(579d) 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