Tuning, measurement and prediction of the impact of freezing on product morphology: A step toward improved design of freeze-drying cycles

Abstract

The control of freezing is crucial as it can influence the freeze-drying operation as well as the chemical and physical properties of the lyophilized product such as the specific surface area, dissolution rate, and drug stability. In this review article, we focus on two areas related to lyophilization in the pharmaceutical industry: (1) advances in our understanding of the relationship between the freezing conditions, product morphology and drying efficiency, and (2) the control of nucleation in solutions to be frozen. The final objective is to accelerate the transition toward a more robust design of freeze-drying cycles, based on deep knowledge of the phenomena involved rather than on empirical observations. While these topics are not new, they are areas of significant current interest to the community engaged in drying in the pharmaceutical industry.Abbreviations: FDM: freeze-drying microscope; GMP: good manufacturing practice; INA: ice nucleating agent; QbD: quality by design; PRT: pressure rise test; SSA: specific surface area, m2; UIIN: ultrasound-induced ice nucleation; VIN: vacuum induced nucleation; VISF: vacuum induced surface freezing.