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Chap. 31 Pharmaceutics and Biopharmaceutics
Chap. 31 PHARMACEUTICS AND BIOPRARMACEUTICS
Tgkeru Higuchi and Kenneth F. Finger School of Pharmacy, University of Wisconsin, Madison, Wisconsin W i l l i a m I. Higuchi School of Pharmacy, University of Michigan, Ann Arbor, Michigan The science of dosage forms and their influence on drug absorption and u t i l i z a t i o n is a r a p i d l y growing medicinal f i e l d . I n t h i s s h o r t review w e have attempted t o present a l i m i t e d b u t r e p r e s e n t a t i v e development i n t h i s area occurring within the p a s t two years. The materials treated, admittedly, are i n t h e areas of p a r t i c u l a r interest t o t h e reviewers. THERMODYNMIC AC’PIVITY,
SOLUBILITY AND COMPLEXING
Although thermodynamic p r o p e r t i e s of medicinal agentsin s o l u t i o n has received r e l a t i v e l y l i t t l e a t t e n t i o n i n the p a s t , there are a number of reasons why they should be of a major concern t o medicinal chemists. One can r e a d i l y show, f o r example, a direct r e l a t i o n s h i p between t h e physiological a c t i v i t i e s of drugs and their thermodynamic a c t i v i t i e s a t the s i t e of action. One should a l s o note t h a t t h e rates of drug t r a n s p o r t and absorption across membrane relate. more t o thermodynamic a c t i v i t y than t o concentration. Drug s o l u b i l i t i e s which are i n v e r s e l y proportional t o thermodynamic a c t i v i t y c o e f f i c i e n t control, of course, rates of d i s s o l u t i o n and a v a i l a b i l i t i e s of many drugs. And f o r p r a c t i c a l purposes it is more convenient and o f t e n necessary i n many instances t o administer parentera1 drugs i n s o l u t i o n thus r e q u i r i n g rather s o p h i s t i c a t e d understanding of s o l u t i o n chemistry t o permit d i s s o l u t i o n of less s o l u b l e pharmaceuticals. For these reasons t h e nature of t h e s t r u c t u r e s of s o l u t i o n s of drugs i n aqueous and nonaqueous s o l v e n t s and the mechanisms of a c t i v i t y of cosolvents i n these systems p a r t i c u l a r l y have been r e c e n t l y subjecQs of increased scrutiny. c o r r e l a t i o n of s o l u b i l i t y p r o p e r t i e s of nonaqueous systems t o a s i n g l e parameter such as dielectric constant has been attempted by s e v e r a l groups i n t h e l a s t two years w i t h l i m i t e d A t r y by Restaino and Martin t o f i t s o l u b i l i t y of benzoic acid i n various n-alkanols3 t o Hildebrande’s theory of s o l u t i o n proved t o be u n f r u i t f u l . I n these instances t h e s o l v e n t phase has been e s s e n t i a l l y assumed t o be a continuum. A more e f f e c t i v e recent a p p r o a ~ h ” ~ has been t o look a t solute-solvent-cosolventinteractions on a molecular basis, the t o t a l s o l u b i l i t y of c r y s t a l l i n e drug A i n solvent B and cosolvent C being represented by a summation
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P'" Total solubility =
knnp
A"B~CP
L
n = 1 m - 0
P * O At saturation the thermodynamic activity of each species present is equal to that of the solid solute. The total solubility behavior furthermore must take into account the interactions between B and C species. The mechanism responsible for increases in solubility induced in aqueous solutions by addition of cosolvent continues to be largely associated with formation of solute containing species in these systems. The species may take the form of simple one to one or one to two molecular complexes between the solubilizing agents and the solubilized solutes as reported recently for a series of or less stoichiometrically defined hydroxyaromatic acid giant aggregates such as micelles or adducts between dispersed polyether surfactants and low molecular weight phenols. ""lo' l2 A rather interesting instance of solubilization and complex which apparently formation was reported by Lach and coworkers'" involves trapping of organic solutes into cage-like structures of cyclodextrins or Schardinger dextrins in aqueous solutions. The observed stability constants are apparently quite high and the chemical behaviors of the bound species are significantly altered in several instances. There may be some relatipgship between these and starch adducts reported by Goudah and Guth.
