchased St.  Hoffman  Pro-  from  Missouri and  before  use.  The  46  country  of  with  the  N.F.  XIII.  To  of  for  the  interfere  test  drugs,  water  a  gm.  of  end  from  solution  room  temperature).  liquldiover  by  the  the  Spectronic  was  absorbed  kaolin  this and  200 t o  It  complied  described  in  the  of  the  procedures  mixed  tube  tank  time  such  Acid,  hours  period,  the  tube  particles minutes,  in  the  at was  separated 10,000  of  the  clear  range  was  recorded  (k)  Sulfuric  (1)  Ammonium H y d r o x i d e ,  Reagent  (m)  Chloroform,  Grade.  (n)  Acetone,  (o)  Ammonium R e i n e c k a t e ,  supernatant using  radiant  energy  Reagent  Reagent  Grade.  Grade. Grade.  Grade. Matheson  Coleman  and  B e l l ,  Norwood,  Ohio. (p)  pH  1.2,  pH  1.2  3.0,  and  5.0  solutions.  solution:  Add  24 m l .  r.p.m.,  solutions.  Hydrochloric  Reagent  tumbled  No  the  40.0 ml.  two  (20  that  for  for  spectrum  (j)  Reagent  with  and  kaolin  350 nm.  substances  505 s p e c t r o p h o t o m e t e r .  by  Acid,  was  centrifugation. The  England.  analytical  reaction  tank  from  presence  centrifuge  of  the  was  procedures  the  50 m l .  the  clay  possible  temperature  At  removed  this  with  0.5  in  constant 37°C.  of  identification  check  might  origin  of  hydrochloric  d i s t i l l e d  water.  resulting  solution  Mix to  acid  to  two  well.  Adjust  1.2  further  by  the  l i t e r s pH  of  addition,  of the  47 dropwise, pH  3.0  hydrochloric  to  two  is  3.0.  5.0  hydrochloric  l i t e r s  acid,  of  d i s t i l l e d  a  0.1N 8.6  Add  solution,  this of  3.  ml.  dropwise,  d i s t i l l e d  Chlorpromazine This  drug  (i)  Spectral Prepare  a  pH  over  was  stock of  was  1  l i t e r .  s t i r r i n g pH  Procedures  for  and  Characteristics  analysed  to  two  reaches  5.0.  of  spectrophotometrically.  of of  CPZ-HCl CPZ-HCl  drug  in  of  this  solution  200 t o  the  350 nm.  were  by  100.0 ml.  spectrum  using  carried  of  to  by of  dissolving water.  1000 m l .  this  with  solution,  range,  on  the  Spectronic  water  as  the  blank.  using  maximum o c c u r s  confirmed  analysis  to  the  solution  spectrophotometer, absorbance  with  the  Record  the  acid  by  Hydrochloride  8.0 ml  water.  solution  u n t i l  Characteristics  mg.  Dilute  Subsequent  the  T e s t -.Drugs .  substance  100.0  water  Analytical  the  value  s t i r r i n g ,  u n t i l  acid  hydrochloric  Stability  This  with  water  hydrochloric  diluting  l i t e r s  An  dropwise,  solution  Prepare  (:a)  acid.  solution  Add  pH  of  at a out  254 nm.  (Figure  B e c k m a n DU at  this  505  12).  spectrophotometer.  wavelength.  0*8  0.0 ' 280  —' 270  '  «  260  250 Wavelength,  ' 240  L  230  (nm.)  F i g u r e 12. S p e c t r a l c h a r a c t e r i s t i c s o f chlorpromazine hydrochloride  (8 mg./lOOO m l . ) .  -  49  Repeat 5.0 on  the  above  solutions. the  Chlorpromazine  value  at was  (ii.)  254 n m . ,  a  Absorptivity  Value  for  solution  water. are  The  2.0,  as  to  be  nm. the  results  analysis.  5.0 The  with  Beer's  of  2 to law:  a  of  3.0,  such  and  solutions  using  the  in  the  a maximum o f  above  B e c k m a n DU  radiant  solvents.  This  spectrophotometer,  CPZ-HCl 8.0, (i)  and  10.0 ml.  above)  to  concentrations 8.0,  and  of  of  the  1000.0.ml. these  1 0 . 0 mg.  values  of  of  solutions  CPZ-HC1/1000.0  these  solutions  B e c k m a n DU . s p e c t r o p h o t o m e t e r  and  ml. at  water  blank. of  five  The  the  determinations  absorptivity error above  solutions  that  Chlorpromazine range  absorbed  absorbance  using  absorptivity  identical  (Part  6.0,  the  9 2 . 65 * ( s t a n d a r d Repeat  6.0,  f i n a l  4.0,  Determine 254  4.0,  spectra  1.2,  blanks.  dissolved using  stock  square  as  by  2.0,  pH  505 s p e c t r o p h o t o m e t e r ,  solvents  when  with  the  hydrochloride  confirmed  Dilute  The  Record  Spectronic  appropriate  energy  procedure  10 mg.  value  estimate  procedure  instead  value  in  of  of  of the  were for =  drug  CPZ-HCl  to  was  least found  0.0014).  with  water  subjected  pH as  in  1.2,  3.0  and  solvent. these  solvents  was  water.  hydrochloride per  1000 m l . ,  concentrations, were  over  calculated  by  the using  50 where  c  =  concentration  A =  absorbance  g  maximum a  s  =  of  value  drug of  value  gm./liter.  solutions  at  the  measured  in  a  absorption,  absorptivity  in  at  the  wavelength  1.0  wavelength  cm.  of  c e l l  where  A  is  s  determined. ( i i i ) S t a b i l i t y The in  this  CPZ-HCl  of  CPZ-HCl  maximum d u r a t i o n investigation in  aqueous  therefore,  was  above) of  single  about  solution  20.0 ml. into  water.  drug  nine  over  experiment hours.  this  50 m l .  The  f i n a l Stopper  in  the  constant  for  the  solution the  the  ml.  Tumble from  a  of  per  place  nine  for  The  period  this  drug  s t a b i l i t y  of  time  of  was,  at  of  value  a  characteristics value  of  for and  CPZ-HCl  maximum a b s o r p t i o n at  254 nm.  20.0  tube  reaction  tube of  for  remained  the  CPZ-HCl.  254  of  tank.  the  aliquot  ml  and  Examine  calculate  at  (i)  0 . 5 mg.  Remove  suitable range  Add  is  centrifuge  37°C.  (Part  tube.  temperature  working  wavelength  absorptivity  hours  the  to  spectral  solution  concentration  Dilute  the  stock  centrifuge  tank.  absorptivity  the  a  studied. Pipette  The  of  the  nm. the  drug  unchanged  and  after  nine  hours. It  was  substance  (at  discolored solution of  this  observed  adsorption  concentrations  after  for  during  two  mixing  with  hours,  at  discolored  solution  of 0.5  37°C. was,  studies  0.125 mg./ml. gm. The  kaolin  or  in  spectral  therefore,  that  the  drug  higher)  40 m l .  of  pH  1.2  characteristics  studied.  51 Separate  the  kaolin  particles  from  centrifugation  (10,000  r.p.m.,  temperature).  Pipette  a  clear  supernatant  solution the  to  the  spectrum  working  using  the  and  aliquot  dilute  range  by  20 m i n u t e s ,  suitable  liquid  solution  of  with  room of  pH  CPZ-HCl.  Spectronic  505  the 1.2  Record  spectro-  photometer . The remained  absorption at  254 nm.  by  measuring  at  254 and  was of  2.50  the  for  degradation  (b)  Codeine A  ion  of  pure  of  for  drug  discolored  degradation  absorbance  value,  CPZ-HCl,  be  these  extent  of  This the  of  to  The  ratio  224 nm.  and,  considered  maximum f o r  values  the  was  assessed  (Pernarowski,  discolored  solution,  under  solutions  these  was  1969)  solution,  2.62.  conditions,  The was  extent therefore,  minimal.  phosphate  spectrophotometric  procedure  was  used  for  the  determinate  CDN-P0 . 4  (i)  Spectral  Characteristics  and A b s o r p t i v i t y  Value  of  CDN-PO. 4  Weigh  10 0 . 0  of  water.  of  the  Codeine 285 a  nm.  determined  at  CDN-PC^  This  is  the  the  solution  spectrum  of  phosphate 13).  absorbs This  2 85  nm.  dissolve  solution.  100.0 ml.  this using  100.0  Dilute  water  blank.  as  the  radiant  ml  17.0  water  on  .agreed:with The  with  in  solution  a maximum o f  value  spectrophotometer.  and  stock to  spectrophotometer  (Figure  B e c k m a n DU  of  stock  record 505  mg.  ml.  and Spectronic  energy  that  found  by  absorptivity  value  was  at using  52  o-.7  r  310  300  290  280  270  Wavelength F i g u r e 13. S p e c t r a l c h a r a c t e r i s t i c s (17 mg./lOO m l . ) .  260  (nm.)  o f codeine phosphate  53  Pipette stock  5.0,  solution  Adjust  to  100.0 ml.  with  water.  Determine  of  CDN-PO^  error  of  estimate  =  Repeat  the  5.0 The maximum  values  analysis.  of  at  of  the  five  these  solutions  absorbance  was  equal  using  values  determinations,  285 nm.  to  the  to  the flasks. the  water  as  least  absorptivity  3.91  (standard  0.00075). above  procedures  with  pH  1.2,  3.0  and  solutions.  absorptivity in  of  volumetric  square  value  17.0 ml.  100 m l .  Subject  basis  14.0 and  five  blank.  the  11.0,  into  absorbance  On  8.0,  these  values,  solutions,  at  were  285 n m . ,  the  identical  absorption  to  the  value  given  above. The 50  to  concentration  170 mg./lOOO  appropriate (ii) The nine  m l . ,  numbers  S t a b i l i t y s t a b i l i t y  hours,  was  The  a  of  CDN-PO^  were  into  of  calculated  Equation  CDN-PO^ the  drug  20.0 ml.  50 m l . f i n a l  Stopper  by  over  the  range  substituting  of  the  5.  in  aqueous  solution  substance,  drug  the  the  centrifuge  suitable  aliquot and  stock  tube.  over  a  for of  nine the  record  tube  solution Add  concentration  tank,  CDN-PO.  of  centrifuge  reaction  for  solutions,  period  of  studied.  Transfer to  of  is and  hours  at  solution the  (see  20.0 ml.  0.5  mg.  tumble,  per in  (i)  of  water.  ml. the  37°C.  Dilute  to  working  spectrum  the of  the  above)  a range  solution  54 on  the  the The  Spectronic  absorptivity  wavelength  absorptivity  value  of at  505 s p e c t r o p h o t o m e t e r . value  of  the  drug  maximum a b s o r p t i o n 285 nm.  remained  at  for  Calculate  285 nm.  CDN-PO^  unchanged  and  after  the  nine  hours. (c)  Morphine (i)  Sulfate  Spectral  Characteristics  and  Absorptivity  Value  of  MOP-SO, 4 Prepare  a  stock  dissolving 17.0  ml.  record  1 0 0 . 0 mg.  of  the  285  nm.  Beckman drug  This  was  stock and  5.0,  solution  adjust  to  absorbance Subject  error  the  basis  as  of  MOP-SO  of  4 estimate  at =  Repeat  the  five  the  the  was  The at  Spectronic  Dilute and  505  spectro-  blank. radiant  confirmed  1 4 . 0 and  by  energy using  value  17.0 ml.  100 m l . with  at  a  of  these  the  least  equal  to  the flasks,  Determine  solutions to  of  volumetric  water.  determinations, was  water.  by  285 nm.  obtained  285 nm.  substance  100.0 ml.  absorptivity  five  of  of  to  a maximum of  100.0 ml.  data  drug  100.0 ml.  11.0,  into  values  the  of  5.0  8.0,  the  solution  value  determined  of  using  spectrophotometer.  Pipette  value  stock  absorbs  14).  substance  On  in  and water  sulfate  (Figure DU  the  spectrum  photometer Morphine  solution  at  285 nm.  square  the 4.02  the  analysis.  absorptivity (standard  0.00049). above  solutions.  procedures  using  pH  1.2,  3.0,  and  55  56  Absorptivity in  these The  of  50  the  to  solutions  a  s t a b i l i t y  period  of  that  to  maximum  absorption  285  remained  over  a  (d).  Atropine A  and  nine  of  by  substituting  5.  in  Aqueous  Solution  drug  in  aqueous  solution,  for  the  studied  CDN-P0 .  absorptivity  of  time,  method  based  using The  4  under  range  37°C,  method  wavelength  value  these  a  at  of  the  of  drug  experimental  at  conditions,  Sulfate  (1952)  was  used  Calibration Weigh of  calculated  above.  the  4  was  maximum  given  over  Equation  hours,  period  value  solutions,  into  the  the absorption the  were  MOP-S0  and  to  m l . ,  unchanged,  hour  285 n m . ,  MOP-SO^  described  colorimetric  Beal (i)  of  nine  similar  nm.  of  numbers  Stability  at  identical  170 mg./lOOO.O  (ii)  over  were  concentration  appropriate  The  values,  Curve  1 0 0 . 0 mg.  water.  3.0,  for  stock  7.0,  solution  Adjust  the  water.  