Case study 608: Characterizing Disorder in Pharmaceutical Materials
by Vapor Sorption Technique

Introduction

The majority of pharmaceutical materials can exist in a preferred crystalline state, characterized by an ordered lattice structure. However, there may be several different crystalline forms of the same material including polymorphs and/or solvated crystal forms. There will typically be one thermodynamically preferred crystal structure with the lowest energy. All other forms are considered metastable and will eventually relax to the more stable form. However, the timescales of these transitions may be long enough at typical storage and processing conditions for the metastable forms to be used for pharmaceutical development. Also, during the processing of pharmaceutical solids (e.g. crystallization, milling, spray drying, tablet compaction, wet granulation, and lyophilization), various degrees of disorder in the form of crystal defects and/or amorphous regions may be generated. In extreme cases, the material may be completely amorphous where there is no longer any long-range structural order. Amorphous materials in pharmaceutical formulations yield complex and challenging problems concerning the performance, processing, and storage of these products

[1]. The presence of amorphous materials can be wanted or unwanted, depending on the desired or undesired unique properties of the amorphous state. Even relatively low levels of amorphous material (<10%), may have a detrimental impact on the stability and manufacturability of the formulated drug product. Disordered materials are inherently metastable and provided with thermal or mechanical energy will tend to revert to a more thermodynamically stable, crystalline form. For these reasons, investigating the level of disorder or thermodynamic state of pharmaceutical materials is critical in their formulation, storage and processing.

This overview paper highlights how vapor sorption techniques can be used to study pharmaceutical solids ranging from the lowest-energy crystalline state, to higher energy polymorphs and solvates, to defect sites, to completely amorphous materials. Dynamic Vapor Sorption (DVS) and Inverse Gas Chromatography (iGC SEA) are well-established techniques used for the determination of surface and bulk properties of powders, fibers, and films. The aim of this paper is to focus on the applications of these techniques as they relate to thermodynamic stability in pharmaceutical materials.