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DRUG STABILITY
Increasing attention has been directed towards elucidation of mechanism responsible for deterioration of medicinal preparations. Since drug formulations often involve relatively complex mixtures of polyfunctional organic and inorganic species, chemistries of their breakdown on storage under varying conditions for periods of months and years can indeed be quite involved. Mechanisms of degradation of cycloheximidef6 of porfiro~~ycin:~ of hydroxocobalmin," of Mannich coopounds,lB of diaminotriazine derivatives,=' of apomorphine,'' of iodoxuridine,22 and of methicillin*' are representative of some of these systems recently studied. Attention should be called to series of papers on an anaerobic loss of ascorbic acid. 24
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Steroids continue to receive attention. Although prednisolone in queous solution undergoes oxidative breakdown catalyzed by metals, s J p * Jensen and Lamb have shown that autoxidation of fluprednisolone acetate is preceded by a hydrolytic step. 27 Participation of other ingredients in formulations affecting drug stability has become increasingly evident. Citrate and tartrate buffers, for example, have been shown to be in slow equilibria with their corresponding acid anhydrides which can react rapidly with any nucleophile which may be present.20’2s’30 Waake and G ~ t t m a n ,on ~ ~the other hand, have found that formation of a borate complex tend to stabilize riboflavine. Lach in his studies on cyclodextrins have shown that these form complexes with drugs often conferring great atability to the bound guest. 32 PHARMACEUTICS OF HETEROGENEOUS SYSTEMS Powders, Su sions and Emulsions: Rippie and his collaborators some noteworthy stur3ies on the segregation have report8 kinetics of particulate solids. These investigators have taken steel and glass balls of various sizes loadzd into cylindrical containers and subjected them to vertical sine wave motion. Samples were taken at various times and standard deviations from the mean composition were determined. Segregation of binary m i x tures of spheres followed an apparent first order approach to equilibrium. Employing this technique the authors have studied the influence of particle size, size distribution, particle densitysize interactions, and the dependence of the agitation upon the segregation rate. Other variables such as particle shape could be studied also. While the idealized experiments have not included (and may not be able to include) some of the factors important in real systems, e.g., particle-particle adhesion, particle wall adbeeion, and electrostatic effetrts, they have quantitatively clarified many aspects of the particulate mixing phenomena and demonstrated the importance of this kind of approach. Shlanta and M i l o s o ~ i c hhave ~ ~ described an apparatus for studying stress relaxation of p e e r beds under constant strain. The technique appears to be useful for studying elastic compressifactors that are bility, relaxation and flow under pressure basic to the understanding of the tabletting process. The Coulter Counter played an important role in research on emulsions and suspnsions of pharmaceutical significance. Lemberger and Mourad 7338 studied the influence of a number of variables on the deaggregation behavior of oil-and-water emulsions. R ~ , s ealso employing the Coulter Counter, studied the effect of emulsifier type and concentration on the particle size distribution of oil-in-water emulsions. Edmundson and Lees4’ determined the dissolution rate of a fine suspension of hydrocortisone acetate in water using the Coulter Counter. These and other work41J42J4swith
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this instrument involving emulsions and suspensions point out the value of this tool in future work with pharmaceutical dispersed systems Dissolution Rate Behavior: A number of studies on the rate of dissolution have been recently reported. Wurster and his a s s ~ c i a t e ~ ~ ~ ~studied ~ ~ ~ *the ~ heffect a ~ e of complex formation on the dissolution rate of drugs and the dissolution behavior of the three different crystalline forms of prednisolone. In the latter study these investigators observed the unusual effect of agitation on the relative dissolution rates of polymorphs first reported by Hamlin et al.47 Theaissolution rate behavior of polyphase systems has recently received the attention of several workers since the report by Sekiguchi and Obir8 that the eutectic mixture of sulfathiazole and urea gives a much higher drug release rate than the pure drug alone. The authors had attributed the greater rate to the c smaller crystals in the eutectic mixture. In their recent work with the chloramphenicol-urea system, Sekiguchi et al.4e found that the drug-urea mixture of 1:4 (W/W) dissolved significantly faster than the eutectic composition. The authors proposed that urea solubilization of the drug was probably the more important factor. Goldberg et. G.’’ has suggested the possibility of solid solution formation in these systems as an alternative explanation. Higuchi et. al. s’ have presented a mathematical analysis of dissolution rates involving polyphase mixtures which should be helpful in resolving the various factors.
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BIOPHARMACEUTICS Current thinking in regard to the absor tion of drugs is based largely on the early studies of OvertonSg and Collander and Barlund” who have advanced the concept of the lipoidal nature of the biological membrane and more recently upon the work of Schanker, Brodie, Hogben and c 0 1 1 a b o r a t o r s ~ who ~ have ~ ~ ~defined ~ ~ ~ ~ the ~ ~ ~ ~ role of lipid/water partition coefficients, ionization and pH in the passive transport of drugs and other foreign compounds across biological membranes. !Chese studies have shown that most drugs are absorbed by passive transport and that the rate of absorption is a function of the concentration gradient of the diffusing moiety across the menibrane which in turn is dependent upon the lipid/water partition ratio of the diffusing moiety. The diffusing moiety for weak electrolytes is the non-ionized portion of the dissolved drug. Passive absorption of lipid-insoluble molecules occurs through small aqueous channels or pores in the membrane if the molecules possess sufficiently small molecular volumes to permit passage through the pores. The transport of highly icpnized, lipidinsoluble compounds, such as the quaternary amines, is not satisfactoily e lained by the above mentioned lipid-partition theory. LevinsB has postulated that the transport of quaternary amines