alkaline  ATP-S0  the  stock  9.0  and  11.0 ml.  to  five  in  each  solution solution  each  and with  Collect  a  beaker  evaporate  of  0.5N  sulfuric  acid  and  dissolve  solution.  funnel  the  in  100.0 ml.  Pipette of  the  to  2 ml.  funnels.  25.0 ml. of  with  10% ammonium  extract  the  10 m l .  portions  of  chloroform  extracts  in  u n t i l and  4  separatory  immediately three  Colby  ATP-S0 .  aliquots  125 m l .  funnel,  chloroform. and  4  of  by  4  is  into  described  determination  ATP-SC>  volume  Add,  hydroxide  for  that  of  This  5.0,  the  on  nearly  then  dry.  completely  Add  5 ml.  evaporate  the of  remaining chloroform.  beaker  a 1% w/v a q u e o u s a m m o n i u m r e i n e c k a t e  Place  the beaker  Collect (fine  Dissolve  with  collect  the colored  flask.  Quantitatively  to  6 0 0 nm.  Record  range  3 x 2  this  i n acetone  the f i l t e r  i n a clean  transfer  funnel  ml. portions of  through  filtrate  10 m l . v o l u m e t r i c f l a s k acetone.  minutes.  Wash t h e  the precipitate  passing small.portions  with  forthirty  suction.  10 m l .  solution.  i n a sintered-glass  using water  and p r e c i p i t a t e  cold water. by  i n an i c e - b a t h  the precipitate  porosity)  beaker  a  Add t o each  and  suction  the solution to  and a d j u s t spectrum  t o volume over  t h e 450  u s i n g t h e S p e c t r o n i c 505  spectrophotometer. This 525 bv  nm.  (Fiqure  usinq  value  solution  absorbed  15 ) .  a maximum o f r a d i a n t  This value aqreed w i t h  a B e c k m a n DU s p e c t r o p h o t o m e t e r .  of this  The  energy  that  at  obtained  absorptivity  ATP-SO^ d e r i v a t i v e was d e t e r m i n e d  at this  wavelenath. Record at  5 2 5 nm.  Subject The found 20  the absorbance usinq  Beer's  a B e c k m a n DU  the data to least  above procedure  that  values of the five  sauare  analysis. times.  value f o rthe reineckate  o f A T P - S O . was 2.93 { s t a n d a r d e r r o r 4 procedure  I t was  and, on t h e b a s i s o f  determinations, the absorptivity  derivative  spectrophotometer.  was r e p e a t e d f o u r  Law was o b e y e d  solutions  0.0069).  The e n t i r e  substance  i n pH 1 . 2 , 3 . 0 , a n d 5.0 s o l u t i o n s .  of estimate =  was r e p e a t e d f o r t h e d r u g In the  0.4  Figure  15. S p e c t r a l c h a r a c t e r i s t i c s of r e i n e c k a t e d e r i v a t i v e of a t r o p i n e ( e q u i v a l e n t to 11 mg. a t r o p i n e s u l f a t e / 2 5 ml. acetone).  sulfate  ^ oo  case  of  pH  hydroxide  1.2  solution,  solution  of  maximum a b s o r p t i o n  unchanged  range  of  above  procedures  into  of  3 to  Equation (ii)  the  The  11 mg.  of  centrifuge  tube.  centrifuge  tube  25.0 ml.  value (e)  given  The  The pH  the  over by  the  using  appropriate  the  quantities  Add  stock  solution  into  water.  Keep  20.0 ml.  stoppered tank  from  Solution  and  tumble  for  nine  the  On  the  at  this  as  basis  of  wavelength  and above.  recorded  showed  three  Withdraw  tube  as  ml.  constant  described  derivative  50  the  the  hours.  centrifuge  derivative  reineckate  in  a  a maximum  of  determinations,  was  identical  to  the  above. -  Sulfadiazine,  Sulfamerazine,  Sulf ametha-'.  Sulf isoxazole  sulfonamides pH  5.0  this  group  of  drugs  acid  solution with  the  original  4  505 s p e c t r o p h o t o m e t e r  value  and  ml.  3.0  of  Sulfonamides  zine,  the  ATP-S0 ,  Aqueous  the  reineckate  525 nm.  absorptivity  of  aliquot  Spectronic at  of  and  to  52 5 n m .  determined  the  in  4  reaction  the  spectrum  absorption the  ATP-SC>  20.0 ml.  prepare  the  pH  of  was  substituting  temperature  using  the  at  prior  5.  Pipette  a  of  25 m l . ,  solution  derivative  4  concentration  per  and  Stability  The  ATP-SC>  irrespective  solution.  4  10% ammonium  wavelength  value  the  of  basify  absorptivity  ATP-S0  2 ml.  to  The  remained  of  used  extraction.  was  4 instead  (80  water).  have  limited  solutions. were  ml.  of  solubility  Therefore,  carried  out  hydrochloric  in  in  water,  adsorption 1:12.5  acid  made  pH  1.2,  studies  .hydrochloric up  to  1000  for  60  (i)^  Spectral of  the  Characteristics  a  stock  solution  m i d e s by  dissolving  in  ml.  100.0  Dilute  a  of  10.0  spectrum of  the  and  220  nm.,  as  using a  at  their  values  respective Pipette the  2.0,  flasks.  the  Adjust  The mides  sulfonamide, merazine,  the  on  four  drug acid  sulfona-  substance solution.  1000.0 ml.  the  the  with  Record  the  Spectronic  1:12.5  occurred  505  hydrochloric  16,  sulfamerazine,  at  17,  243,  18  maximum and  five  the  the  19).  determined  absorption. 10.0  ml.  aliquots  1:12.5  hydrochloric  absorbance value  wavelength of  the  readings  for  each of  of  volumetric  of  maximum  1:12.5 h y d r o c h l o r i c  Subject  243,  spectrophotometer.  1000ml.  volume w i t h  243,  and  a B e c k m a n DU  8.0  into  at  acid to  solution  least  analysis.  s a m e p r o c e d u r e was  studied.  of  Record  using  blank.  the  sulfonamides were  6.0,  to  solutions  square  the  solution  absorption  the  sulfadiazine,  using  4.0,  solution.  these  as  of  to  (Figures  wavelength  stock  acid  Values  blank.  sulfisoxazole  respectively.  absorptivity  of  solution.  solution  These v a l u e s were c o n f i r m e d The  acid  a b s o r p t i o n maximum f o r and  mg.  aliquot  spectrophotometer  sulfamethazine,  each of  1:12.5 h y d r o c h l o r i c  ml.  solution  of  100.0  1:12.5 h y d r o c h l o r i c  The  Absorptivity  Sulfonamides  Prepare  acid  and  On  the  used  basis  absorptivity  sulfamethazine  and  of  five  values  the  four  determinations for  for  sulfadiazine,  sulfisoxazole  were  58.82/  sulfonaeach sulfa-  61  Figure  16.  Spectral characteristics (10 m g . / l O O O m l . ) .  of  sulfadiazine  62  6,3,  64  0.6  \  0.5  0.1-  r  . 1  0  0  250  i 240  —  :  f  230  1  220 Wavelength  F i g u r e 19.  S p e c t r a l c h a r a c t e r i s t i c s of (10 mg./lOOO ml.).  1  210 (nm.) sulfisoxazole  1  200  65  57.54,  5 0 . 11  0. 0 0 0 6 8 ,  and  solutions  to  10.0  mg.  (ii)  of the per  of  The  sulfonamides, over  of  the  namide i n t o ml.  of  the  tube  tumble  tank  suitable  aliquot  tube  dilute  505  of  of  for a  the stock s o l u t i o n  a 50 m l .  reaction  spectrum  of  2.0  using Equation  of these drugs, over  centrifuge  1:12.5 h y d r o c h l o r i c  and  the range  5.  sulfonamide this  period  studied.  ml.  and  The c o n c e n t r a t i o n  adsorption study  stability  20.0  0. 0 0 0 8 3 ,  Sulfonamides  o f an  therefore,  Pipette  respectively.  ml., were c a l c u l a t e d  duration  hours.  t i m e , was,  four  1000  Stability The  two  (standard errors of estimate =  0.00054 and-0.00077).,  of  was  45.05  tube.  acid  hours  of the s o l u t i o n  the drug  substance  sulfo20.0 Stopper  temperature  a t 37°C.  t o the working  Add  solution.  i n the constant  f o r two  of a  Remove  from  range.  the  a  centrifuge  Record  the  using the S p e c t r o n i c  spectrophotometer.  None o f t h e  four  s u l f o n a m i d e s showed any  a b s o r p t i o n maxima o r change i n a b s o r p t i v i t y  shift  value at  in this  wavelength.  5.  Adsorption Characteristics Test  The of  methods used  the t e s t  drugs  were  of  The  Drugs  to study the similar.  adsorption characteristics  The  mazine h y d r o c h l o r i d e are g i v e n below  procedures as  an  for  example.  chlorpro-  66 (a)  Adsorption  Studies  Weigh  accurately  250.0  ml.of  in  250.0  water.  exactly  35.0  40.0 ml.of  50  ml.  0.5 tube  in  the  and  at  temperature). a  suitable  make  aliquot  appropriate  concentration drug the  of  substance f i n a l  from  Remove  the  10,000  Calculate  of  i n i t i a l l y  by  each  tubes. tank the  from  solution  r.p.m.,  room  tube,  pipette solution,  the  the  amount  of  subtracting  remaining  present.  of  from  determine  kaolin  CPZ-HCl  the  supernatant  CPZ-HCl. onto  exactly  tubes  and  30.0.  volume  particles  clear  in  eight  reaction  centrifuge  the  25.0, to  stopper  dilutions  bound  amount  that  liquid  temperature  each of  20.0,  containing  (20.minutes,  From  dissolve  solution.  solution  the  kaolin  and  stock  15.0,  water,and  the  centrifugation  the  each  37°C.  separate  CPZ-HCl  stock  Adjust  constant  hours  is  tubes,  kaolin.  Solution  of  10.0,  the  40.0 ml.with  two  tank by  of  to  Tumble for  5.0,  centrifuge  gm.  mg.  This  Transfer and  Aqueous  in  Determine  solution the  adsorption  isotherm. (b)  Adsorption Weigh  accurately  in  about  pH  of  220  pH  the  the  in  of  resulting  meter by  and  pH  addition  to  1.2, of  1.2  250 m l .  with pH  1.0N  solutions. a  and  the  value  5.0  and  solution.  the of  3.0  CPZ-HCl  solution  adjust  hydroxide  solution  pH  250 mg.  100 m l .  necessary, sodium  Studies  dissolve  Measure  the  Accumet to  1.2,  hydrochloric  Quantitatively  volumetric  Solution  flask,  if or transfer and  adjust  67 to volume with pH solution. 25.0,  1.2  solution.  T r a n s f e r e x a c t l y 5.0,  30.0,  35.0,  and  40.0  ml.  T h i s i s the  stock  10.0,  20.0  15.0,  of the stock s o l u t i o n  to e i g h t 50 ml. c e n t r i f u g e tubes each c o n t a i n i n g e x a c t l y 0.5  gm.  of k a o l i n . A d j u s t the l i q u i d volume  of each tube to 40.0 tumbling  and  ml. with pH  1.2  solution. After  c e n t r i f u g i n g the tubes i n the manner  d e s c r i b e d above, p i p e t t e a s u i t a b l e a l i q u o t of c l e a r supernatant  l i q u i d and measure the  Record t h i s value as the pH  the  pH.  f o r the a d s o r p t i o n  pro-  cess. MMake a p p r o p r i a t e d i l u t i o n of the a l i q u o t w i t h pH  1.2  s o l u t i o n and determine the c o n c e n t r a t i o n  CPZ-HCl i n the supernatant  liquid.  C a l c u l a t e the  amount of drug adsorbed on k a o l i n and determine a d s o r p t i o n isotherm. using pH The had  3.0  Repeat theciabove  and pH 5.0  i n water, pH  solutions.  1.2,  t i o n s , were s t u d i e d i n 1:12.5 HC1  the  procedures  a d s o r p t i o n c h a r a c t e r i s t i c s of the sulfonamides,  low s o l u b i l i t y  of  pH  3.0,  solution.  and pH 5.0  which solu-r .  The procedures were  s i m i l a r to t h a t used f o r s t u d y i n g a d s o r p t i o n of CPZ-HCl from aqueous s o l u t i o n .  For the other t e s t drugs, namely, codeine  phos-  phate, morphine s u l f a t e , and a t r o p i n e s u l f a t e , a d s o r p t i o n s t u d i e s were c a r r i e d , out i n a manner s i m i l a r to t h a t d e s c r i b e d f o r CPZ-HCl.  D i f f e r e n c e s ' noted with r e s p e c t to d u r a t i o n f o r  a d s o r p t i o n e q u i l i b r i u m w i l l be r e p o r t e d i n the next s e c t i o n .  6.  Desorption T e s t Drugs  C h a r a c t e r i s t i c s of the  68  The  conditions  pre-determined No  f o r d e s o r p t i o n s t u d i e s were based  adsorption characteristics  d e s o r p t i o n s t u d i e s were c a r r i e d  because they For  showed no  the other four  conducted  i n water  water  added  its from  was  fullest  test  drugs,  a t 37°C.  capacity,  drug.  an  The  f o r every test  Preparation  of Sample  a stock solution  exactly  100  of water. a  50 m l .  0.5  gm.  40.0 in  T r a n s f e r 15.0  of k a o l i n .  