Martha Davidovich

The evolution of hot-stage microscopy to aid solid-state characterizations of pharmaceutical solids

A variety of techniques can be used to characterize the physical properties of pharmaceutical solids, including thermal analysis, hot-stage microscopy, X-ray powder diffraction, spectroscopic and micromeritic analysis. Comprehensive characterizations of the physical properties of pharmaceutical solids require a multi-disciplinary approach, since no single technique is capable of characterizing the materials completely. The combination of traditional hot-stage microscopy with new technologies such as high-resolution micrography, image capture, storage manipulation, and presentation, have permitted more comprehensive physical property characterizations to be conducted. As a result of these technological advances, it is possible to present the results of these microscopic analyses, as they were initially collected by the microscopist, outside of the laboratory. An evolutionary trail detailing the use of hot-stage microscopy in the Materials Science Group, from a simple melting point apparatus to the current hot-stage DSC microscopy instrument, will be presented. Examples of materials characterized using the hot-stage microscopy system will also be presented. # 1998 Elsevier Science B.V. All rights reserved.

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

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.

Use of enthalpy and Gibbs free energy to evaluate the risk of amorphous formation

The control of crystalline and amorphous phases is important during the development of a new drug candidate. Our approach begins with an understanding of the thermodynamics of these two phases. We have developed a quantitative yet practical work flow consisting of three steps towards the analysis of the risk of amorphous material formation. First, we derive the thermodynamic equations to calculate the enthalpy, Gibbs free energy, and the solubility of each phase and their differences as a function of temperature. The enthalpy for each crystalline drug substance at its melting point is selected as the reference state to enable a consistent approach for all analysis. Second, we use data from DSC measurements and the derived thermodynamic equations to construct the enthalpy, Gibbs free energy and solubility diagrams so as to compare the characteristics of these two phases. Finally, we use the results of these calculations to evaluate the potential risk of crystalline-to-amorphous phase conversion during processing of either the drug substance or the drug product. In addition, the impact of amorphous formation on solubility is evaluated. Two drug candidates are used to illustrate this workflow for risk analysis.