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may Be dependent upon the interaction of these highly ionized molecules with a phosphatido-peptide constituent of the membrane and it is this complex that is the diffusing moiety in the transport of quaternary &nes across biological membranes. Such an interaction satisfactorily explains the rapid, but short lived oral absorption characteristics of the quaternary amines observed in man and other animals. The mechanism of permeation of biol ical membranes has * been the subject of several recent reviews. eo31 From the biopharmaceutical standpoint, the absorption of a drug into the body encompasses other parameters in addition to the permeation of the biological membrane. Included among these are dissolution properties (rate of dissolution and absolute solubility), drug interactions affecting drug availability and diffusion of the drug from its site of dissolution to the absorptive surface. These parameters will constitute the subject material to be discussed in the following paragraphs. Rate of Dissolution and Drug-Absorption: Both absolute solubility and the rate of solubility are important parameters in the overall absorption processes, It-has long been known that a compound must possess sufficient aqueous solubility to be effectively absorbed from the gastro-intestinal tract as well as other obsorptive sites, More recently, Nelson" has clearly elucidated the role of the rate of solubility in the absorption process and pointed out the theoretical relationships that exist between the rate of dissolutfon of a particle and its surface area, diffusion layer pH and the concentration gradient of drug across the diffusion layer. The rate of dissolution principles have provided the theoretical bases for many recent biopharmaceutical studies. The effect of particle size of sulfisoxazole on its oral absorption in dogs has been studied by Fincher, Adams and BeaLeS These authors concluded that the rate of absorption of sulfisoxazole was a &unction of the particle size of the crystals administered, faster and higher blood levels of the drug being obtained with the smaller crystal sizes. Their results indicate that while the rate of absorption was affected by particle size, there was no alteration in the total percentage of administered dose absorbed thus giving rise to the possibility that the blood levels of sulfisoxazole could be controlled by regulating the particle size of the administered drug. The rate determining step in the absorption of salicylate from pharmaceutical dosage forms appears to be the dissolution p r o c e ~ s ? ~More ' ~ recently, ~ ~ ~ ~ Truitt and Morganes have studied the absorption of buffered and non-buffered dosage forms of acetylsalicylic acid in humans and have related their in vivo findings to differences in dissolution rates of the administered aspirin. Their results indicate that (a) statistically significant differences in the rate of aspirin absorption from buffered and non-buffered tablets do exist and (b) the enhancing effects of bufferbmg are primarily upon the rate of dissolution of the acetylsalicyclic acid.
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'Fhue, when the buffered a s p i r i n formulation w a s administered as a s l u r r y o r as a solution, buffering had no enhancing e f f e c t u p n the overall rate of absorption of a c e t y l s a l i c y l i c acid. Only when the tableted form of a s p i r i n w a s administered d i d the enhancing effect of buffering appear, suggesting that the r o l e of the buffer is t o a l t e r diffusion layer pH and thus increase the dissolution rate of the aspirin. The importance of dissolution rate on the rate of absorption of s a l i c y l a t e was a l s o shown bY Lieberman and Wood7' who found that higher blood s a l i c y l a t e levels and more rapid absorption of s a l i c y l a t e occurred when the analgesic w a s administered i n the form of a solution than when administered as either a buffered o r non-buffered tablet. Their data indicate t h a t buffering enhanced the overall absorption rate of a c e t y l s a l i c y l i c acid when administered i n tablet form. Levy and I i ~ l l i s t e r ~ were ~'~* a l s o able t o show a relationship between the rate of dissolution and the rate of absorption of a c e t y l s a l i c y l i c acid i n humans. These authors employed both
conventional compressed tablets and an experimental sustained release preparation employed produced a s i g n i f i c a n t l y reduced dissolution rate as compared t o the dissolution rate obtained f o r the compressed tablets. Similarly, the f i r s t order rate constants f o r absorption following the administration of the sustained release from were s i g n i f i c a n t l y lower than those obtained w i t h the compressed tablets. I n addition, the sustained release dosage form caused a delay i n the onset of absorption i n most patients. Despite the delay i n onset of absorption and the much slower rate of absorption, the t o t a l amount of s a l i c y l a t e absorbed f r o m the sustained release dosage from compared favorably w i t h that obtained from t h e conventional tablet. These r e s u l t s i n d i c a t e again the r o l e of the rate of dissolution i n the over-all absorption rate of acetyls a l i c y l i c acid. The importance of rate of dispersion and dissolution of a drug w a s made evident by the work of Calesnick, Katchen and Black7' who administered various dosage forms of diazoxide and obtained blood levels and biological response data i n humans. Comparing tablet and capsule forms w i t h an aqueous solution of the drug, these authors found the highest blood levels were obtained when the aqueous solution of diazoxide w a s administered, lowest blood levels being obtained w i t h the tableted form and the administration of the encapsulated drug producing blood levels intermediate between those obtained w i t h the solution and tablet forms. It w a s evident from their data t h a t the dispersion of the formulation contained w i t h i n the capsule w a s the rate determining s t e p i n the dissolution of the drug when u t i l i z e d i n this form. Very rapid dissolution rates were observed when the capsule contents were emptied and evenly dispersed throughout the dissolving media as compared t o the very slow dissolution rate observed when the i n t a c t capsule w a s placed i n the media. Similar findings i n tegard t o blood