for  CPZ-HCl.  tube  from  tion  study.  At  The  Samples of o t h e r drugs Differences  in initial  equilibrium w i l l  be  ml  substance of the  Stopper  of  reaction  this  samples,  prepared  as  volume and  until hours  remove  immediately begin the  in a similar time  to  tumble  i s two  period,  to  exactly  tank  which  c o n c e n t r a t i o n and  ml  stock solution  the tube  reported i n the next  Four  i n 100.0  liquid  were p r e p a r e d  Desorption Studies  dissolving  Adjust the  and  (b)  Similar  desorption pro-  contains  t h e end  drug  removed  below.  equilibrium,  the tank  to  o f C P Z - H C l by  the constant temperature reaches  adsorbed,  tube which  ml. w i t h water.  adsorption  of  determined.  drug.  of the drug  centrifuge  had  amount  for Desorption Studies  Prepare  mg.  were  amount o f d r u g  f o r CPZ-HCl i s d e s c r i b e d i n d e t a i l  (a)  drugs.  kaolin.  excess  which  the  sulfonamides  desorption studies  r e s p e c t t o t i m e was  procedures were used  tion  f o r the  In general,  a test  the t e s t  a d s o r p t i o n on  t o a sample of k a o l i n  the k a o l i n with  cedure  significant  out  of  on  the  desorp-  manner.  f o r adsorp-  section.  d e s c r i b e d above, were  used  69 for  the desorption experiment.  One w a s c e n t r i f u g e d  10,000 r.p.m., room t e m p e r a t u r e ) assayed tank. was  and t h e supernatant  f o r CPZ-HCl immediately a f t e r The amount  o f drug  (20 m i n u t e s ,  adsorbed  removal  on k a o l i n  from  liquid  the reaction  was c a l c u l a t e d a n d  taken as t h e zero-time d e s o r p t i o n value. Quantitatively  transfer  250 m l . r e a c t i o n Add  t h r e e samples  bottles  160.0 m l . o f w a t e r  labelled  t o each  liquid  v o l u m e t o 200.0 m l .  bottle  and tumble  tion at  tank  a t 37°C.  fuge  The ATP-S0 . 4  reaction  Remove t h e b o t t l e  amount  centrifuge  o f drug  (20 m i n u t e s ,  4  hundred m l . o f t h e c l e a r  for  t h e assay  o f t h e drug  reac-  t h e tank  Pour  appro-  a 50 m l . c e n t r i -  f o r CPZ-HCl.  r.p.m., Determine  t o CDN-PO^, MOP-SO^ a n d content ofthe  t o a 200 m l . c e n t r i f u g e  (20 m i n u t e s ,  One  from  10,000  experiments, the t o t a l  was t r a n s f e r r e d  T h i s was c e n t r i f u g e d  stopper the  r e m a i n i n g on k a o l i n .  same p r o c e d u r e s w e r e a p p l i e d I n the ATP-S0  t o adjust the  time period.  40 m l . o f t h e c o n t e n t s i n t o  tube,  bottle  bottle  Immediately  room t e m p e r a t u r e ) , and a s s a y the  1,3, a n d 6 h o u r s .  i n the constant temperature  t h e end o f t h e l a b e l l e d  ximately  t o three  10,000 r.p.m, room  supernatant l i q u i d  substance.  was  tube.  temperature). withdrawn  70 .V. Adsorption  i s an e q u i l i b r i u m  time must, t h e r e f o r e , valid  R E S U L T S AND  1.  Equilibrium  Preliminary  process.  be d e t e r m i n e d  adsorption studies  DISCUSSION Equilibrium  before experimentally  c a n be c a r r i e d o u t .  Time  studies  f o r the Adsorption  indicated  that  the sulfonamides  are not adsorbed  by K a o l i n .  equilibrium  s t u d i e s were n o t n e c e s s a r y .  an  time  aqueous s t o c k s o l u t i o n  pared.  Therefore, f o r these  containing  S e v e n 40.0 m l . a l i q u o t s  transferred 5 0 0 . 0 mg.  t o seven  The t u b e s  1 5 m i n . , 30 m i n . , 1 h o u r , labelled  0 m i n . was  were  2 hours  immediately  assayed  kaolin  was  adsorption manner  drug  calculated value.  after  reaction  tank  adsorbed  Table  f o r CPZ-HCl.  The  a n d was  drugs,  For CPZ-HCl,  mg./ml. was  pre-  of the stock solution tubes, each  labelled  were  containing  0 min., 6 min.,  and 4 hours.  The  tube  c - e n t r i f u g e d (20 m i n . ,  10,000 r.p.m., room t e m p e r a t u r e ) . then  0.5  50 m l . c e n t r i f u g e  of kaolin.  Process  The  amount  supernatant of drug  fluid  adsorbed  was  by  c o n s i d e r e d t o be t h e z e r o - t i m e  The o t h e r t u b e s  they had been tumbled f o r the labelled  were t r e a t e d  i n a  i n the constant  periods of time.  by k a o l i n w i t h r e s p e c t t o time  similar  temperature  The  amount  of  i s shown i n  1. These r e s u l t s  takes within  show  place rapidly, 15 m i n u t e s .  that  a d s o r p t i o n o f CPZ-HCl by  adsorption being essentially  kaolin  complete  However, f o r e x p e r i m e n t a l p u r p o s e s ,  a two-  71 Table  1.  The e f f e c t o f . t i m e on t h e amount o f chlorpromazine h y d r o c h l o r i d e * a d s o r b e d p e r gm. o f kaolin.  Time  of Tumbling (min.)  Mg. Gm.  Adsorbed Kaolin**  0  15 . 7 8  6  15.97  15  16.69  30  16.64  60  16.69  120  16.69  240  17.08  * I n i t i a l concentration: 0.5 * * C a l c u l a t e d on t h e b a s i s of  hour  time  similar after or  fore,  and  solutions used  as  chosen showed  for that  CPZ-HCl  had  for  hours  the  two  adsorption  studies.  no  adsorption  been  equilibrium  .  mg./ml. two d e t e r m i n a t i o n s .  further  equilibrated This  time  time  for  in  Further,  pH  period  occurred 1.2,  was,  adsorption  3.0  there-  studies  in  solutions. Similar  CDN-PO are  was  experiments  kaolin  5.0  such  period  per  4  ,  MOP-SO., 4  given  indicate minutes  in  for  used which  in to  4  each  ,  a l l study  was  the  time  of at  and  2,3,  the  and  subsequent  same  test  and  results  were  used  of  by  by  Ridout  for  these  studies  These  results  to  within  allow  mixtures  of  equilibrated  studies.  ATP-SO^  out  attained  However,  CDN-PO. were 4  of  carried  intervals,  adsorption  that  were  respectively.  drugs.  time  adsorption as  4,  The  conditions  shorter  kaolin  the  studies  ATP-SO.. 4  equilibrium  errors  and MOP-SO  and  Tables  that  possible  hours  equilibrium  The  30  for kaolin for  two  time-period  kaolin (1968a) .  was The  45  minutes  same  72  Table  2. T h e e f f e c t o f t i m e o n t h e a m o u n t o f c o d e i n e a d s o r b e d p e r gm. o f k a o l i n . Time o f Tumbling (min.)  Table  3.  Mg. Gm.  Adsorbed per Kaolin**  0  8.87  10  9.45  20  9.23  30  9.34  60  9.13  12 0  9.10  240  9.13  The e f f e c t o f t i m e on t h e amount o f m o r p h i n e a d s o r b e d p e r gm. o f k a o l i n .  Time o f T u m b l i n g (min.)  Mg. Gm.  sulfate  Adsorbed per I Kaolin**  0  9.83  10  10.29  20  10.58  30  10.53  60  10.45  120''  10.48  240  10.52  **Calculated  phosphate  on t h e b a s i s  o f two  determinations.  73 Table  4.  The e f f e c t o f t i m e on t h e amount o f a t r o p i n e a d s o r b e d p e r gm. o f k a o l i n .  Time o f T u m b l i n g (min.)  Table  5.  Mg. Gm.  sulfate  Adsorbed per Kaolin**  0  8.67  10  10.48  20  10.76  30  10.80  60  10.50  120  10.26  240  10.31  The e f f e c t o f t i m e on t h e amount o f c h l o r p r o m a z i n e h y d r o c h l o r i d e * a d s o r b e d p e r gm. o f k a o l i n .  Time o f T u m b l i n g (min.)  Mg. Gm.  Adsorbed per Kaolin**  0  17.18  6  18.13  15  18.44  30  18.61  60  18.13  120  18.39  240  18.61  *Initial  concentration:  **Calculated  on t h e b a s i s  .  1 mg./ml. o f two  determinations.  equilibrium  times were used  3.0  solutions.  and  5.0  Since range  a d s o r p t i o n s t u d i e s were c a r r i e d  of drug  variable purpose  on  of t h i s E^O  f o r the  used.  concentrations,  the e q u i l i b r i u m  CPZ-HCl/ml. used  The  was  results  on  the  with  of  15 m i n u t e s  test  drugs  i n pH  over  time  that  1.2  wide  this  investigated.  For  containing  1  same p r o c e d u r e s solutions  the e f f e c t  the  mg.  as  those  were  adsorption equilibrium  and  5.  was  of concentra-  i s minimal.  desorption characteristics  are herein  a  study are reported i n Table  that  a d s o r p t i o n and  The  out  of  t h e more d i l u t e  such  the e q u i l i b r i u m  The  t i m e was  prepared.  indicate  reached w i t h i n  the e f f e c t  study, a stock solution  studies  These r e s u l t s  tion  for adsorption studies  d i s c u s s e d on  a drug  to  of  drug  basis.  2. (a)  Adsorption Characteristics The  standard  format  throughout  the  k a o l i n was  a r e shown i n T a b l e  used  calculated  i n solution  present.  For  an  was  initial  for recording  investigation.  remaining  liquid  i n Aqueous  Solution  d a t a f o r t h e a d s o r p t i o n o f CPZ-HCl by  aqueous s o l u t i o n s  by  Chlorpromazine Hydrochloride  from  2.0  this  amount o f d r u g  subtracting  ml.  the  the c e n t r i f u g e  adsorbed  t h e amount o f  from  of the  CPZ-HCl c o n c e n t r a t i o n of  being  from  adsorption data  at equilibrium  example,  removed  by  The  6,  kaolin  that  clear  initially  supernatant  tube which  20.0  drug  mg./40.0  contained ml.  Table 6. A d s o r p t i o n data f o r chlorpromazine  I n i t i a l Concentration (mg./lOOO ml.)  Equilibrium C o n c e n t r a t i o n (C) (mg./lOOO ml.)  h y d r o c h l o r i d e by k a o l i n * .  Mg. Adsorbed per Gm. (x/m) ± range  C/(x/m)  125  11.51  9.08+0.08  1.27  250  61.52  15.08+0.10  4.08  375  178.09  15.75±0.35  11.31  500  293.04  16.5610.22  17.70  625  412.03  17.04±0.26  24.18  750  536.07  17.12+0.35  31.32  875  655.51  17.56±0.78  37.33  1000  776.40  17.89±0.26  43.40  *500 mg. o f k a o l i n were suspended i n 40.0 ml. o f drug s o l u t i o n i n water a t a temperature o f 37°C. C a l c u l a t e d values are based on three determinations.  The a l i q u o t was metric  flask.  s o l u t i o n was meter.  diluted  with water  The a b s o r b a n c e v a l u e recorded  The r e s u l t  using  of three  a r a n g e o f ± 0.005.  value, into  yields  5,  value  and t a k i n g i n t o  The amount o f d r u g  of drug  amount o f d r u g fore,  equal  calculated 0.22  was  adsorbed  adsorbed  account  mean  nm. factor,  o f 293.04  Therefore,  mg./  b y 5 0 0 . 0 mg.  20-11.72 =  of kaolin.  of kaolin  The r a n g e o f t h i s  (^) w a s , x/m  The there-  value,  f r o m t h e r a n g e o f t h e mean s b s o r b a n c e  20.  On  the basis of Equation  of  C/(x/m) v e r s u s  of  0.9996 was adsorption  cally,  C,  a straight  obtained. isotherm  o f t h e L2 t y p e ,  co-workers ; (1960).  this  straight  were  found  monolayer and  absorbance  value i s  mg.  Figure  his  0.543  i n 40.0 m l . o f  A graphical representation of the data  the  were  the dilution  (C) v a l u e  remaining  b y o n e gm.  t o 1 6 . 5 6 mg.  this  of  o f C P Z - H C l a t 254  s o l u t i o n w a s , t h e r e f o r e , 1 1 . 7 2 mg. 8.2 7 mg.  this  spectropho-  a mean v a l u e  an e q u i l i b r i u m c o n c e n t r a t i o n  1000 m l .  of  independent determinations  Substituting  and t h e a b s o r p t i v i t y  Equation  a t 2 5 4 nm.  t h e B e c k m a n DU  - 0.538, 0.547, a n d 0.544, g i v i n g with  t o 100.0 m l . i n a v o l u -  line  line  ( F i g u r e 21)  i s shown i n  4, t h a t i s , a with  a correlation  This  indicates that  i s o f t h e L a n g m u i r t y p e , more based  on t h e c l a s s i f i c a t i o n  The s l o p e  (that i s , l / a  a n d 1/ab  equal  specifi-. and  of  i n Equation 4),  (a),i s , therefore, equal  the adsorption coefficient.(b),  factor  of Giles  and i n t e r c e p t v a l u e s  t o be 0.0554 a n d 1.0796, r e s p e c t i v e l y . capacity  plot  The  t o 1 8 . 