Crystal Morphology and Size Control in Pharmaceutical Industry

Crystal Morphology and Size Control in Pharmaceutical Industry

Junbo Gong^1,2* , Yan Wang^1,2, Jingkang Wang^1,2

¹ National Engineering Research Center of Industry Crystallization Technology, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China;

² The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin, China;

E-mail address: junbo_gong@tju.edu.cn ^*   wangyan57@tju.edu.cn

Abstract

Crystal shape and size engineering is an integral part of pharmaceutical crystallization. It aims to design and control crystal habit and particle size distribution (PSD) of drug substance. This program is of great significance due to the strong impact of product quality, including bioavailability, dissolving rate, flowability, etc. Downstream particle handling is also affected, such as filtration, drying and compaction. The factors influencing crystal morphology and size come from two groups: the one is the operating condition, which includes supersaturation, temperature, the hydrodynamics of the crystallizer (e.g., stirring rate, mixing conditions) and external field (e.g., magnetic field, ultrasound field), and the other is chemical composition of the solution which consists of solvents and additives. In order to control crystal shape and PSD, experiments should be designed and carried out to monitor crystal growth process. The influence on crystallization thermodynamics and kinetics should also be investigated. During the research, microscopy techniques, like polarizing optical microscope, scanning electron microscopy (SEM) and atomic force microscope (AFM) will be applied to analyze crystal shape. Particle sizing techniques are also used to count for PSD, like the laser diffraction (LD) and focused beam reflectance measurement (FBRM). On the other hand, the use of additives has attracted increasing attention in the drug manufacturing process. The presence of additives could substantially affect the solid forms and morphology. High throughput screening (HTS) techniques to additives should be developed to accelerate the screening efficiency. The effects of additives on crystal shape may be resulted from the specificity of interaction between the additive and the solute molecule, charge distribution, hydrophilic-hydrophobic property, stereoselectivity as well as diffusion rate and competitive adsorption, etc. With fast advances made in computational techniques, modeling and prediction of crystal morphology can be realized in the absence or presence of additives. They not only provide powerful tools to design and screen effective additives, but lead to further understanding of crystal growth mechanisms.

Fig. 1. SEM of the drug substance without (a) with (b) the modification of the crystallization environment