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levels obtained with encapsulated aspirin VS. tableted aspirin In this study, a significant delay in the appearance of salicylate in the blood was observed in those persons receiving aspirin in the form of capsules as compared with those receiving the analgesic in the form of tablets. In addition, the blood levels of total salicylate were lower in the group receiving the capsules than was found in those receiving the aspirin in the form of a tablet. Hollister and KanterTs compared enteric coated dosage forms of aspirin with compressed tablet preparations. They observed significant delays in onset of serum salicylate levels when the enteric coated preparations were employed. The delay in absorption found in their study was of such magnitude (three to six hours) that they concluded that enteric forms of salicylate should not be employed where an immediate analgesic or antipyretic effect was desired. Percutaneous Absorption: The influence of solubility and lipid/ water partition ratios in the percutaneous absor tion of the corticosteroids were studied by Katz and Shaikh. Fa The results of their study are in agreement with the theoretical postulates of Higuchi and their results show that the efficiency of percutaneous absorption absorption of the corticosteroids may be a function of the partition coefficient and the square root of the aqueous solubility. In their continuing studies pertaining to the factors influencing percutaneous absorption, Wurster and M u n i e ~ ~ have ~ , shown ~ ~ that the degree of hydration of the stratum corneum played an important role in the transport of methyl ethyl ketone. These workers have shown that dehydration delays percutaneous absorption while hydration of the skin above normal values enhances absorption. Thus, percutaneous as well as oral absorption of chemical substances appears to be a function of the lipid/water partition coefficient and aqueous solubility parameters of the diffusing moiety and intimately associated with the integrity and physico-chemical properties of the biological melldbranes. Drug Interactions: The interaction of dissolved drugs with either endogenous or exogenous materials present in the vicinity of the absorptive site may have a pronounced effect on the absorbability of the drug. Interaction of the drug with these materials may either facilitate or inhibit drug absorption. Sorby'' has shown that promazine adsorbed to the surface of both attapulgite and activated charcoal and this interaction of drug and adsorbent resulted in altered absorption patterns of promazine. When admixed with attapulgite, the absorption of promazine was significantly delayed, however, only minor decreases in the proportion of the administered dose absorbed was observed. On the other hand, when admixed with charcoal, the drug-adsorbent interaction resulted in both a decrease in the rate and the extent of absorption of promazine. Althou h absorption characteristics were not studied, BlaUg and crosse8 investigated the adsorption of antichlolinergic drugs by
were obtained by Wood.74
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various antacids and found appreciable binding of atropine, methantheline, propantheline and oxyphenonium to the antacids, particularly magnesium trisilicate. In ldea of the frequent coadministration of anticholinergic drugs and antacids, definitive in vivo absorption studies are necessary to define the possible effects of the antacids on the therapeutic efficacy of the anticholinergic drugs. The intestinal absorption of water soluble dyes such as bromthymol blue, methyl orange and eosine-B and certain lipid soluble coTlexes of the dyes have been investigated by Levy and Matsuzawa.8 Their data suggests that the lipid/water partition ratio of the dye complexes did not reflect the intestinal absorption characteristics observed. The absorption characteristics of Certain metal-acid complexes of tetracycline and demethylchlortetracycline have also been investigated and it has been shown that some of the metal-acid-tetracycline complexes enhance the absorption of the tetracyclines.82 Diffusion: Diffusion of the drug from the site of dissolution to the absorbing surface may have a pronounced effect on the maintenance of the concentration gradient across the absorbing membrane and thus an effect on the rate of absorption. This parameter of the over-all absorption process was the subject of a report by Levy and J u ~ k o . ~ ~ These workers studied the oral absorption characteristics of both ethanol and salicylic acid in rats as a function of the viscosity of dissolving media. Their results indicated that diffusion of the drug molecules to the absorbing membrane was significantly decreased and the rate of gastrointestinal transit of the solutions was also decreased. Urinary Excretion: In lieu of the frequent use of urinary excretion data as an index of drug absorption and elimination rates in the evaluation of pharmaceutical dosage forms, it would appear to be of value to call the reader's attention to the recent works of Beckett et al.84resr8s pertaining to the excretion of drugs in man. These workers have investigated the influence of urinary PH and urine output on the renal excretion of several dru 8 . In regard to their studies on the excretion of amphetamine," the authors state that the alterations in excretion rates observed as a function of urinary pH and urine volume can be explained on the basis that the unionized portion of the amphetamine is reabsorbed by the Kidney and the passive reabsorption process is p H and volume dependent. The more alkaline the urine, the higher the percentage of unionized amphetamine present and hence a greater reabsorption of the drug and consequently a lawer excretion rate. Similar finding8 were reported by Beckett and collaborators for chlorpheniramine and methylamphetamine. 86 While these studies are largely applications and extensions of the basic studies reported much earlier,87 J 88 J 8s J 0 the kinetic approach to data evaluation and implications deduced from their findings throughout their reports are indicative of the value of these reports to the biopharmaceutical literature.
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84. 85 86. 87. 88. 89 90.
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(lm).
Sorby, I b i d , 677 BlaUg and M. Gross, G. Levy and T. Matsuzawa, E. G. Remers, W. C. Barringer, G. M. S i e g e r and A. Bid, 49 (1965). G. Levy and W. J. Jusko, I b i d , 54 219 (1965). A. H. Beckett and M. Rowland, J, Pharm. Pharmacol. D.
341
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53,
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17,
628
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H. Beckett and M. J. Orloff and R. W. B e r l i n e r , J. C l i n . Invest. M. H. Jacobs, Cold Spring Harbor Symposium, M. D. Milne, B. H. Scribbner and M. A. Crawford, Am. J. Med. 24, 709 (1958). W. J. Waddell and T. C. B u t l e r , J. C l i n . Invest. 36, 1217 A.
