Habit modification in pharmaceutical crystallization: A review

Besides size and purity, habit represents a critical quality attribute of pharmaceutical crystals, influencing effi-ciencies of downstream processing steps and final drug product's qualities. In particular, needle-like habit poses problems in pharmaceutical manufacturing due to its difficult handling. Various habit modification strategies based on both chemical and physical routes have been developed to suppress needle-like crystal formation. Lately, habit modification is also performed on non-needle crystalline drugs to improve their qualities. The present review discusses recent advances in in situ crystal habit modification strategies for both small-molecule pharmaceuticals and biopharmaceuticals. The following modification strategies are reviewed, namely (1) su-persaturation variation, (2) solvent selection, (3) addition of habit modifiers, (4) pH variation, (5) temperature profile, and (6) ultrasound application. Integrated approaches that combine multiple strategies and incorporate ex situ/in situ milling, feedback process control, and habit monitoring are also presented. Positive impacts of habit modification on crystals' dissolution rate, flowability, stability, and tabletability are discussed. Solvent selection stands out as the most popular habit modification strategy, particularly for small-molecule pharma-ceuticals, followed by supersaturation and temperature variations. The impacts of several habit modification strategies are often found to be drug-specific, necessitating development and validation of habit predictive models over broader experimental conditions.