0 6 mg./gm.,  t o 0.051  liter/mg.  25  0  I  0  1  i  i  100  200  300  i  400  i  500  »  600  E q u i l i b r i u m Concentration  »  1  700  «  800  (mg./lOOO  900  1000  ml.)  F i g u r e 20. A d s o r p t i o n isotherm at 37°C f o r chlorpromazine h y d r o c h l o r i d e by k a o l i n suspended i n water. E q u i l i b r i u m pH of suspension: 5.8.  -j  50 r  0  1  ' 100 1  0  « 200  • 300  *  a  •  •  •  400  500  600  700  800  E q u i l i b r i u m Concentration F i g u r e 21. Langmuir isotherm a t 37°C f o r chlorpromazine suspended i n water.  •  *  900  1000  (mg./lOOO ml.) h y d r o c h l o r i d e by k a o l i n  00  79 Sorby by  and  k a o l i n and  for  the  drug  Plein found  is  of  t o be  cannot account adsorptive  Several  only  8.53  (1946) n o t e d  ). T h i s  two-fold  of  kaolin.  samples of  I t was  amount t o Martin  samples of  from  18%  minutes. these  231.0  to  of  mg.  25.0  the  s o l u t i o n were adsorbed  per  by  one  and  Plein  t h e r e f o r e , be  chemical  investigations.  of  gm.  0.04%  the  therefore, in  influence and  Gupta  markedly gm.  each  methylene  blue  that  8.0  to  gm.  a  8.5.  amount o f  samples of  the  In  of  of  neglianother  eight  different  mg./ml.  histamine  in this of  a  Under these  portions  of  adsorption  2.5  capacity values  a reflection the  each of of  in  of  adsorbent.  of  that obtained  p r o p e r t i e s of  of  portions  initial  difference i n adsorptive (1961) and  size,  reported  gm.  ml.  The  could,  a  from s o l u t i o n  k a o l i n samples v a r i e d from  s o l u t i o n a t pH  42%  effect,  Mukherjee  ml.  (1954) a d d e d one  kaolin to  hydrochloride  solutes  T h e y : r e f l u x e d 0.05  solution  on  However,  kaolin differed  25.0  methylene blue  used  values.  composition.  f o r 30  kaolin.  d i f f e r e n c e observed  seven k a o l i n samples w i t h  study,  of  CPZ-HCl  kaolin  authors  study.  adsorption  of  of  mg./gm. o f  adsorption  (page 9  capacity  that  mineral  gible  capacity  factors, including particle  adsorptive  their  adsorption  adsorptive  the  small  capacity  the  i n v e s t i g a t i o n , these  on  f o r the  studied  the  f o r the  temperature  expected  the  present  termperature  effect  that  s u b s t a n c e was  Compared t o the lower  (1961)  histamine  conditions,  chloride in  these  k a o l i n samples; „  reported  by  Sorby  present i n v e s t i g a t i o n  inherent  k a o l i n used  physical i n the  and  two  80 Khalil  and  interaction  of  Moustafa  s i x adsorbents,  anticholinergic their  (1973)  results,  drugs, the  and  p o s i t i v e charges  molecules  i s perhaps  take the  place."  They  localized  responsible get  claimed on  the  a primary  varying  Since  On  "the  nitrogen  that  the  degrees  the  basis  of  of these  for adsorption "the  to which has  several  presence  nitrogen  chlorpromazine  with  atoms of  requirement  p o s i t i v e c h a r g e on  adsorbed."  that  further suggested  f o r the  adsorption  including kaolin,  tranquilizers.  authors  localized  i n v e s t i g a t e d the  to  magnitude a t o m s may  the  a pK  of be  compounds  value  of  9.2  a to  9.3,  CPZ-HCl i s present  a q u e o u s s o l u t i o n (pH the be  side chain  charged (b)  kaolin surface  was  The  pH  values  the  course  this an  to pH  used  of  pH  of  the  may  interfere  the  7  The  to prepare  the  an  adsorption  1.5  pH  the  chlorpromazine  pH  mixture  was No  of  1.2,  adsorption  as  medium,  adsorption  chloride,  sulfate,  and  citrate  uptake  crystal  by  on  cation  the  3.0  may  negatively  the  3.0  and  and  5.0  found to the  kaolin  are  the  being  liquid  to  of  of for  the  maintain  buffering  For  ions  example,  known t o  (Armstrong  during  In view  e q u i l i b r i u m pH  process.  ions  solutions.  increase  supernatent  because  Solution  increase  solution.  the  5.0  gastrointestinal  systems were used  the  violet  5.0  the  taken  buffer  to  1.2,  experiment,  u n i t s i n pH pH  in  ).  s o l u t i o n s were  final  form  p o s i t i v e charge  adsorbate  with  of  ionic  a c i d , a c o n s t i t u e n t of  process.  the  (page  these  change,  adsorption  atom o f  of  about  adsorption  5.8).  C h a r a c t e r i s t i c s i n pH  Hydrochloric fluid,  to  i n the  f o r a t t a c h i n g the  Adsorption  equal  equal  nitrogen  responsible  mainly  and  affect  the  Clarke,  81  1973). in  Since  the  amount o f  contribute of  chloride ions  the  to  test  chloride ions  the  drugs  the  same a u t h o r s  the  adsorption  of  the  valency  the  chloride  i o n on  minimal. tics  of  of  probably  due  Figure f r o m pH  1.2,  f r o m pH  3.0  solution The  and  and  Freundlich  C.  The  0.455 a n d vairous  pH  profile  of  drugs  5.0  pH)  Hence, the  the  test  drugs  above mentioned  adsorption  5.0  1.240.  pH  of  solutions.  of  should  be  solutions  C P Z - H C l by  Adsorption to  Langmuir adsorption i n pH 24).  1.2 A  f o r the The  media,  adsorption from  6.1.  are  of  1.2  are of  to  3.1  rather  the  relatively  solution.  The  i s of  against  are  1/n  f o r CPZ-HCl 7.  4  and  high  in 22,  when  in  adsorption  ATP-SO^  degree of  adsorption  =  Figure  increased -  the  obtained  i n Table  then  23).  (Figure  is plotted  u n i q u e pH  4  is  aqueous  k a o l i n decreased  and  C D N - P 0 , MOP-SC>  from  equation  summarized  CPZ-HCl  however,  constants  CPZ-HCl by  of  equation  straight line  Freundlich  kaolin  that  solution,  adsorption  1.2  This  i s c a u s e d by f r o m pH  effect  with  differences i n adsorption characteris-  i n the  (Figure  (adsorption  CPZ-HCl  of  interference in  k a o l i n decreases  solutions i s similar  changed of  ion.  However,  effects.  and  adsorption  was  may  solutions.  magnitude of  s u b s t a n c e by  adsorption the  and  the  interfering  constants  k =  solutions  with  a basic  3.0  f a c t o r = 0 . 9 9 8 5 ) w h e n l o g x/m  shows t h a t t h e the  that  isotherm  type  (correlation log  noted  obeys the  adsorption  s o l u t i o n s used  5.0  1.2,  shows t h e  3.0  difference  i n pH  t o pH 22  i n the  a  adsorption -characteristics  the  test  adsorption,  d i f f e r e n c e s i n the  Therefore, the  affect  of  increases adsorption drug  from  Equilibrium  Concentration  (mg./lOOO  ml.)  F i g u r e 22. A d s o r p t i o n isotherm a t 37 C f o r chlorpromazine h y d r o c h l o r i d e by k a o l i n suspended i n pH 1.2 (—& — ), pH 3.0 ( • ) , and pH 5.0 (Q) s o l u t i o n s . E q u i l i b r i u m pH of suspensions: 1.2, 3.1, and 6.1 " r e s p e c t i v e l y . A d s o r p t i o n from pH 1.5 s u l f u r i c a c i d s o l u t i o n r e p r e s e n t e d by ^ •  •«  0  100  200  300  400  500  Equilibrium  •  — I  600 Concentration  •  700  800  1  I  900  100  (mg./lOOO ml.)  F i g u r e 23. Langmuir isotherm at 37°C f o r chlorpromazine h y d r o c h l o r i d e by k a o l i n suspended i n pH 3.0 (O), and pH 5.0 (O) solutions.  1.5  0.5  I 1.0  •  t  1.5 log(Equilibrium  .  2.0 Concentration  »  2.5 i n mg./lOOO  F i g u r e 24. F r e u n d l i c h isotherm at 37°C f o r chlorpromazine k a o l i n suspended i n pH 1.2 s o l u t i o n .  3.0 ml.)  hydrochloride  by  00  Table  7. A d s o r p t i o n o f chlorpromazine  Adsorption Medium  Equilibrium. pH  Adsorption Isotherm  '  5.8  Langmuir  pH 1.2 s o l u t i o n -  1.2  Freundlich  water  h y d r o c h l o r i d e by k a o l i n a t 37 C.  Langmuir Constants a b mg./gm. liter/mg. (mM o f base (liter/mM of per gm.) base)  18.06 (50.83)  —  0.051 (18.12)  —  Freundlich Constants 1/n  k mg./gm.  —  —  0.46  1.24  pH 3.0 s o l u t i o n  . , 3. 1  Langmuir  13.25 (37.29)  0.044 (15.63)  —  —  pH 5.0 s o l u t i o n  6.1  Langmuir  18.89 (53.16)  0.041 (14.57)  —  —  pH  1.2  s o l u t i o n i s lower  concentrations  but higher  concentrations. adsorption  than  of  by t h e s e  sodium ions  applied  sulfuric  acid  study  s o l u t i o n (the data  22  ).  kaolin  system under  by k a o l i n f r o m  interest.  no  to that  i n pH  for this i n pH  1.2  1.2  conditions  1.5  are plotted  solution i n CPZ-HC1-  theoretical effect  i o n s were c a r r i e d o u t .  Two  f o r t h e drug were  approaches have been used  characteristics  of a drug-adsorbent  consists of repeatedly  system w i t h  method  a  of the drug  f u r t h e r i n v e s t i g a t i o n s on t h e  studies  (Sorby,  be  Further,  of the  i s of  Desorption  drug  sodium  hydrochloric  study  C h a r a c t e r i s t i c s o f CPZ-HCl  method  of  cannot  the behaviour  Desorption  water.  explana-  o f C P Z - H C l f r o m pH  E l u c i d a t i o n of the behavior  However,  0.10N  competition  investigation.  isotherm  these  f o r the  and t h e e f f e c t  that  points  Figure  of  sites  a c i d s o l u t i o n s showed  higher  observed  on t h e  on t h e a d s o r p t i o n  solution i s similar  other  was  at  drug  e t a l . , 1966b).. The  based  to the present  the adsorption  (c)  (Sorby  authors,  alongside  of  from water  situation  f o r adsorption  directly  this  that  a t low  on t h e p h y s i c a l p r o p e r t i e s o f t h e d r u g  preliminary  in  from water  of promazine hydrochloride  given  chloride  than  A parallel  sodium c h l o r i d e s o l u t i o n s tion  that  t o study  system.  washing  the  fresh aliquots of adsorption  released  i n each e l u t i o n  1965; K h a l i l requires  step  and M o u s t a f a ,  carried  out i n  the  The  desorption  elution  adsorbent-adsorbate  medium.  The  amount  i s then c a l c u l a t e d  1973).  t h e a d d i t i o n o f an e x c e s s  The  high  amount  of  dilution adsorption  87  medium  to  released Levy,  the  latter  rate  the  drug  of  The the  the  from  amount  drug  1965; Tsuchiya  and  information  with  desorption  process,  was  for  the  was  added  hundred  analytical the  saturate for  be  reduced  to  if  desorption  a  of  of  mg.  where  water  The  to  amount  time  was  the  sample  respect  of  then  amount shown  of in  equilibrium  this  Table in  less  to  obtained  mg.  of  large  by  study  that prepare  would  desorbed, to  be  from  (Figure  kaolin  determined  conditions,  equilibrium  was  con-  20).  equilibrating  in  (page  40.0  ml.  68)  manner.  retained 8.  used  CPZ-HCl  180 m g . / l i t e r ,  desorption  CPZ-HCl  an  drug  medium  sufficiently,  at  of  drug  a d s o r p t i o n .of  500.0  in  of  be  maximum  such  adsorption amount  be  was  Under  saturation  for  achieve  adsorbate  the  would  with  was,therefore,prepared  reached  of  concentration  the  concentration  CPZ-HCl The  is  in  approximately  15.0  time  adopted  k a o l i n must  To  studies.  drug  reaches  from  used.  i n i t i a l  example,  equilibrium  The  respect  kaolin with  occured,  This  water.  procedures  level  kaolin  of  ml.  mixture.  desorbed  desorption  For  centration  drug  the  concentration  by  sixty  drug-kaolin  lowest  the  detected.  and  kaolin with  of  sample  to  of  provides  One  the  of  (Sorby,  amount  .  sensitivity,  water  followed  The  which  equilibrated  released  would  is  method,  study.  determined  by  time  system.  1972).  present to  adsorbent-adsorbate  with  The to  an  The than  on  kaolin with  r e s u l t : shows t h a t six  hours.  