-
( 1957
g,
,
,
,
Tgkeru Higuchi and Kenneth F. Finger School of Pharmacy, University of Wisconsin, Madison, Wisconsin W i l l i a m I. Higuchi School of Pharmacy, University of Michigan, Ann Arbor, Michigan The science of dosage forms and their influence on drug absorption and u t i l i z a t i o n is a r a p i d l y growing medicinal f i e l d . I n t h i s s h o r t review w e have attempted t o present a l i m i t e d b u t r e p r e s e n t a t i v e development i n t h i s area occurring within the p a s t two years. The materials treated, admittedly, are i n t h e areas of p a r t i c u l a r interest t o t h e reviewers. THERMODYNMIC AC’PIVITY,
SOLUBILITY AND COMPLEXING
Although thermodynamic p r o p e r t i e s of medicinal agentsin s o l u t i o n has received r e l a t i v e l y l i t t l e a t t e n t i o n i n the p a s t , there are a number of reasons why they should be of a major concern t o medicinal chemists. One can r e a d i l y show, f o r example, a direct r e l a t i o n s h i p between t h e physiological a c t i v i t i e s of drugs and their thermodynamic a c t i v i t i e s a t the s i t e of action. One should a l s o note t h a t t h e rates of drug t r a n s p o r t and absorption across membrane relate. more t o thermodynamic a c t i v i t y than t o concentration. Drug s o l u b i l i t i e s which are i n v e r s e l y proportional t o thermodynamic a c t i v i t y c o e f f i c i e n t control, of course, rates of d i s s o l u t i o n and a v a i l a b i l i t i e s of many drugs. And f o r p r a c t i c a l purposes it is more convenient and o f t e n necessary i n many instances t o administer parentera1 drugs i n s o l u t i o n thus r e q u i r i n g rather s o p h i s t i c a t e d understanding of s o l u t i o n chemistry t o permit d i s s o l u t i o n of less s o l u b l e pharmaceuticals. For these reasons t h e nature of t h e s t r u c t u r e s of s o l u t i o n s of drugs i n aqueous and nonaqueous s o l v e n t s and the mechanisms of a c t i v i t y of cosolvents i n these systems p a r t i c u l a r l y have been r e c e n t l y subjecQs of increased scrutiny. c o r r e l a t i o n of s o l u b i l i t y p r o p e r t i e s of nonaqueous systems t o a s i n g l e parameter such as dielectric constant has been attempted by s e v e r a l groups i n t h e l a s t two years w i t h l i m i t e d A t r y by Restaino and Martin t o f i t s o l u b i l i t y of benzoic acid i n various n-alkanols3 t o Hildebrande’s theory of s o l u t i o n proved t o be u n f r u i t f u l . I n these instances t h e s o l v e n t phase has been e s s e n t i a l l y assumed t o be a continuum. A more e f f e c t i v e recent a p p r o a ~ h ” ~ has been t o look a t solute-solvent-cosolventinteractions on a molecular basis, the t o t a l s o l u b i l i t y of c r y s t a l l i n e drug A i n solvent B and cosolvent C being represented by a summation
332 -
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Topics in Chemistry
P'" Total solubility =
knnp
A"B~CP
L
n = 1 m - 0
P * O At saturation the thermodynamic activity of each species present is equal to that of the solid solute. The total solubility behavior furthermore must take into account the interactions between B and C species. The mechanism responsible for increases in solubility induced in aqueous solutions by addition of cosolvent continues to be largely associated with formation of solute containing species in these systems. The species may take the form of simple one to one or one to two molecular complexes between the solubilizing agents and the solubilized solutes as reported recently for a series of or less stoichiometrically defined hydroxyaromatic acid giant aggregates such as micelles or adducts between dispersed polyether surfactants and low molecular weight phenols. ""lo' l2 A rather interesting instance of solubilization and complex which apparently formation was reported by Lach and coworkers'" involves trapping of organic solutes into cage-like structures of cyclodextrins or Schardinger dextrins in aqueous solutions. The observed stability constants are apparently quite high and the chemical behaviors of the bound species are significantly altered in several instances. There may be some relatipgship between these and starch adducts reported by Goudah and Guth.
