Interesting Morphological Behavior of Organic Salt Choline Fenofibrate: Effect of Supersaturation and Polymeric Impurity

Abstract

Crystal habit of drug molecules can have significant influence on the processing and performance of pharmaceutical products. During the development of Trilipix, a pharmaceutical product used for the treatment of mixed dyslipidemia, several crystal habits were observed for the active ingredient choline fenofibrate. The dissolution and performance of the drug product were not impacted by changes in crystal habit of the active ingredient due to high solubility of the drug. However, the formulation process was impacted by variations in crystal habit of the active ingredient, requiring robust control of the crystal habit. The crystal habit was greatly influenced by supersaturation during crystallization from a mixed solvent system comprising methanol and isopropanol. In addition to supersaturation, trace levels of a polymeric impurity in the starting material fenofibrate had a detrimental effect on the crystal habit. This article discusses the effects of these factors on the crystal habit of choline fenofibrate and the design of a crystallization process to deliver the target crystal habit, most suited to the formulation process. The article also provides preliminary mechanistic insights into the crystal habit of this organic salt using an extension of the spiral growth model for morphology prediction of organic molecular crystals. An attempt is made to explain the effect of supersaturation and impurity on the crystal habit of choline fenofibrate using the concepts of stability of surfaces, building units, periodic bond chain theory, and the spiral growth model.