Solid-State Interactions of a Drug Substance and Excipients and Their Impact on Tablet Dissolution: A Thermal-Mechanical Facilitated Process-Induced Transformation or PIT

ABSTRACT The polymorphic and/or pseudo-polymorphic phase transformation of Drug Z API, from Form I to Form II, occurs during the wet granulation step. It was observed that dissolution of the tablets slowed down under certain manufacturing conditions. Factors responsible for the slowdown in tablet dissolution were investigated in this study. Two levels of shear during premixing and two wet granulation drying temperatures were investigated by measuring the dissolution profiles of the tablets. The interaction between API and excipients was examined using differential scanning calorimetry and X-ray powder diffraction. When stearic acid was present with Form I as the starting material in the formulations, the dissolution slowdown was significant under the conditions of higher shear during premixing or higher drying temperature. However, there was little impact of lower shear premixing or lower drying temperature. When Form I was replaced with Form II, the slowdown in dissolution was mainly observed with higher drying temperature. The tablet dissolution slowdown was due to the interaction between Form II and stearic acid that facilitated the formation of Form I. The transformation back to the Form I material reported here may be classified as a thermal-mechanical facilitated PIT and represents a new subclass of the phenomena. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3849–3862, 2010