''
'"
DRUG STABILITY
Increasing attention has been directed towards elucidation of mechanism responsible for deterioration of medicinal preparations. Since drug formulations often involve relatively complex mixtures of polyfunctional organic and inorganic species, chemistries of their breakdown on storage under varying conditions for periods of months and years can indeed be quite involved. Mechanisms of degradation of cycloheximidef6 of porfiro~~ycin:~ of hydroxocobalmin," of Mannich coopounds,lB of diaminotriazine derivatives,=' of apomorphine,'' of iodoxuridine,22 and of methicillin*' are representative of some of these systems recently studied. Attention should be called to series of papers on an anaerobic loss of ascorbic acid. 24
Chap. 31
Biopharmaceutic s
Higuchi, Finger and Higuchi
333 -
Steroids continue to receive attention. Although prednisolone in queous solution undergoes oxidative breakdown catalyzed by metals, s J p * Jensen and Lamb have shown that autoxidation of fluprednisolone acetate is preceded by a hydrolytic step. 27 Participation of other ingredients in formulations affecting drug stability has become increasingly evident. Citrate and tartrate buffers, for example, have been shown to be in slow equilibria with their corresponding acid anhydrides which can react rapidly with any nucleophile which may be present.20’2s’30 Waake and G ~ t t m a n ,on ~ ~the other hand, have found that formation of a borate complex tend to stabilize riboflavine. Lach in his studies on cyclodextrins have shown that these form complexes with drugs often conferring great atability to the bound guest. 32 PHARMACEUTICS OF HETEROGENEOUS SYSTEMS Powders, Su sions and Emulsions: Rippie and his collaborators some noteworthy stur3ies on the segregation have report8 kinetics of particulate solids. These investigators have taken steel and glass balls of various sizes loadzd into cylindrical containers and subjected them to vertical sine wave motion. Samples were taken at various times and standard deviations from the mean composition were determined. Segregation of binary m i x tures of spheres followed an apparent first order approach to equilibrium. Employing this technique the authors have studied the influence of particle size, size distribution, particle densitysize interactions, and the dependence of the agitation upon the segregation rate. Other variables such as particle shape could be studied also. While the idealized experiments have not included (and may not be able to include) some of the factors important in real systems, e.g., particle-particle adhesion, particle wall adbeeion, and electrostatic effetrts, they have quantitatively clarified many aspects of the particulate mixing phenomena and demonstrated the importance of this kind of approach. Shlanta and M i l o s o ~ i c hhave ~ ~ described an apparatus for studying stress relaxation of p e e r beds under constant strain. The technique appears to be useful for studying elastic compressifactors that are bility, relaxation and flow under pressure basic to the understanding of the tabletting process. The Coulter Counter played an important role in research on emulsions and suspnsions of pharmaceutical significance. Lemberger and Mourad 7338 studied the influence of a number of variables on the deaggregation behavior of oil-and-water emulsions. R ~ , s ealso employing the Coulter Counter, studied the effect of emulsifier type and concentration on the particle size distribution of oil-in-water emulsions. Edmundson and Lees4’ determined the dissolution rate of a fine suspension of hydrocortisone acetate in water using the Coulter Counter. These and other work41J42J4swith
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3 34
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VI - Topics in Chemistry
S m i s s m a n , Ed.
this instrument involving emulsions and suspensions point out the value of this tool in future work with pharmaceutical dispersed systems Dissolution Rate Behavior: A number of studies on the rate of dissolution have been recently reported. Wurster and his a s s ~ c i a t e ~ ~ ~ ~studied ~ ~ ~ *the ~ heffect a ~ e of complex formation on the dissolution rate of drugs and the dissolution behavior of the three different crystalline forms of prednisolone. In the latter study these investigators observed the unusual effect of agitation on the relative dissolution rates of polymorphs first reported by Hamlin et al.47 Theaissolution rate behavior of polyphase systems has recently received the attention of several workers since the report by Sekiguchi and Obir8 that the eutectic mixture of sulfathiazole and urea gives a much higher drug release rate than the pure drug alone. The authors had attributed the greater rate to the c smaller crystals in the eutectic mixture. In their recent work with the chloramphenicol-urea system, Sekiguchi et al.4e found that the drug-urea mixture of 1:4 (W/W) dissolved significantly faster than the eutectic composition. The authors proposed that urea solubilization of the drug was probably the more important factor. Goldberg et. G.’’ has suggested the possibility of solid solution formation in these systems as an alternative explanation. Higuchi et. al. s’ have presented a mathematical analysis of dissolution rates involving polyphase mixtures which should be helpful in resolving the various factors.
.
