Characterization and Quality Control of Pharmaceutical Cocrystals

Abstract

Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/ or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

New Preparation Method Using Microwave, Kinetics, In Vitro Dissolution‐Diffusion, and Anti‐Inflammatory Study of Diclofenac‐ Proline Co–Crystal

“…The aim of this study was to develop a method for the preparation of DPC using a domestic microwave (MW) with low energy (399 W). This trial was based on previous conventional methods that are solvent‐drop grinding and neat grinding –. The process was then further investigated to better understand the dynamic co‐crystal formation with the MW.…”

“…Usually, starting materials are still found in the resulting co‐crystal product, corresponding to low yield . Some methods have been reported to address these issues, including neat grinding, liquid‐assisted grinding, hot extrusion, and slow evaporation, all of which have specific advantages and disadvantages . Mechanochemical processes such as grinding, with or without solvents, is laborious in terms of maintaining the continuity due to particle size, surface property changes, and the electrostatic effect during the process .…”

Hydrated Solid Forms of Theophylline and Caffeine Obtained by Mechanochemistry

“…Hydration of an API can affect its biopharmaceutical properties, the manufacturing process and the stability of the final product [4]. Instrumental methods such as infrared spectroscopy, X-ray powder diffraction or single X-ray diffraction are used to identify solid forms of API´s [5].…”

Raman Spectroscopy of Pharmaceutical Cocrystals in Nanosized Pores of Mesoporous Silica

“…[1][2][3][4][5][6] The physicochemical properties of cocrystals are determined by not only their constituent species, but also by the intermolecular bonds between the APIs and coformers. Therefore, the appropriate selection of coformers improves the physicochemical properties of pharmaceuticals, such as the solubility, solution stability, and processability, without altering the nature of the APIs.…”