ABSTRACT
The thermodynamically most stable polymorph under ambient conditions is almost without exception the most desirable crystalline form for development by a pharmaceutical company. It is, therefore, beneficial to discover and to characterize this polymorph at the earliest possible stage of development. A screen for discovering the stable polymorph of a pharmaceutical compound early in the drug discovery-development process is developed and described. In this screen, a small amount of compound is suspended in a diverse group of solvents for two weeks in an effort to crystallize the most stable polymorph. The solubility of the compound in each solvent utilized in the stable polymorph screen is also simultaneously determined using a simple gravimetric method. Ritonavir and an early development candidate (Pfizer compound A) are used as model compounds to demonstrate the utility of the screen for finding the stable polymorph early in the drug discovery-development process.
Subject(s)
Drug Design , Pharmaceutical Preparations/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Isomerism , Pharmaceutical Solutions , Ritonavir/chemical synthesis , Ritonavir/chemistry , Solvents , Spectrum Analysis, Raman , Thermodynamics , X-Ray DiffractionABSTRACT
A rapid gravimetric method for determining drug candidate solubility in organic solvents has been developed. The scale, speed, precision, and accuracy of the method make it ideal for solubility screening of pharmaceutical compounds during early development. The method utilizes a thermogravimetric analyzer to automate drying and weighing. Results for model compounds compare favorably with literature values.