-i-
BIOPHARMACEUTICS Current thinking in regard to the absor tion of drugs is based largely on the early studies of OvertonSg and Collander and Barlund” who have advanced the concept of the lipoidal nature of the biological membrane and more recently upon the work of Schanker, Brodie, Hogben and c 0 1 1 a b o r a t o r s ~ who ~ have ~ ~ ~defined ~ ~ ~ ~ the ~ ~ ~ ~ role of lipid/water partition coefficients, ionization and pH in the passive transport of drugs and other foreign compounds across biological membranes. !Chese studies have shown that most drugs are absorbed by passive transport and that the rate of absorption is a function of the concentration gradient of the diffusing moiety across the menibrane which in turn is dependent upon the lipid/water partition ratio of the diffusing moiety. The diffusing moiety for weak electrolytes is the non-ionized portion of the dissolved drug. Passive absorption of lipid-insoluble molecules occurs through small aqueous channels or pores in the membrane if the molecules possess sufficiently small molecular volumes to permit passage through the pores. The transport of highly icpnized, lipidinsoluble compounds, such as the quaternary amines, is not satisfactoily e lained by the above mentioned lipid-partition theory. LevinsB has postulated that the transport of quaternary amines
Chap. 31
Biopharmaceutic s
Higuchi, Finger and Higuchi
may Be dependent upon the interaction of these highly ionized molecules with a phosphatido-peptide constituent of the membrane and it is this complex that is the diffusing moiety in the transport of quaternary &nes across biological membranes. Such an interaction satisfactorily explains the rapid, but short lived oral absorption characteristics of the quaternary amines observed in man and other animals. The mechanism of permeation of biol ical membranes has * been the subject of several recent reviews. eo31 From the biopharmaceutical standpoint, the absorption of a drug into the body encompasses other parameters in addition to the permeation of the biological membrane. Included among these are dissolution properties (rate of dissolution and absolute solubility), drug interactions affecting drug availability and diffusion of the drug from its site of dissolution to the absorptive surface. These parameters will constitute the subject material to be discussed in the following paragraphs. Rate of Dissolution and Drug-Absorption: Both absolute solubility and the rate of solubility are important parameters in the overall absorption processes, It-has long been known that a compound must possess sufficient aqueous solubility to be effectively absorbed from the gastro-intestinal tract as well as other obsorptive sites, More recently, Nelson" has clearly elucidated the role of the rate of solubility in the absorption process and pointed out the theoretical relationships that exist between the rate of dissolutfon of a particle and its surface area, diffusion layer pH and the concentration gradient of drug across the diffusion layer. The rate of dissolution principles have provided the theoretical bases for many recent biopharmaceutical studies. The effect of particle size of sulfisoxazole on its oral absorption in dogs has been studied by Fincher, Adams and BeaLeS These authors concluded that the rate of absorption of sulfisoxazole was a &unction of the particle size of the crystals administered, faster and higher blood levels of the drug being obtained with the smaller crystal sizes. Their results indicate that while the rate of absorption was affected by particle size, there was no alteration in the total percentage of administered dose absorbed thus giving rise to the possibility that the blood levels of sulfisoxazole could be controlled by regulating the particle size of the administered drug. The rate determining step in the absorption of salicylate from pharmaceutical dosage forms appears to be the dissolution p r o c e ~ s ? ~More ' ~ recently, ~ ~ ~ ~ Truitt and Morganes have studied the absorption of buffered and non-buffered dosage forms of acetylsalicylic acid in humans and have related their in vivo findings to differences in dissolution rates of the administered aspirin. Their results indicate that (a) statistically significant differences in the rate of aspirin absorption from buffered and non-buffered tablets do exist and (b) the enhancing effects of bufferbmg are primarily upon the rate of dissolution of the acetylsalicyclic acid.
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.
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3 36 -
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'Fhue, when the buffered a s p i r i n formulation w a s administered as a s l u r r y o r as a solution, buffering had no enhancing e f f e c t u p n the overall rate of absorption of a c e t y l s a l i c y l i c acid. Only when the tableted form of a s p i r i n w a s administered d i d the enhancing effect of buffering appear, suggesting that the r o l e of the buffer is t o a l t e r diffusion layer pH and thus increase the dissolution rate of the aspirin. The importance of dissolution rate on the rate of absorption of s a l i c y l a t e was a l s o shown bY Lieberman and Wood7' who found that higher blood s a l i c y l a t e levels and more rapid absorption of s a l i c y l a t e occurred when the analgesic w a s administered i n the form of a solution than when administered as either a buffered o r non-buffered tablet. Their data indicate t h a t buffering enhanced the overall absorption rate of a c e t y l s a l i c y l i c acid when administered i n tablet form. Levy and I i ~ l l i s t e r ~ were ~'~* a l s o able t o show a relationship between the rate of dissolution and the rate of absorption of a c e t y l s a l i c y l i c acid i n humans. These authors employed both
conventional compressed tablets and an experimental sustained release preparation employed produced a s i g n i f i c a n t l y reduced dissolution rate as compared t o the dissolution rate obtained f o r the compressed tablets. Similarly, the f i r s t order rate constants f o r absorption following the administration of the sustained release from were s i g n i f i c a n t l y lower than those obtained w i t h the compressed tablets. I n addition, the sustained release dosage form caused a delay i n the onset of absorption i n most patients. Despite the delay i n onset of absorption and the much slower rate of absorption, the t o t a l amount of s a l i c y l a t e absorbed f r o m the sustained release dosage from compared favorably w i t h that obtained from t h e conventional tablet. These r e s u l t s i n d i c a t e again the r o l e of the rate of dissolution i n the over-all absorption rate of acetyls a l i c y l i c acid. The importance of rate of dispersion and dissolution of a drug w a s made evident by the work of Calesnick, Katchen and Black7' who administered various dosage forms of diazoxide and obtained blood levels and biological response data i n humans. Comparing tablet and capsule forms w i t h an aqueous solution of the drug, these authors found the highest blood levels were obtained when the aqueous solution of diazoxide w a s administered, lowest blood levels being obtained w i t h the tableted form and the administration of the encapsulated drug producing blood levels intermediate between those obtained w i t h the solution and tablet forms. It w a s evident from their data t h a t the dispersion of the formulation contained w i t h i n the capsule w a s the rate determining s t e p i n the dissolution of the drug when u t i l i z e d i n this form. Very rapid dissolution rates were observed when the capsule contents were emptied and evenly dispersed throughout the dissolving media as compared t o the very slow dissolution rate observed when the i n t a c t capsule w a s placed i n the media. Similar findings i n tegard t o blood
