The successful development and commercialization of an active pharmaceutical ingredient (API) require adequate processability, stability, and bioavailability (1
). However, APIs with desired biological activities rarely exhibit adequate physical properties to meet all of the requirements. Crystal engineering, the design of molecular solids in the broadest sense (2
), is gaining an increased interest within the pharmaceutical industry because it enables preparation of materials with tailored physical properties.
One persistent challenge in the development and manufacturing of APIs is poor tabletting performance (4
). Crystal habit, or morphology, is a crucial attribute of powdered materials that affects the ease with which a pharmaceutical formulation can be pressed into a tablet. In particular, equidimensional crystals are usually preferred in the industry as they have better handling and processing characteristics such as flowability and compactability (6
). Crystal morphology engineering is therefore a valuable tool to enhance processing properties of solid materials for a specific formulation.
Control of crystal morphology can be achieved by solvent selection (9
) and/or tailor-made additives (13
). In the context of pharmaceutical solids, the solvent-induced crystal habit modification approach is limited by the solvent toxicity and cost, crystallization efficiency, and the purity requirements of the final product. Hence, the use of additives as crystal habit modifiers of APIs is usually preferred. Furthermore, employing pharmaceutically accepted excipients as additives represents the most practical alternative for such a highly regulated industrial sector as the pharmaceutical industry.
This study therefore aims to (1) investigate crystallization in the presence of pharmaceutically accepted excipients as a tool for crystal morphology engineering of APIs and (2) evaluate compaction properties of the additive-modified crystals. Erythromycin A dihydrate (EMAD; Fig. a), a widely prescribed macrolide antibiotic possessing poor compaction properties, was selected as a model API, while hydroxypropyl cellulose (HPC; Fig. b) was chosen as a crystal habit modifier, based on the preliminary additive screening experiments in our laboratory.
Molecular structures for the model API, erythromycin A a and hydroxypropylmethylcellulose, a pharmaceutical excipient used as crystal habit modifier in this study b. The relevant oxygen atoms are numbered in panel a