(381g) Crystal Form and Morphology Control of Obeticholic Acid by Crystallization in Selected Solvents

Crystal Form and Morphology Control of Obeticholic Acid by Crystallization
in Selected Solvents

Shichao Du^{1, 2}, Yan Wang^{1, 2},
Junbo Gong^{1, 2*}, Xiaoyue Tan³

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;

³ Department of Pathology, Medical School of Nankai University,
Tianjin China

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

Abstract

Obeticholic Acid (OCA, Fig. 1), a novel effective drug to cure
primary biliary cirrhosis, non-alcoholic fatty liver disease, etc., has an
extensive clinical application prospect. By now, most literatures about OCA have
focused on the medical aspects, but research on the crystal form and the
particle property of OCA is poor. The product of OCA is easy to agglomerate, which
results in poor dispersibility and fluidity, thus making the formulation more
difficult.

In this work, we aim to develop novel crystal form and better
morphology of OCA by controlling the crystallization process. First, solution
crystallization and solvent assisted grinding were applied to screen new
crystal forms. Then the formation mechanism of the developed crystal form and
crystal morphology were investigated by PAT analysis and molecular simulation
method. Moreover, the crystallization thermodynamics and kinetics of OCA were
studied and provided important instructions for the crystallization process
control.

Two novel crystal forms of OCA (Fig. 2) were successfully developed
and analyzed by PXRD, SXRD, DSC, TGA, FTIR, Raman, etc. Form I was crystallized
by anti-solvent method with two selected organic solvents (ester + methylbenzene), which
was needle-like shape and difficult to be optimized by altering the
crystallization parameters. Interestingly, form II could be obtained when adding
some water into (ester + methylbenzene) mixed solvents though water can cause
liquid-liquid phase separation. Moreover, form II was block-shape and improved
the dispersibility and fluidity, indicating that water played a vital role of controlling
both crystal form and morphology in the crystallization of OCA.

It was also found that OCA had a wide metastable zone and led to
extensive nucleation, making the crystallization uncontrollable. PAT analysis
indicated that temperature, seeding, mixing and solvent composition were the
main factors influencing the crystallization. We optimized these parameters
based on the thermodynamic and kinetic studies of OCA. Finally, we developed a controllable
crystallization process using selected solvents to obtain the pure crystal form
II with good morphology which showed a promising prospect.

Fig. 1 The chemical structure
of OCA

Fig.2 PXRD patterns of OCA