Polymorphic transformations under compression

Wenjin Cao, Purdue University

Abstract

Compaction-induced polymorphic transformations of APIs were investigated. Understanding of compression-induced transformations is important to ensure product quality and meet regulatory requirements. The objectives of this project were: (1) develop a method for direct analysis of drug compacts/tablets containing different polymorphs; (2) study the controlling factors of compaction-induced transformations. I. The quantitative analysis for polymorph compacts containing different polymorphs was developed using parallel beam X-ray powder diffraction (XRPD) technique. The modified parallel beam geometry minimizes artifacts from sample surface geometry, which gives XRPD the ability to analyze intact compacts/tablets without sample preparation (e.g. grinding). Moreover, other functions that come with the new setup, such as high X-ray intensities, large beam size, and symmetrical peak shape, are also beneficial to the analysis of compressed samples. The quantitation method was developed for glycine and chlorpropamide compacts. A further study was conducted to model the XRPD intensity variations in compressed samples. A model was developed to describe the XRPD intensity variation as a function of solid fraction and thickness and tested on glycine compacts. With this model, intensity variations from compacts made at different compression conditions can be normalized, making the method transferable to various tablet geometries, facilitating the analysis over the expected range of formulation compositions and process variation. II. For a complex process such as compression, factors like pressure and temperature could all induce transformations. Pressure-induced transformation was studied in a quasi-static high-pressure environment using a diamond anvil cell and transformations were followed by Raman spectroscopy. A hypothesis, density rule violators should transform under high pressure, was also tested in this work. Resorcinol results from literature support the proposed hypothesis. Studies on indomethacin were consistent but inconclusive. Based on the model, an estimation of the transformation potential based on the physical properties of a compound is possible. The combined effects of two major factors, pressure and temperature, on inducing transformations were investigated in another study of chlorpropamide. Results showed that pressure alone is unlikely to induce the polymorphic transformations within the typical pressure range used to manufacture tablet dosage forms. The effects of pressure and temperature must be considered in compaction-induced transformation.

Degree

Ph.D.

Advisors

Morris, Purdue University.

Subject Area

Pharmacology|Pharmaceuticals

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