The  respect desorption  amount  of  88 Table  8 Effect of f i v e - f o l d d i l u t i o n of chlorpromazine h y d r o c h l o r i d e - k a o l i n s u s p e n s i o n w i t h w a t e r on chlorpromazine hydrochloride adsorption.  Time  (hours)  13.72  1  12.84  3  12.54  6  12.50  drug  r e t a i n e d on  12.50  mg./gm. o f remains  obeys the  (see  can  (*) m  where a and T  gives that of  2  =  kaolin  basis at  on  one  C P Z - H C l on  (0.5ab +  the  end  determinations.  of  this  theoretical  gm.  of  0.2  Langmuir  amount o f  adsorption  a =  the  two  kaolin  time period  amount o f  (-j) , i f the  is  drug  adsorption  isotherm,  and  process  is  using  the  following  equation  + bT)  - + m  abT  (Eq.  derivation):  total  12.49  obtained  -  of  The  calculated  are  i n the  substituting  be  for  b  i s the  present  the  adsorbent.  adsorbed  Appendix  0.5b  and  the  on  Langmuir a d s o r p t i o n  reversible,  Remain Adsorbed Gm. Kaolin*  0  *Calculated  that  Mg. per  18.06, b mg.  drug  =  Comparing  this  i s completely  the  T == 15  that  for  the  reversible.  6)  drug  and  free,  equation  theoretical  indicates  test  adsorbed  Solving  0.051, and  0  f o r the  i n mg.,  system.  experimentally kaolin  constants  =  by  CPZ-HCl,  value  to  adsorption  89 (d)  Adsorptive  Interaction  of  CPZ-HCl  and  If  the c l i n i c a l  administration (25  mg.),  between of  be for  s i t u a t i o n of a patient  of normal therapeutic  t h e s e two  t h e CPZ-HCl  ( 6 gm.),  drug  dose  (P) t h a t  using  an a d s o r p t i v e  will  i n 40.0  be  occur.  -  2  ( 6 a b + 0.04  mg.  After  solving  + bS)P +  equation  6ab =  reach  98.91%  adsorbed  equilibrium.  and k a o l i n  i n pH  3.1  respectively.  i t was  cent  6 gm.  of  solution  can  ( E q . 7)  The  values  and  corresponding  6.1  These  solutions values  f r o m 40 m l .  t o 100 m l . r e d u c e s  adsorbed  t o 97.73%;  a tenrfold increase  that  same a u t h o r  f o r the  the  drug  and:  insensitive to  In water,  a  volume  percentage  i n volume,  the desorption  proceeded quickly  three minutes.  i s allowed  t o 400  91.64%.  (1965) n o t e d  hydrochloride within  to  medium volume.  of the  a r e 98.37%,  are quite  dose  f o r CPZ-HCl  99.08%  process  increase  changes .this v a l u e  values  i f the adsorption  i n adsorption  Sorby  and S i s t h e  shown t h a t  changes  the  per  (see Appendix  0  substituting the appropriate  the equation,  d o s e w o u l d be to  The  a d s o r b e d by  where a and b a r e t h e Langmuir c o n s t a n t s  and  CPZ-HCl interaction  ml. o f aqueous  the following  the  derivation):  bSP  in  Doses  requires  doses of  s u b s t a n c e s may  equilibrium,  calculated  Therapeutic  Kaolin  and k a o l i n  kaolin,at  between  and  of promazine  equilibrium  However, i n a l a t e r  and L i u (1966a) o b s e r v e d  was  i n vivo  that  the  reached study,  urinary  ml.  90 level  of  after  administering  in  promazine  divided  doses,  hydrochloride 50 m g .  of  an  of  attapulgite  per  large  quantity  adsorbent,  investigation, dose.  was  Therefore,  possible CPZ-HCl  that may  the  f l .  able on  oz.)  to  the  drug  to  a  adsorb  basis  with  and  mixture  to  most  of  of  their  reduced  f l .  oz.,  (containing  subject.  that  used  the  This in  between  absorption  of  this  administered  observations,  interaction  the  2.5  human  similar  adsorptive  interfere  the  significantly  antidiarrheal  4 gm.  of  was  the  i t  is  kaolin drug  and  in  vivo.  3.  (a)  Adsorption The  aqueous in  data  between  =  A  C/(x/m)  values  =  is  given  this  C  Codeine  in  Aqueous  of  Table  (correlation  i s ,  CDN-PO^ 9 and  by  kaolin  shown  (see  Figure  26)  therefore,  of  Langmuir  calculated  from  line,  liter/mg.  are  the -  a  value  0.9906).  slope  The type.  and  intercapacity)  b(adsorption  liter/mM of pK  exists  a(adsorptive  base/gm.);  (3.5  with  the  from  graphically  =  mM o f  phosphate,  Solution  factor  straight  (30.26  0.0085  in  relationship  constants, of  Phosphate  adsorption  linear and  12.30 mg./gm.  cient)  the  isotherm  Langmuir  cept  for  25.  adsorption The  Characteristics  solution  Figure  Codeine  of  c o e f f i -  base). 9.9,  w i l l  be,  to  a a  significant  (pH  =  5.9).  codeine the  extent, The  cation  negatively  in  positive  (see  the  charge  section  charged  ionic  on  kaolin  on  form the  Theory) surface.  in  aqueous  nitrogen should  be  solution  atom of adsorbed  the onto  T a b l e 9 . A d s o r p t i o n data f o r codeine phosphate by k a o l i n * .  I n i t i a l Concentration (mg./lOOO ml.)  Equilibrium C o n c e n t r a t i o n (C) (mg./1000ml.)  Mg. Adsorbed per Gm. (x/m) ± range  C/(x/m)  125  54.40  5.65±0.44  9.63  250  158.40  7.33±0.54  21.62  375  275.13  7.99±0.94  34.44  500  390.34  8.77±0.69  44.49  625  510.88  9.13±0.08  55.96  750  619.45  10.44±0.20  59.31  875  736.95  11.0410.20  66.73  1000  861.62  11.07+0.00  77.83  *500 mg. o f k a o l i n were suspended-in 40.0 ml. o f drug s o l u t i o n i n water a t a temperature o f 37°C. C a l c u l a t e d values are based on three determinations.  0  100  200  300  400  500  600  E q u i l i b r i u m Concentration  700  800  900  1000  (mg./lOOO ml.)  F i g u r e 25. A d s o r p t i o n isotherm a t 37°C f o r codeine phosphate by k a o l i n i n water. E q u i l i b r i u m pH o f suspension: 5.9.  suspended  to  (b)  Adsorption  C h a r a c t e r i s t i c s i n p H 1 . 2 , 3.0 a n d 5.0  Solution The  adsorption  isotherms  f o r CDN-PC>  aregiven  i nFigure  27 a n d a r e s h o w n t o c o n f o r m  solutions the pH  Langmuir adsorption and t h e Langmuir  substance in  Table  from 10.  isotherm  constants  thevarious  i n p H 3.0 a n d 5.0  4  (Figure  28).  The a d s o r p t i o n  Figure  27).  co-workers  According (1960),  isotherm  i n p H 1.2 s o l u t i o n  Such isotherms the  possible  mately  areobtained,  or molecules  according  of another  that, at this  16.13  sites  adsorbed  l o w pH v a l u e ,  saturation value,  increased  with  studies The  creased  authors, with  ions  when  solvent I t i s competed  on k a o l i n .  a t pH 1 . 5 , w a s e q u a l  t o approxi-  The a d s o r p t i v e  t o 1 1 . 6 6 mg./gm. a t p H 3.1 a n d t o  an i n c r e a s e  This  change t o h i g h e r  i n pH w a s a l s o o b s e r v e d  i n v o l v i n g ATP-r-S0  adsorption  methantheline  (Figure 2 ) .  species.  hydrogen  sites  mg./gm. o f k a o l i n a t p H 6.4  values  o f G i l e s and h i s  t o these  for substrate  curvature  c o n c e n t r a t i o n s . (See  i s o f t h e S2 t y p e  4 mg. o f d r u g p e r gm. o f k a o l i n .  capacity  ion  isotherm  CDN-PO^ f o r t h e a d s o r p t i o n The  drug  concave  to theclassification  a b s o r b a t e must compete  molecules  with  off a t higher  this  o f t h e drug  media s t u d i e d a r e given  ( e q u i l i b r i u m p H = 1.5) i n d i c a t e s a n i n i t i a l followed by a l e v e l l i n g  The e q u i l i b r i u m  for theadsorption  adsorption  with  4  i n adsorpt-  a n d MOP-S0 4  o f both propanthelane bromide and  bromide by k a o l i n from phosphate b u f f e r s i n -  by approximately  6.7 t o 8.5 ( B l a u g (1966) r e p o r t e d  4 0 % w h e n t h e pH w a s c h a n g e d  and Gross,  that  1965).  theadsorption  Sorby  and h i s  o f promazine  from  co-workers  hydrochloride  Equilibrium  Concentration  (mg./lOOO  ml.)  F i g u r e 27. A d s o r p t i o n isotherm a t 37 C f o r codeine phosphate by k a o l i n suspended i n pH 1.2 (A) , PH 3.0 ( • ) , and pH 5.0 (O) solutions. Equilibrium pH of suspensions: 1.5, 3.1, and 6.4 r e s p e c t i v e l y .  <s0  12 O  r  0  100  200  300  400  500  Equilibrium F i g u r e 28. Langmuir i n pH 3.0  600  700  Concentration  800  and pH 5.0  (O)  solutions.  1000  (mg./lOOO ml.)  isotherm a t 37°C f o r codeine phosphate by k a o l i n (•)  900  suspended vo en  Table 10. A d s o r p t i o n o f codeine phosphate by k a o l i n a t 37 C.  Adsorption Isotherm  Langmuir Constants b. a liter/mg. mg ./gm. (liter/mM o f base) (mM of base/gm.)  5.9  Langmuir  12 .30 (30 .27)  solution  1.5  concave initial portion  i pH 3.0 s o l u t i o n  3.1  Langmuir  11 .66 (28 .69)  0.0029 (1.19)  pH 5.0 s o l u t i o n  6.4  Langmuir  16 .13 (39 .69)  0.015 (6.10)  A d s o r p t i o n Medium  water  pH 1.2  Equilibrium pH  0.0085 (3.45)  -  98  and  f l u p h e n a z i n e by k a o l i n ,  buffers,  showed  to  These authors  6.5.  protonated also  the  f r e e base,  due t o i t s l o w e r adsorbed  t h e most r e a d i l y  i s shown  free  step  2.5  may  An e q u i l i b r i u m  adsorbed  species i s  below:  base  y,  form  *  t h e c o n c e n t r a t i o n o f f r e e base  equilibrium  solubility,  form.  Protonated  Since  from  2 becomes more  adsorbed  form  i n c r e a s e s w i t h pH,  important  than  step  a d s o r p t i o n w o u l d be expected, t o be g r e a t e r a t h i g h e r values. other  These authors  than  (c)  propose,  onto  Desorption  Desorption  Characteristics  into  this  Equation  onto k a o l i n of  drug  This  value  4  present  value  pH  factors  to explain  o f CDN-PO^ i n Table  w i t h i n one hour.  The  i n t h e s y s t e m w a s 2 5 . 0 mg.  and t h e a p p r o p r i a t e Langmuir  11.  total Sub-  constants  6 s h o w e d t h a t , i f t h e a d s o r p t i o n o f CDN-PC>  i s reversible,  should  i n order  f o r CDN-PO^ a r e g i v e n  e q u i l i b r i u m occurs  o f CDN-PC>  stituting  that  1 and  kaolin.  The d e s o r p t i o n d a t a  amount  i n essence,  c h a r g e must be c o n s i d e r e d  adsorption  phosphate  were o f t h e o p i n i o n t h a t t h enon-  readily  i n which  free base,  and c h a r c o a l , from  i n c r e a s e s a s t h e pH w a s r a i s e d  be t h e more  diagram,  talc,  a theoretical  amount  r e m a i n o n o n e gm. o f k a o l i n  agreed  with  the experimental  4  o f 5.94 mg.  atequilibrium.  value  at the sixth  99  Table  11.Effect of f i v e - f o l d d i l u t i o n kaolin suspension with water adsorption.  Time  by  (5.83  kaolin  (d)  The of  mg.) is  1  5.51  3  5.98  6  5.83  antidiarrheal  mg.  of  CDN-PO^.  ing  the  that  of  However,  which  of  of  determinations.  adsorption  between  preparation, this  of  CDN-P0  the  gm.),  of  Langmuir  CDN-PO.  phosphate It  capacities  the  relationship discussed  between in  the  drug  Equation  4  Doses  w i l l  be  seldom  is  usually  of  7  therapeutic on  listed  contains  combined (after for  used  the  codeine  section  is  adsorbed  is  1973,  which  constants  0.5% c o d e i n e . S i n c e  adsorptive  Therapeutic  Drugs,  Pabizol,  amount  (6  diarrhea.  contains  be  the  Non-Prescription  kaolin  and  w i l l  of  If  codeine  treatment  that  two  Kaolin  appropriate  90.41%  of  Interaction  and  4  Handbook  dose  basis  reversible.  CDN-P0  normal  the  indicating  one  in  on  phosphatephosphate  Remain Adsorbed Gm. K a o l i n *  9.69  Adsorption  The  codeine codeine  0  *Calculated hour  Mg. per  (hours)  of on  as  with  the  such  for as  antidiarrheal morphine  doses  of  morphine  shows  kaolin.  administered  and  a  substitut-  CDN-PO^)  by  32.4  are  kaolin sulfate.  