This project is a study of the chemical processes that can be used to modify the dissolution rates of drug molecules. Using experimental and mathematical studies, a rational strategy for modifying the dissolution behavior of neutral and ionizable molecules will be developed. Processes will be studied with the goal of controlling the location, rate and chemical mechanism of drug dissolution where these factors affect its therapeutic value. The absorption rate of many orally-administered drugs can be limited by their slow dissolution rate in the contents of the gastrointestinal (GI) tract. this is true especially for drugs having poor aqueous solubility. For other agents, dissolution may be too rapid, resulting in blood plasma concentrations that are potentially toxic or too short in duration. Further, ionizable drugs can change form as they pass through the changing environment of the stomach and GI tract, shifting from soluble to insoluble forms. Frequently, a buffer is incorporated into the formulation, although without a rational basis for its use with the particular drug. Also, the GI fluids contain surfactants which can enhance or reduce the rate of absorption of particular drugs; thus the composition of the GI tract can influence drug dissolution. Standard dissolution rate tests are conducted in in vitro conditions with rapid stirring. Because the rate of dissolution is affected by the fluid flow surrounding the drug tablet, that test gives little information on the actual time course of the tablet in the body. This grant will attempt to identify the critical properties of neutral and ionizable drugs which affect dissolution by studying dissolution under laminar flow conditions similar to that in the GI tract, and in varied pH and surfactant concentrations. Based on this information, it will investigate the use of a buffer co-compressed with the solid drug as a means of altering that environment. The mathematical analysis of dissolution in laminar flow will be conducted to determine the dominant factors in the interaction between the drug and the buffer as both components dissolve, interact and are transported away. The goal is to determine the optimal type and proportion of buffer based on the drug solubility characteristics, its interaction with the GI milieu, and its desired dissolution rate. In accomplishing this goal, a formal strategy will be developed to use the undesirable properties of drugs to design buffered formulations """"""""tailor-made"""""""" to optimize their dissolution rates.
| Neervannan, Seshadri; Southard, Marylee Z; Stella, Valentino J (2012) Dissolution of weak acids under laminar flow and rotating disk hydrodynamic conditions: application of a comprehensive convection-diffusion-migration-reaction transport model. J Pharm Sci 101:3180-9 |
