Bridging in vitro Dissolution Tests to in vivo Dissolution for Poorly Soluable Acidic Drugs.

Abstract

Developing meaningful in vitro dissolution methods is critical for evaluating the drug in vivo performance and providing a better standard for biowaiver tests. For Biopharmaceutical Classification System (BCS) Class II poorly soluble drugs, the dissolution tests are especially important because in vivo dissolution is the rate-limiting process in oral absorption of drugs. There are many factors affecting the in vivo dissolution processes that may have not been fully considered when designing the in vitro dissolution tests. In this dissertation, in order to bridge the gaps between the in vitro dissolution tests with the in vivo dissolution, the human intestinal fluid (HIF) was characterized in terms of buffering species and buffer effect on dissolution of acidic drugs using a miniature rotating disk dissolution apparatus; Mathematical models such as film and reaction plane models were utilized and refined to study the dissolution media factors such as pH, buffering species, and buffer strength on the dissolution of poorly soluble acidic drug with known physicochemical properties; Other factors such as CO2 partial pressure, the effect of enzymatic reaction in the case of bicarbonate buffer were also investigated and discussed. The bicarbonate buffer contributes up to 74% to the buffer capacity in human intestinal fluid and dissolution of the model drug, ibuprofen, in HIF decreased by 48% when HCO3-/CO2 was depleted from ex vivo human intestinal fluid. The two mathematical models were in reasonable good agreement of the buffer effect on dissolution of ibuprofen. Physiological bicarbonate buffer has been compared with United States Pharmacopeia (USP) acetate buffer. With physiochemical properties of the drug known, and dissolution buffer can be equated to USP buffer species of proper buffer strength to reflect the in vivo dissolution. Other factors, especially partial pressure of CO2 and enzyme like carbonic anhydrase have also been shown to affect the dissolution through their effect on bicarbonate buffer system. The results provide important information and a valuable approach for developing in vitro dissolution test for poorly soluble acidic drugs for better in vitro- in vivo correlation (IVIVC) and scientific basis for setting biowaiver test standards.