title: In Vivo Predictive Dissolution: Comparing the Effect of Bicarbonate and Phosphate Buffer on the Dissolution of Weak Acids and Weak Bases.
abstract: Bicarbonate is the main buffer in the small intestine and it is well known that buffer properties such as pKa can affect the dissolution rate of ionizable drugs. However, bicarbonate buffer is complicated to work with experimentally. Finding a suitable substitute for bicarbonate buffer may provide a way to perform more physiologically relevant dissolution tests. The dissolution of weak acid and weak base drugs was conducted in bicarbonate and phosphate buffer using rotating disk dissolution methodology. Experimental results were compared with the predicted results using the film model approach of (Mooney K, Mintun M, Himmelstein K, Stella V. 1981. J Pharm Sci 70(1):22-32) based on equilibrium assumptions as well as a model accounting for the slow hydration reaction, CO2 + H2 O → H2 CO3 . Assuming carbonic acid is irreversible in the dehydration direction: CO2 + H2 O ← H2 CO3 , the transport analysis can accurately predict rotating disk dissolution of weak acid and weak base drugs in bicarbonate buffer. The predictions show that matching the dissolution of weak acid and weak base drugs in phosphate and bicarbonate buffer is possible. The phosphate buffer concentration necessary to match physiologically relevant bicarbonate buffer [e.g., 10.5 mM (HCO3 (-) ), pH = 6.5] is typically in the range of 1-25 mM and is very dependent upon drug solubility and pKa .
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Krieg
authors.affiliation: Department of Chemical Engineering, Laval University, Quebec, Quebec City, G1V 0A6, Canada.
authors.forename: Seyed Mohammad
authors.initials: SM
authors.lastname: Taghavi
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109.
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Amidon
mesh_terms: D000136:Acid-Base Equilibrium; D000143:Acids; D001639:Bicarbonates / Q000737:chemistry*; D002021:Buffers; D002255:Carbonic Acid / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D010710:Phosphates / Q000737:chemistry*; D011237:Predictive Value of Tests; D012995:Solubility
chemical_list: D000143:Acids; D001639:Bicarbonates; D002021:Buffers; D010710:Phosphates; D002255:Carbonic Acid
keywords: Dissolution; acid-base equilibria; diffusion; gastrointestinal; in vitro models; mathematical model; physicochemical properties; transport