the opium a c i t i v i t y similar, and  opium  100 4. (a)  Adsorption The  29. can  Morphine S u l f a t e  Characteristics  adsorption isotherm  The a d s o r p t i o n d a t a be i l l u s t r a t e d  i n the linear  and i n t e r c e p t values  mg./gm. k a o l i n liter/mg. which  The to  should  that f o r codeine  (b)  base.  line,  a r e 12.91  should  Further,  of kaolin  be  adsorbed  Langmuir i n molar  f o r morphine  experimentally. i s similar  (30.26mM o f b a s e / g m . ) a n d t h e a d s o r p t i o n o f magnitude  - 5.12 l i t e r / m M o f m o r p h i n e ) . of a hydroxyl  t h e morphine nucleus  exerts  little  Characteristics  ['•'..  (3.45  liter/mM  Therefore, the  group by a methoxyl  of the molecule.  Adsorption  Morphine,  T h i s was c o n f i r m e d  a r e o f t h e same o r d e r  characteristics  from t h e  respectively.  t o codeine,  o f t h e f r e e bases.  substitution of  straight  b e c o m p a r a b l e when e x p r e s s e d  adsorptive capacities  codeine  the values  ( 3 4 . 0 3 mM o f m o r p h i n e b a s e / g m . ) , a n d 0 . 0 1 4  t h e form o f t h e protonated  coefficients of  (b), calculated  of this  i schemically similar  quantities  12.' T h e i s o t h e r m  The a d s o r p t i v e c a p a c i t y (a)  (5.12 l i t e r / m M o f base)  constants  i n Table  form by p l o t t i n g  30.  the adsorption coefficient  slope  in  f o r MOP-SO^ i s s h o w n i n F i g u r e  are given  shown o n t h e a x i s o f F i g u r e and  i n Aqueous S o l u t i o n  effect  group on carbon-3  on t h e a d s o r p t i o n  ......  i n p H 1 . 2 , 3.0 a n d 5.0  Solutions The pH  adsorption isotherm  o f MOP-SO^ i n p H 3.0 a n d  5.0 s o l u t i o n s a r e s h o w n i n F i g u r e  obey t h e Langmuir equilibrium  adsorption equation  pH a n d t h e L a n g m u i r  31.  These  isotherms  (Figure 32).  constants  The  f o r t h e adsorp-  200  300  400  500  600  E q u i l i b r i u m Concentration  700  800  900  (mg./lOOO ml.)  A d s o r p t i o n isotherm a t 37°C f o r morphine s u l f a t e by k a o l i n suspende i n water. E q u i l i b r i u m pH of suspension: 6.2.  Table'T2.  A d s o r p t i o n data f o r morphine s u l f a t e by k a o l i n * .  I n i t i a l Concentration (mg./lOOO ml.)  Equilibrium C o n c e n t r a t i o n (C) (mg./lOOO ml.)  Mg. Adsorbed per Gm. (x/m) ± range  C/(x/m)  125  46.68  6.27+0.80  7.45  250  146.10  8.3110.70  17.58  375  254.98  9.6010.39  26.55  500  368.78  10.50+0.25  35 .13  625  487.56  11.00+0.00  44.34  750  604.48  11.6410.80  51.92  875  728.86  11.6910.20  62.34  1000  849.92  12.01+0.89  70.79  *500 mg. o f k a o l i n were suspended i n 40.0 ml. o f drug s o l u t i o n i n water a t a temperature o f 37°C. C a l c u l a t e d values are based on three determinations.  1  100  200  300  400  500  Equilibrium  600  Concentration  700  800  I  1  900  1  1000  (mg./1000 ml.)  F i g u r e 31. A d s o r p t i o n isotherm a t 37 C f o r morphine s u l f a t e by k a o l i n suspended i n pH 1.2 PH 3.0 (•) and pH 5.0 (O) s o l u t i o n s . E q u i l i b r i u m pH o f suspensions: 1.2, 3.3 and 6.2 r e s p e c t i v e l y .  (A)f  g >^  140  f  100  200  300  400  500  600  700  E q u i l i b r i u m Concentration Figure  800  900  (mg./lOOO ml.)  32. Langmuir isotherm at 37°C f o r morphine s u l f a t e by k a o l i n suspended i n pH 3.0 (•) and pH 5.0 ( Q ) s o l u t i o n s .  1000 H  106 tion  o f MOP-S0  given  i nTable  (expressed indicates and  similar  t h e a d s o r p t i o n media A comparison  q u a n t i t i e s ) i nTables  that theadsorption 4  areclosely  Further,  o f MOP-S0  o f f a t approximately  4  the adsorption  ( F i g u r e 31) i s v e r y  I ti sinitially  4  constants  10 a n d 1 3  characteristics  related.  t o t h a t o f CDN-P0 . levels  studied are  o f t h e Langmuir  f o r MOP-SC^ i n p H 1.2 s o l u t i o n  gradually As  13.  i nmolar  CDN-P0  isotherm  from  4  concave b u t  4 mg./gm.  kaolin.  i t i s i n t h e case o f CDN-P0 , t h e a d s o r p t i o n  o f MOP-S0  4  4  i n c r e a s e s w i t h pH. (c)  Desorption The  The  in  desorption  data  less  C h a r a c t e r i s t i c s o f MOP-SC> data  f o r MOP-SC>  indicate that desorption  than  three  hours.  The t o t a l  t h e s y s t e m w a s 2 5 . 0 mg.  Langmuir  constants  4  4  a r e shown i n T a b l e 14.  reached  e q u i l i b r i u mi n  a m o u n t o f MOP-SC>  I fthis  value  aresubstituted into  4  present  and t h e appropriate  Equation  6,  X  — = 7.59 mg./gm., t h a t kaolin  i sreversible,  retained  i s , i ftheadsorption this  q u a n t i t y o f drug  o n o n e gm. o f k a o l i n  when compared w i t h  o f MOP-S0  value  This  7 . 1 6 mg./gm., i n d i c a t e d t h a t t h e a d s o r p t i o n o f  MOP-S0  4  (d)  value,  at the sixth  hour,  on k a o l i n  on  s h o u l d be  at equilibrium.  theexperimental  4  i s reversible.  The A d s o r p t i o n  I n t e r a c t i o n between  Therapeutic  D o s e s o f MOP-SO. a n d K a o l i n 4 Opium T i n c t u r e U.S.P. a n d P o w d e r e d Opium U.S.P. (which into  c o n t a i n morphine)  areincorporated with  antidiarrheal- .preparations  Parepectolin  and Pomalin  Specialties,  1975).  s u c h a s D o n n a g e l PG,  (Compendium o f  None o f t h e s e  kaolin  Pharmaceutical  preparations  a r e simple  Table 13. A d s o r p t i o n o f morphine s u l f a t e by k a o l i n a t 37°C.  A d s o r p t i o n Medium  Equilibrium pH  Adsorption Isotherm  Langmuir Constants b a liter/mg. mg./gm. (liter/mM o f base) (mM o f base/gm.)  12.91 (34.03)  water  6.2  Langmuir  pH 1.2 s o l u t i o n  1.2  concave initial portion  pH 3.0 s o l u t i o n  3.3  Langmuir  pH 5.0 s o l u t i o n  6.2  Langmuir  0.014 (5.12)  -  -  9.86 (25.99)  0.0025 (0.94)  13.15 (34.65)  0.012 (4.55)  108  Table  14 E f f e c t o f f i v e - f o l d d i l u t i o n kaolin suspension with water adsorption.  Time  In  mixtures  addition  to  1  7.51  3  7.31  6  7.16  of  on  the  kaolin  these  two  basis and  of  drugs,  contains  sulfaguanidine,  pectin,  contains  pectin  in  these  as  a  these from the  the  recommended  a  2 4 . 0 mg.  dose  of  MOP-SO^)  2.4  dose  and  appropriate a  P  value  of  for  on  the  this  30 m l . )  powdered mg.  of  6 gm.  solution.  Donnagel  and  PG  alcohol;  alcohol;  opium  kaolin. constants  is  of  and  was  morphine  not  Pomalin Parepectolin  of  Using  Donnagel  U.S.P.  If  obtained,  is  (which,  this  are  the  or  in  3.2 4  in  obtained as  example,  dose  turn, mg.  into of  con-  implies  of  dosage  96.16%  an  tablespoon-  This  MOP-SC>  i s ,  PG  two  substituted  that  However,  data  hours.  morphine  kaolin  interaction  basis  three  by  studied.  preparation  every  anhydrous  of  Langmuir 96.16%  aqueous  adsorptive  investigation.  fuls(approximately tains  the  analysed  present  and  systems  approximation, is  pectin,  characteristics  multi-component  systems  in  alcohol.  adsorption  f i r s t  determinations.  constituents,  anticholinergic  and  two  MOP-SO^  major  sulfatesulfate  Remain Adsorbed Gm. K a o l i n *  10.50  contains  The  morphine morphine  0  *Calculated binary  Mg. per  (hours)  of on  and  the  Equation the  dose  7,  109 of  M0P-S0  brium.  will  4  be adsorbed  Adsorption  b y t h e 6 gm. o f k a o l i n a t e q u i l i -  e q u i l i b r i u m (which only  must o c c u r when t h e t w o d r u g same p r e p a r a t i o n . on  the adsorption  charcoal,  noted  a greater  effect  tract  Sorby  o f promazine hydrochloride  on t h e uptake  absorption.  i n evaluating  of phenylpropanolamine  tion  of charcoal.  the  the decrease net effect  intestinal lowed the  adsorption  The a d s o r p t i o n  considered respect  of this  equilibrium factors, obtained,  with  into  a therapeutic  i n several  combined w i t h suggest  that  the absorp-  Their  similar  probably  process  suggested  represented  a t the higher  observation  pH o f  fluid  fol-  i n d i c a t e s .that  o f t h e drug must be  e v a l u a t i o n c a n b e made  o f drugs  to that  The a u t h o r s  the intestinal  characteristics  adsorption  that  drug,  pH.  by k a o l i n .  o f a morphine dose i s adsorbed  and t h i s  also  e f f e c t s on i n v i v o  adsorption  absorption.  t o the adsorption  the gastrointestinal  o f t h e drug must  o f t h e drug  and desorption  adsorption  before  percentage kaolin  i n absorption  by subsequent  systems had  was d e c r e a s e d b y t h e c o - a d m i n i s t r a -  o f f u r t h e r drug  fluids  intrinsic  by a t t a p u l g i t e and  (1972) o b s e r v e d  CDN-PO^ a n d MOP-SO^, i n c r e a s e d  that  from  i n the  systems.  Tsuchiya and Levy  tion  of  o f drug  minutes)  of h i s studies  that p r e - e q u i l i b r a t e d drug-adsorbent  the pH-adsorption p r o f i l e  be c o n s i d e r e d  30  a r e combined  (1968), on t h e b a s i s  than non-equilibrated Further,  substances  requires  with  However, a  large  by a dose o f  i s allowed  t o proceed t o  antidiarrhealpreparations.These the pH-adsorption p r o f i l e the absorption  t o be a f f e c t e d by t h e a d s o r p t i o n  results  o f t h e drug  interaction with  i s likely kaolin.  .  110 The to  adsorption  those  characteristics  o f MOP-SO^.  into  consideration  that  f o r MOP-SO.. 4  Ridout tions the  (1968a) s t u d i e d  approximately (1968b),  of  up t o 0.4:1.  of  ATP-S0  acid  solution  kaolin  i nthis  This weight ratio The also  investigation  (ofdrug  o f ATP-SO^ a n d k a o l i n  kaolin)  the adsorption hydrochloric  0.01:1 t o 0.2:1. closer-to  i nantidiarrheal  characteristics  to  r a t i o o f drug t o  from  i sconsiderably  concentra-  t h e same  investigation,  varied  55).  concentration  study,  ratios  The w e i g h t  (19  o f 9 gm./lOOO m l . ,  f r o m p H 1 . 2 , 3.0 a n d 5.0  r a t i o range  desorption  weight  In the present  drug  at this  In a latter  aqueous  and Barr  a t higher  to kaolin  was s t u d i e d .  taking  be s i m i l a r t o  from  concentration  investigated  by k a o l i n  4  should  by Evcim  adsorption  2:1).  kaolin,  Sulfate  has been i n v e s t i g a t e d  weight r a t i o o f drug  author  with  o f ATP-SO^ b y k a o l i n  (up t o a n e q u i l i b r i u m  being  t h e dosage  preparations.  o f ATP-SO^- k a o l i n  system  were  investigated.  (a)  Adsorption Figure  by  Atropine  adsorption  solution  I t sinteraction  dosage d i f f e r e n c e s ,  5.  The  o f CDN-PO^ a r e s i m i l a r  kaolin  Table  15.  Characteristics  i n Aqueous  33 s h o w s t h e a d s o r p t i o n  from  aqueous s o l u t i o n .  The i s o t h e r m  The  adsorptive  capacity  are  9 . 9 9 3 mg./gm. k a o l i n  isotherm  Solution f o r ATP-SO^  The d a t a a r e p r e s e n t e d i n  i s o f t h e Langmuir  type  (a) a n d t h e a d s o r p t i o n ( 2 8 . 5 9 mM o f a t r o p i n e  (Figure 34).  c o e f f i c i e n t (b) base/gm.) a n d  100  200  300  400  500  600  E q u i l i b r i u m Concentration  700  800  (mg./lOOO ml.)  F i g u r e 3 3 . A d s o r p t i o n isotherm a t 37°C f o r a t r o p i n e s u l f a t e by k a o l i n suspended i n water. E q u i l i b r i u m pH o f suspension: 6.4.  900  100  Table 15. A d s o r p t i o n data f o r a t r o p i n e s u l f a t e by k a o l i n * .  I n i t i a l Concentration (mg./lOOO ml.)  Equilibrium C o n c e n t r a t i o n (C) (mg./lOOO ml.)  