Preformulation considerations for controlled release dosage forms. Part II. Selected candidate support.

Practical examples of preformulation support of the form selected for formulation development are provided using several drug substances (DSs). The examples include determination of the solubilities vs. pH particularly for the range pH 1 to 8 because of its relationship to gastrointestinal (GI) conditions and dissolution method development. The advantages of equilibrium solubility and trial solubility methods are described. The equilibrium method is related to detecting polymorphism and the trial solubility method, to simplifying difficult solubility problems. An example of two polymorphs existing in mixtures of DS is presented in which one of the forms is very unstable. Accelerating stability studies are used in conjunction with HPLC and quantitative X-ray powder diffraction (QXRD) to demonstrate the differences in chemical and polymorphic stabilities. The results from two model excipient compatibility methods are compared to determine which has better predictive accuracy for room temperature stability. A DSC (calorimetric) method and an isothermal stress with quantitative analysis (ISQA) method that simulates wet granulation conditions were compared using a 2 year room temperature sample set as reference. An example of a pH stability profile for understanding stability and extrapolating stability to other environments is provided. The pH-stability of omeprazole and lansoprazole, which are extremely unstable in acidic and even mildly acidic conditions, are related to the formulation of delayed release dosage forms and the resolution of the problem associated with free carboxyl groups from the enteric coating polymers reacting with the DSs. Dissolution method requirements for CR dosage forms are discussed. The applicability of a modified disintegration time (DT) apparatus for supporting CR dosage form development of a pH sensitive DS at a specific pH such as duodenal pH 5.6 is related. This method is applicable for DSs such as peptides, proteins, enzymes and natural products where physical observation can be used in place of a difficult to perform analytical method, saving resources and providing rapid preformulation support.