(548c) PAT Based In Situ Monitoring and Control of the Polymorphic Purity of Pharmaceuticals In Batch Cooling Crystallization

Sulfathiazole, an antibiotic compound, has been reported to have five polymorphs [1].  Although its polymorphism has been extensively and repeatedly investigated by various researchers, it remains difficult to produce a pure polymorph; most of the time, the desired polymorph contains impurities from at least one other form [2].  In this paper the application of Process Analytical Technology (PAT) tools such as focused beam reflectance measurement (FBRM), and attenuated total reflectance ultraviolet/visible (ATR-UV/Vis) spectroscopy in combination with chemometrics will be corroborated for the in-situ monitoring and control of the polymorphic purity of sulfathiazole.  The approach will use a feedback control strategy, which will drive the process in the phase diagram by manipulating the operating temperature profile to achieve a desired polymorphic form.  An experimental case study demonstrates that the proposed approach is able to selectively control the formation of form I and form IV of the sulfathiazole crystals. In this case, form IV is the desirable polymorph and in order to eliminate the presence of form I, the operating profile is driven in such a way that after the nucleation of an unknown polymorph or a mixture of the polymorphs, it is controlled to operate below the solubility curve of form I but in the supersaturation region of form II.  An additional case study for the polymorphic control of o-amino benzoic acid is also presented. Characterization of the polymorphs obtained will be performed using x-ray diffraction, thermal and microscopy methods to validate the success of the control approach.

[1]  D. S. Hughes, M. B. Hursthouse, T. Threlfall and S. Tavener, (1999), Acta Cryst. C, 55, 1831.

[2] A. Hakkinen, K. Pollanen, M. Karjalainen, J. Rantanen, M. Louhi-Kultanen and L. Nystrom, (2005),  Biotechnol. Appl. Biochem., 41, 17.