Mg. Adsorbed per Gm. (x/m) ± range  C/(x/m)  125  44.10  6.47+0.07  6.82  250  144.59  8.43+1.20  17.15  375  266.89  8.65+1.09  30.86  500  373.29  10.1410.55  36.82  625  499.23  10.06+1.20  49.62  750  630.63  9.55+1.96  66.04  875  749.76  10.02±0.44  74.83  1000  882 .52  9.40+0.00  93.90  *500 mg. o f k a o l i n were suspended i n 40.0 ml. o f drug s o l u t i o n i n water a t a temperature o f 37°C. C a l c u l a t e d values are based on three d e t e r m i n a t i o n s .  114 0.056  liter/mg.  These v a l u e s (10.4 the is  are very  mg./gms  liter/mM of base), c l o s e t o those  two times This  chemical  higher  than  (SeeP a r t  b a s e = 9.9) e x i s t s  the value  (pH =  2(a)).  (b)  obtained  and Barr  2 1 . 0 mg./gm.  i n the present  mainly  kaolin  samples used  Atropine  6 . 4 ) . The p o s i t i v e  i n t h e two  sulfate  i nthe ionized  the atropine cation i sprobably  charged  by Evcim  reported by Ridout,  differences i nthekaolin  solution  obtained  d i f f e r e n c e may b e d u e t o t h e i n h e r e n t p h y s i c a l  investigations pine  respectively.  a n d 0 . 048 l i t e r / m g . , respectively).... .'However,  adsorptive capacity value  study.  of  (19.36  charge  (pKao f a t r o -  form  i naqueous  on t h e n i t r o g e n atom  attracted  to thenegatively  surface.  Adsorption Characteristics  i n p H 1 . 2 , 3.0 a n d  5.0 S o l u t i o n The a d s o r p t i o n i s o t h e r m s  f o r ATP-S0  pH  5.0 s o l u t i o n s a r e s h o w n i n F i g u r e  pH  1.2 a n d 5.0 s o l u t i o n  Table  4  35.  f o r t h e a d s o r p t i o n o f ATP-SO^  media s t u d i e d .  The i s o t h e r m s i n  a r e o f t h e Langmuir  16 s h o w s t h e e q u i l i b r i u m p H v a l u e s  constants  i n p H 1 . 2 , 3.0 a n d  The a d s o r p t i o n i s o t h e r m  type  (Figure36).  and t h e Langmuir from  the adsorption  i n p H 3.0  solution  shows a maximum a t a n e q u i l i b r i u m c o n c e n t r a t i o n o f a p p r o x i mately  3 0 0 mg./lOOO m l .  occurred This to and  type  of isotherm  h i s co-workers attraction  belongs  begins  t o t h e mx s u b g r o u p 2.  maxima solutions.  according  According  a m a x i m a may o c c u r  to Giles  i f thesolute-  t o i n c r e a s e more r a p i d l y  attraction.  adsorption isotherm  that  i n p H 2.3 a n d 3.5  shown i n F i g u r e  (1960),  adsorbent-substrate the  also reported  i n the adsorption isotherm  theclassification  solute  Ridout  than t h e  I t i s n o t known why  f o r ATP-SO.  deviates  from t h e n o r -  10  c  •H rH O X,  O JH 0) ft T3 CD  o CO  -a  <  bO  100  200  300  i+00  500  Equilibrium  600  700  Concentration  800  (mg./10 0 0  900  1000  ml.)  F i g u r e 35. A d s o r p t i o n i s o t h e r m a t 3 7°C f o r a t r o p i n e s u l f a t e by k a o l i n s u s p e n d e d i n pH 1.2 (A)? PH 3.0 ( • ) , and pH 5.0 (O) solutions. Equilibrium pH o f s u s p e n s i o n s : 1.3, 3.1, and- 6.1 r e s p e c t i v e l y .  100  200  400  300  500  600  700  E q u i l i b r i u m Concentration  800  900  (mg./lOOO ml.)  F i g u r e 3 6 . Langmuir isotherm at 37°C f o r a t r o p i n e s u l f a t e by k a o l i n suspended i n pH 1.2 (A) pH 5.0 (Q) solutions. a  n  d  100<  Table 16. A d s o r p t i o n o f a t r o p i n e s u l f a t e by k a o l i n a t 37°C.  A d s o r p t i o n Medium  Equilibrium pH  Adsorption Isotherm  Langmuir Constants b a liter/mg. mg./gm. (liter/mM o f base) (mM of base/gm.)  water  6.4  Langmuir  9.93 (28.58)  0.056 (19.36)  pH.1.2 s o l u t i o n  1.3  Langmuir  4.14 (11.91)  0.024 (8.29)  pH 3.0 s o l u t i o n  3.1  showed a maximum  pH 5.0 s o l u t i o n  6.1  Langmuir  -  10.48 (30.17)  -  0.050 (17.37)  mal of  Langmuir the  these  type  rather  Langmuir type isotherms  i n pH  was  1.2  obtained  pendent determinations tion  abruptly  characteristics  and  of  i n pH  and  5.0  ATP-SO  s o l u t i o n but  solutions.  from the  probably  3.0  results  reflect  i n these  of  the  is  Each  of  three true  inde-  adsorp-  solutions.  Figure  35  4 shows t h a t with (c)  the  adsorption  The  The  mg.  of  data  4  drug  binding  of  (Chapter  s t i l l  base)  than  and  increases  MOP-S0  to  desorb.  (d)  Adsorption  of  4  be  end  CPZ-HCl  than (5.12  that  of  on  into  one  the  hours,  gm.  4  in  the  surface  of  (3.45  base).  f o r the  kaolin.  adsorption  liter/mM  liter/mM  of  of  The  adsorbent  f o r CDN-PC>  liter/mM  was  involved  (19.36  4  17.  consideration,  forces  (18.23  responsible  six  from k a o l i n .  f o r ATP-SC>  of  base)  base) and  liter/mM  This  inability  greater of  the  Doses  Kaolin  s u l f a t e has  preparations  which  Donnagel, Donnagel w i t h (Compendium o f  to  system  I n t e r a c t i o n between Therapeutic  ATP-SO. and 4  Atropine  the  taken  desorbed  shown i n T a b l e  i n the  i s r e l a t e d t o ;the  higher  drug  of  not  that  f o r c e may  are  4  present  adsorbate molecules  binding  heal  kaolin  remain adsorbed  I I , section 2),  higher  4  e r r o r s are  which  significantly of  ATP-S0  i s probably  coefficient,  is  by  4  ATP-SO^  f o r ATP-S0  shows t h a t , a t  Even i f a n a l y t i c a l ATP-S0  data  amount o f  mg.  11.08  C h a r a c t e r i s t i c s of  desorption  total  20.0  ATP-S0  pH. Desorption  The  of  been i n c o r p o r a t e d  also contain  into  kaolin.  N e o m y c i n , D o n n a g e l PG  Pharmaceutical  Specialties,  antidiarr-  Examples and  1975).  are  Enterogel None  of  119 T a b l e 17 E f f e c t o f f i v e - f o l d d i l u t i o n kaolin suspension with water adsorption.  Time  10.65  1  10.47  3  10.81  6  10.21  preparations  kaolin the  on  in  above  hydrobromide, contains dients  are  aqueous two  simple  pectin  and  characteristics  of  the  by  of  these  the  presence  approximation,  the  drug  substances  from  the  the  present  recommended  is  Each  dose  contains  ATP-SO  substituted  4  into  PG  with  ATP-SO^  for  dose  and  Equation  Donnagel  .opium  on  of the 7,  three and  P  value  may as  the  is  0.0192  of  ingre-  contains  be a  the  affected f i r s t  the  data  two  hours,  appropriate a  l i s t e d  Enterogel  preparation  kaolin  Neomycin  between of  to  adsorption  system  basis  addition  Enterogel  .The  and  4  hyoscine  the  However,  Using  every  in  with  a l l  and  kaolin  the  ATP-S0  sulfate,  contains  -  of  contains,  interaction  this  30 m l . ) 6 gm,  mixtures  components.  analysed  sulfatesulfate  determinations.  .Donnagel.  adsorption  dose  (approximately  this  alcohol;  investigation.  fuls  If  binary  powdered  incorporated  three  hypscyamine  Donnagel and  of  Donnagel  constituents,  Donnagel  ingredients  basis  solution.  neomycin;  in  the  atropine atropine  Remain Adsorbed Gm. K a o l i n *  0  *Calculated  these  Mg. per  (hours)  of on  as  two obtained  an  example,  tablespoonr  or  as  prescribed.  mg.  of  ATP-SC> .  Langmuir 98.81%  4  constants is  are  obtained,  120 that  i s , a t e q u i l i b r i u m , 9 8 . 8 1 % o f t h e d o s e o f ATP-SC>  a d s o r b e d b y 6 gm. included before  by k a o l i n ,  4  pH.  like  The e f f e c t  factors, desorbed,  that  The  suggest that  incorporated  profile  on t h e a b s o r p t i o n  the observation the absorption  into  one o f t h e f o u r  a c t i o n would  Kectil  drug These  i s likely  4  to  kaolin,  kaolin.  The p r o d u c t  that  between drug p a r t i c l e s  adsorption  characteristics  sulfamerazine,  were i n v e s t i g a t e d w i t h  and  sulfonamides  exist  onto k a o l i n .  i n the anionic  the  adsorption  interaction  the  n e g a t i v e l y charged was i l l u s t r a t e d  by C l a r k e  They n o t e d  that  Under  The  solvent  such  showed  pH s o l u t i o n s ,  an a n i o n i c  species  i s probably  and Armstrong  of benzoic  namely  form and, t h e r e f o r e ,  kaolin surface  on t h e a d s o r p t i o n kaolin.  of such  inter-  and s u l f i s o x a z o l e ,  sulfonamides  In high  suspen-  kaolin.  i n d i s s o l v e d form.  conditions, the four  adsorption  i s a  of the sulfonamides,  sulfamethazine  the drugs  Special-  an a d s o r p t i o n  1:12.5 h y d r o c h l o r i c a c i d s o l u t i o n .  experimental  studied, i s  (Compendium o f P h a r m a c e u t i c a l  also contains  occur  sulfadiazine,  with  sulfate.  of ATP-S0  sulfonamides  and i t i s , t h e r e f o r e , u n l i k e l y  study  of a  t h a t ATP-SO. i s n o t 4  interaction with  sion,  This  increas-  e q u i l i b r i u m and t h e s i g n i f i -  1975) w h i c h  little  of  with  4  ties,  u s e d was  The a d s o r p t i o n  occurs  Sulfonamides  Sulfadiazine,  The  equilibrium  i n t h e s e c t i o n on morphine  combined w i t h  be  substances are  f o r MOP-SC> , i n c r e a s e s  a f f e c t e d by t h e a d s o r p t i o n  (b)  adsorption  of adsorption  have been d i s c u s s e d  t h e two drug  i s administered.  cance o f t h e pH-adsorption  be  Since  i n t h e same p r e p a r a t i o n ,  the preparation  ATP-S0 ing  of kaolin.  will  4  with  small.  (1972)  i n their  a c i d , an a n i o n i c  species,  a m a x i m u m o f 0.4 m g . o f  benzoic  121  a c i d was  adsorbed  hydrochloric in  acid  the^anionic  b y o n e gm. solution,  these  sulfonamides  but  i t i s known t h a t acetic  practical  i n highly  purposes,  group on t h e s u l f o n a m i d e Formation  of a cation,  tion,  i s highly  fore,  probably  molecule.  acetous  impossible,  unlikely.  of these  perchloric  acid  i s , f o r all,'.' t h e amino  i s extremely weakly  i n 1:12.5 h y d r o c h l o r i c The l a c k  due t o t h e l a c k  pattern)  sulfonamides i n  indicating that  molecule  even  The i o n i z a t i o n  present  a c i d i c medium i s n o t known  the t i t r a t i o n  acid with  H o w e v e r , i n 1:12.5  t h e amount o f s u l f o n a m i d e  f o r m w o u l d be m i n i m a l .  for  glacial  of kaolin.  of adsorption  o f charge  basic.  acid  solu-  i s , there-  on t h e drug  122  VI.  1.  Kaolin Mixture and of  2.  SUMMARY AND  with  has been used  CONCLUSIONS  P e c t i n NF  f o r over  (or i t s equivalent) i s  200 y e a r s  f o rthe  treatment  diarrhea.  The m u l t i p l e c a u s e s o f d i a r r h e a viral  infections,  parasitic  include bacterial  infestations,  and  lack of  adequate d i g e s t i v e enzymes, p a t h o l o g i c a l c o n d i t i o n s o f the  intestinal  disturbances, resulting  mucosa, v a r i o u s increased  i n decreased  operations  metabolic  and hormonal  gastrointestinal transit  time,  upon t h e d i g e s t i v e t r a c t  motility  and v a r i o u s (Federal  surgical  Register,  1975) . 3.  Since  c e r t a i n drugs  phosphate,  and morphine  circumstances, are  Further,  to  as a n t i d i a r r h e a l a g e n t s ,  into  or are administered  Specialties,  and/or  antibiotics  with  Although  the Advisory  drug products  (Compendium o f  are often  incorporated  form o r are  administered  the a n t i d i a r r h e a l preparation  (Compendium o f P h a r m a c e u t i c a l 5.  along  of diarrhea i s infection,  t h e k a o l i n c o n t a i n i n g dosage  the patient along  they  1975).  s i n c e one o f t h e causes  sulfonamides  sulfate,ae0deine  s u l f a t e a r e , under c e r t a i n  kaolin containing preparations  Pharmaceutical  into  as a t r o p i n e  classified  often'incorporated  with  4.  