INVESTIGATION OF THE POLYMORPHISM OF SULFATHIAZOLE BY A COMBINED DSC-HSM APPROACH M. R. Abu Bakar, C. D. Rielly, Z. K. Nagy † Department of Chemical Engineering, Loughborough University, Loughborough, Leics., LE11 3TU, United Kingdom † E-mail: Z.K.Nagy@lboro.ac.uk A combination of differential scanning calorimetry (DSC) and hot-stage microscopy (HSM) has been used to investigate the polymorphism of sulfathiazole. The approach provides a unique insight into the polymorphic transformations and thermal behaviour exhibited by this compound. The results of the experiments show that sulfathiazole tends to crystallize as mixtures of polymorphs, although the literature methods of producing pure polymorph were followed. The use of light intensity profile obtained from the HSM images, as an alternative way to present results of HSM analysis is also introduced here. It was found to correspond very well with the DSC thermogram. 1. Introduction Crystallizations of active pharmaceutical ingredients (APIs) particularly those that possess multiple polymorphic forms are amongst the most critical, yet least understood pharmaceutical processes. Statistically, about 85% of APIs exhibit polymorphism and 50% have multiple polymorphic forms [KAR06]. The polymorphs of a crystal can exhibit a variety of structures, which have different inter- and intra-molecular interactions. Thus, they have different free energies and consequently different physico-chemical properties and mechanical behaviours [HIL06]. These have an impact on downstream process operations, such as isolation, filtering and drying, and can affect the therapeutic properties of the final product. Therefore, it is desirable for pharmaceutical manufacturers to characterise extensively all known polymorphs of an API. Since all the available characterisation techniques may deliver dubious results, a combination of techniques is used to provide a comprehensive characterisation of the sample. A reliable technique that can quickly differentiate between different polymorphs and determine if a solid contains a pure polymorph or a mixture of polymorphs would be preferable. One of the most widely used techniques for the investigation of polymorphism is differential scanning calorimetry (DSC). The technique basically involves the application of a heating/cooling signal to a sample and the subsequent measurement of the temperature and energy associated with thermal events including melting and polymorphic transformation [REA07]. The popularity of DSC is due to its simplicity and rapidity of measurement, as well as its requirement for a small sample size. Another technique for the investigation of polymorphism is hot-stage microscopy (HSM), which combines microscopy and thermal analysis, and allows visual observation of the behaviour of a sample through a microscope during heating or cooling [VIT98]. Recent technological advances have expanded the capabilities of HSM, for example with the use of software, which not only captures the image, but also performs an image analysis by computing the total light intensity. The latter may be calculated as the sum of the grey levels in all pixel (pixel value ranges from black = 0 to white = 255). As the image becomes brighter, the light intensity value becomes higher. This provides an alternative way of presenting the results of analysis. Sulfathiazole has been chosen as the model system in this study. It has four polymorphs that are well characterised and clearly described in the literature ([AND01], [APP99],