Chap. 31
Biopha r m a c eu ti c s
Higuchi, Finger and Higuchi
337 -
levels obtained with encapsulated aspirin VS. tableted aspirin In this study, a significant delay in the appearance of salicylate in the blood was observed in those persons receiving aspirin in the form of capsules as compared with those receiving the analgesic in the form of tablets. In addition, the blood levels of total salicylate were lower in the group receiving the capsules than was found in those receiving the aspirin in the form of a tablet. Hollister and KanterTs compared enteric coated dosage forms of aspirin with compressed tablet preparations. They observed significant delays in onset of serum salicylate levels when the enteric coated preparations were employed. The delay in absorption found in their study was of such magnitude (three to six hours) that they concluded that enteric forms of salicylate should not be employed where an immediate analgesic or antipyretic effect was desired. Percutaneous Absorption: The influence of solubility and lipid/ water partition ratios in the percutaneous absor tion of the corticosteroids were studied by Katz and Shaikh. Fa The results of their study are in agreement with the theoretical postulates of Higuchi and their results show that the efficiency of percutaneous absorption absorption of the corticosteroids may be a function of the partition coefficient and the square root of the aqueous solubility. In their continuing studies pertaining to the factors influencing percutaneous absorption, Wurster and M u n i e ~ ~ have ~ , shown ~ ~ that the degree of hydration of the stratum corneum played an important role in the transport of methyl ethyl ketone. These workers have shown that dehydration delays percutaneous absorption while hydration of the skin above normal values enhances absorption. Thus, percutaneous as well as oral absorption of chemical substances appears to be a function of the lipid/water partition coefficient and aqueous solubility parameters of the diffusing moiety and intimately associated with the integrity and physico-chemical properties of the biological melldbranes. Drug Interactions: The interaction of dissolved drugs with either endogenous or exogenous materials present in the vicinity of the absorptive site may have a pronounced effect on the absorbability of the drug. Interaction of the drug with these materials may either facilitate or inhibit drug absorption. Sorby'' has shown that promazine adsorbed to the surface of both attapulgite and activated charcoal and this interaction of drug and adsorbent resulted in altered absorption patterns of promazine. When admixed with attapulgite, the absorption of promazine was significantly delayed, however, only minor decreases in the proportion of the administered dose absorbed was observed. On the other hand, when admixed with charcoal, the drug-adsorbent interaction resulted in both a decrease in the rate and the extent of absorption of promazine. Althou h absorption characteristics were not studied, BlaUg and crosse8 investigated the adsorption of antichlolinergic drugs by
were obtained by Wood.74
3 38 -
Sect. VI
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Topics i n Chemistry
S m i s s m a n , Ed.
various antacids and found appreciable binding of atropine, methantheline, propantheline and oxyphenonium to the antacids, particularly magnesium trisilicate. In ldea of the frequent coadministration of anticholinergic drugs and antacids, definitive in vivo absorption studies are necessary to define the possible effects of the antacids on the therapeutic efficacy of the anticholinergic drugs. The intestinal absorption of water soluble dyes such as bromthymol blue, methyl orange and eosine-B and certain lipid soluble coTlexes of the dyes have been investigated by Levy and Matsuzawa.8 Their data suggests that the lipid/water partition ratio of the dye complexes did not reflect the intestinal absorption characteristics observed. The absorption characteristics of Certain metal-acid complexes of tetracycline and demethylchlortetracycline have also been investigated and it has been shown that some of the metal-acid-tetracycline complexes enhance the absorption of the tetracyclines.82 Diffusion: Diffusion of the drug from the site of dissolution to the absorbing surface may have a pronounced effect on the maintenance of the concentration gradient across the absorbing membrane and thus an effect on the rate of absorption. This parameter of the over-all absorption process was the subject of a report by Levy and J u ~ k o . ~ ~ These workers studied the oral absorption characteristics of both ethanol and salicylic acid in rats as a function of the viscosity of dissolving media. Their results indicated that diffusion of the drug molecules to the absorbing membrane was significantly decreased and the rate of gastrointestinal transit of the solutions was also decreased. Urinary Excretion: In lieu of the frequent use of urinary excretion data as an index of drug absorption and elimination rates in the evaluation of pharmaceutical dosage forms, it would appear to be of value to call the reader's attention to the recent works of Beckett et al.84resr8s pertaining to the excretion of drugs in man. These workers have investigated the influence of urinary PH and urine output on the renal excretion of several dru 8 . In regard to their studies on the excretion of amphetamine," the authors state that the alterations in excretion rates observed as a function of urinary pH and urine volume can be explained on the basis that the unionized portion of the amphetamine is reabsorbed by the Kidney and the passive reabsorption process is p H and volume dependent. The more alkaline the urine, the higher the percentage of unionized amphetamine present and hence a greater reabsorption of the drug and consequently a lawer excretion rate. Similar finding8 were reported by Beckett and collaborators for chlorpheniramine and methylamphetamine. 86 While these studies are largely applications and extensions of the basic studies reported much earlier,87 J 88 J 8s J 0 the kinetic approach to data evaluation and implications deduced from their findings throughout their reports are indicative of the value of these reports to the biopharmaceutical literature.
Chap. 31
Biopharmaceutic s
Higuchi, F i n g e r and Higuchi
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