such  Specialties,  Review Panel  (Federal Register,  on  1975)  1975).  over-the-counter classifies  123  certain l i s t s  of  no  kaolin  however (the NF)  above  evidence  are  example,  the  more  that  the  Company  liricomycin  various  antidiarrheal  In  the  further  Chlorpromazine administered  The  research drugs  in  the  by  with the  kaolin  study studies  phosphate,  as  and  hydrochloric  5.0 for  hydrochloric out  the  hydrochloride  at  Mixture  their  or  with of,  They  for do,  Kaopectate with  1966)  necessary  vitro  Pectin and  before  the  combinations  in  37°C  adsorption  atropine  were a  can  sulfate  which  test  sulfate water,  acid  solution.  codeine  and  four  sulfamethazine  not  normally,  and as  was  compound. hydrochloride,  atropine  well  solutions.  were  is  preparations,  chlorpromazine  in  of  investigated.  drug  a model  sulfonamides  acid  aqueous  * ydrochlor  drugs  alone.  sulfamerazine,  morphine  3.0,  In  NF  between  containing  for  out  (a)  in  kaolin  carried  carried  and  sulfate,  were  studies  such  (Wagner,  is  presents  administration  Kaolin  hydrochloride,  adsorption  codeine  of  (sulfadiazine,  sulfisoxazole)  included  interaction  study,  morphine  sulfonamides and  of  i t  c l a s s i f i e d .  present  phosphate,  the  hydrochloride  that  properly  than  brand  suggest  be  effective,  Mixture;withrfP.ectin  reference  and  as  combinations  effective  Kaolin  Upjohn  drugs  carried  Desorption  as  in  sulfate pH  Adsorption out  in  studies  1:12.5 were  water. solution, was  18.06 mg.  adsorbed  by  one  of gm.  chlorpromazine of  1.2,  kaolin  at  124  equilibrium.  The v a l u e  a t pH  6.1 w a s  aqueous s o l u t i o n b u t decreased then increased (b) or  One  gm.  equal  with  of k a o l i n adsorbed,  to approximately  gm.  4 mg.  profile  o f morphine  (d)  gm.  adsorption similar (e) with  p,  profile  the following Adsorption 1.2  and  increased  The  mg.  pH-  sulfate i s qualitatively  a t e q u i l i b r i u m , 9.93  s u l f a t e dissolved i n water.  A l l adsorption  pH  1.5  value  phosphate.  of atropine  t o that o f codeine  (i)  a t pH  This  mg.  a t e q u i l i b r i u m , 12.91  of k a o l i n adsorbed,  the atropine  and  1.2.  s u l f a t e dissolved i n water.  to that of codeine  of  t o 3.1  i n t h e pH o f t h e i n v e s t i g a t e d s o l u t i o n s .  similar One  changed  a t e q u i l i b r i u m , 12.30  of k a o l i n adsorbed,  the morphine  adsorption  to that i n  phosphate d i s s o l v e d i n water.  an i n c r e a s e  .(c) One of  i n s o l u t i o n s o f pH  the codeine  was  a s pH  similar  The  mg.  pH-  sulfate i s qualitatively  phosphate.  isotherms  were o f the Langmuir  type,  exceptions. of chlorpromazine  hydrochloride  s o l u t i o n obeyed t h e E r e u n d l i c h  from  adsorption  equation. (ii)  Adsorption.isotherms  morphine  s u l f a t e f r o m pH  f o r codeine phosphate 1.5  a n d pH  respectively,  showed an i n i t i a l  then  levelled  o f f at higher  Such  isotherms  the  belong  classification  (iii)  The  toethe  S2  isotherm  solutions,  concave p o r t i o n and  equilibrium  s y s t e m shown  adsorption  1.2  and  type,  concentrations.  according  i n Figure  f o r atropine  to  2. sulfate  i n pH 3.1 solution?;showed a maximum a t an e q u i l i b r i u m c o n c e n t r a t i o n o f about 300 mg./lOOO ml. Such isotherms are o f the Lmx type, a c c o r d i n g t o the c l a s s i f i c a t i o n system shown i n F i g u r e 2. (f) None o f the sulfonamides s t u d i e d were adsorbed by k a o l i n from 1:12.5 h y d r o c h l o r i c a c i d  solution.  (g) The a d s o r p t i o n o f chlorpromazine h y d r o c h l o r i d e , codeine phosphate, be r e v e r s i b l e .  and morphine s u l f a t e appeared t o  However, the amount o f a t r o p i n e s u l f a t e  adsorbed on one gm. o f k a o l i n remained  unchanged a f t e r  e q u i l i b r a t i n g the adsorbent-adsorbate system w i t h an excess of water  f o r s i x hours.  A p o s i t i v e l y charged c e n t r e on the molecule appears t o be one o f the requirements f o r a d s o r p t i o n o f a drug substance onto k a o l i n .  However, on the b a s i s o f the  data presented i n t h i s t h e s i s , i t i s not p o s s i b l e t o e x p l a i n the d i f f e r e n c e s i n the degree o f a d s o r p t i o n o f chlorpromazine h y d r o c h l o r i d e , codeine phosphate, s u l f a t e and a t r o p i n e s u l f a t e .  morphine  Such d i f f e r e n c e s are  probably r e l a t e d t o the molecular s t r u c t u r e o f these drug substances.  The o n l y . e v i d e n c e f o r such an explan-  a t i o n i s d e r i v e d from the data o b t a i n e d f o r codeine and morphine.  I f r e s u l t s are expressed on a molecular b a s i s ,  34.03 mM o f morphine base and 30.26 mM o f codeine base are adsorbed by one gm. o f k a o l i n from aqueous s o l u t i o n . The e f f e c t o f a d s o r p t i o n on drug a b s o r p t i o n depends on the e x t e n t o f a d s o r p t i o n , on whether the drug and adsor-  126" bent  are allowed t o e q u i l i b r a t e  (Sorby, drug  1968)  on  ( T s u c h i y a and  teristics 11.  and  (a) On  the basis  investigation, hydrochloride  i n 40  by  ml.  a r e 90.41  %,  was  calculated  The  %,  f r o m pH  98.81  and  or  respectively.  was  atropine  With  the  adsorption of codeine phosphate,  and  atropine  The  %,  atropine  76.71  the e x c e p t i o n of chlorpromazine  onto  i n t h e pH  %  and  adsorption of  process,  i n those preparations combining  kaolin  sulfate  kaolin  solutions.  (c)  i n pH  and  i s a relatively rapid  at equilibrium  alkaloids  3.1  of  corresponding data  from data o b t a i n e d f o r the  phosphate  chlorpromazine conditions,  sulfate,  and  present  (6 gm.)  of dosedadsorbed  (b) A d s o r p t i o n , w h i c h  12.  dose o f  dose  morphine  96.16  lowest percentage  crease  importance.  equilibrium  of water.  The  opiate  under a normal  codeine phosphate,  s h o u l d be  desorption charac-  are of secondary  (25 mg.),  suspended  codeine  The  99.0 8 % o f a n o r m a l  adsorbed  sulfate  19 7 2 ) .  of the data obtained i n the  s h o u l d be  for  administration  the pH-adsorption p r o f i l e f o r the  Levy,  of a drug  before  kaolin  range  and  kaolin.  hydrochloride,  morphine  sulfate,  increases with  of.one  Tdataata presented i n this  sulfate  an  i n - '  to s i x .  thesis  suggests  the  fol-  lowing : (a) S u l f o n a m i d e s  are not  are  into  incorporated  their that  solubilities t h e y s h o u l d be  bacteria  and  adsorbed  kaolin charge  absorbed  by  kaolin.  containing  I f they  preparations,  d i s t r i b u t i o n are or act d i r e c t l y  i n the g a s t r o i n t e s t i n a l  tract.  on  such  127  (b)  Atropine  and  should  tures  sulfate  n o t be  unless  Such evidence  amount o f  be  kaolin  developed  may  be  analytical  by  kaolin  c o n t a i n i n g mix-  i n d i c a t e s no  change  in  cross-over experi-  difficult  atropine sulfate  that highly sensitive to  adsorbed  following well-designed  m e n t s i n man. the  incorporated into  i n v i v o evidence  plasma l e v e l s  since  is irreversibly  to  obtain  administered  techniques  i s  would  such  have  to detect possible differences i n  ab-  sorption'. (c) O p i u m a l k a l o i d s corporated  into  p h o s p h a t e and but,  at  the  have,  kaolin  morphine  same t i m e ,  f o r many y e a r s , b e e n i n -  containing preparations. sulfate are  desorbed  conditions.  Although  loids  incorporated into  can  tions, clays As  be  limited  atropine sulfate,  will  difficult  should  a guide  not  be  to  containing kaolin to  adsorb  drug  or  occur  to  other  substances.  kaolin vitro  t h a t such  alka-  prepara-  drugs  i n drug  and  absorption. although  obtain. (Kaolin Mixture  in vivo effect  any  in  for other  In v i t r o  d i s r e g a r d e d when  by  antidiarrheal  d r a m a t i c a l l y decrease  lincomycin hydrochloride. best,  under  i n vivo.evidence,  I t i s known t h a t K a o p e c t a t e NF)  adsorbed  suggest  i n d i c a t e s t h a t c h a n g e s do  with  Pectin  at  may  i n v i v o evidence  d e s i r a b l e , w o u l d be (d)  this  are  Codeine  the  with  absorption  of  adsorption data i s , but,  at  the  same  time,  formulating.products clay with  a  propensity  128 VII.  REFERENCES  A r m s t r o n g N . A . a n d C D . Clarke 2 3 , 9 5 S . The A d s o r p t i o n o f  (1971). J . Crystal  Pharm. P h a r m a c , V i o l e t by K a o l i n .  Armstrong N.A. and C D . C l a r k e (1973). J . Pharm. S c i . , 62, 379. Influence of Solution Electrolyte Content and D i e l e c t r i c Constant on Drug A d s o r p t i o n by K a o l i n . Barr  M. and E . S . A r n i s t a (1957). J . Amer. Pharm. A s s n . 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Pharm. S c i . , 50_, 35. S t a b i l i t y o f Morphine i n Aqueous S o l u t i o n I I I . K i n e t i c s of Morphine Degradation i n Aqueous S o l u t i o n .  LEAF 132 OMITTED IN PAGE NUMBERING.  133  APPENDIX  Derivation  of Equation  In a d r u g - k a o l i n suspension,  6 and E q u a t i o n the following  7 relation. ~ _  applies: T = F + A where T = t o t a l amount o f d r u g and  amount o f d r u g remaining  A = amount o f d r u g  quantities At  (i)  adsorption  dissolved  adsorbed  a r e measured  present  i n t h e system;  i n t h e a d s o r p t i o n medium;  by the k a o l i n .  = V.C  ( i i ) ( i i i )  equations, V i s the volume,in  liters,of  a d s o r p t i o n medium;  C being  mg./liter,  i n t h e a d s o r p t i o n medium;  o f drug  amount o f k a o l i n  present  adsorbed  of  p e r gm.  Substituting  the  the equilibrium concentration,in  i n gm.;;and'—  W being the  i s t h e mg.  of  equations  ( i i ) and  (iii)  W.* m  into  (i) yields: (iv)  (iv) gives:  c =  T - W.-  - - •••  , . ( V )  m  V When t h i s  value  drug  kaolin.  T = V.C.+ rearranging  A l l three  i n mg.  A = W.m these  =  equilibrium:  F  in  F  of C i s substituted  into  the Langmuir  134  adsorption  equation  (Eq. 3 ) , t h e f o l l o w i n g T -  i s obtained:  Welti  ab ( x  V 1  +  T -  (  b  W.*HL) V  or x  ab ( T - W.-,) m  =  V + b ( T - W.£ ) m  m  Expanding  ( v i )and r e a r r a n g i n g  bW_(^)  ( abW  2  -  In  the adsorption  of  these  + V + bT  studies,  quantities  0 . 5 b . (-)  -  2  into  ( v i i ) Substitution  (vii) yields: + bT  )  + abT = 0 m  Consider  in  give:  W = 0.5, V = 0.2.  ( 0 . 5 a b + 0.2  i s Equation  ,(S mg.)  terms  ) „ ~ + abT = 0  m which  , . . (vi)  6.  the case  i n which  i s suspended w i t h  a normal dose o f a  a normal dose o f k a o l i n  40 m l . o f a d s o r p t i o n m e d i u m ,  drug (6  gm.)  then:  T = S W = 6 V = With  these  0.04  substitutions, equation x m  a  M  0.04  8  "  I  6  (vi)i s rewritten  (viii)  }  + b( S -  as:  6^)  135 The is  p e r c e n t a g e of dose expressed  (P) a d s o r b e d b y  6 gm.  of  kaolin  as: 6*SL  P =  or x m substituting  this  ;  (x) a n d bSP  which  2  -  ab( 0.04  7.  + 0.04  into  1 - P + bS(  rearranging  ( 6ab  i s Equation  ,.  value of —  P _ 6. Expanding  PS 6 (viii)  ) 1 - P  terms + bS  yields:  )  K  give:  ) P + 6ab  =  0  . . '  v  

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