Solid-State Transformations of Sulfathiazole Polymorphs: The Effects of Milling and Humidity

Abstract

The effect of milling on the solid-state transitions of sulfathiazole polymorphs in the absence and presence of solvent and excipients was monitored by X-ray powder diffraction (XRPD), attenuated total reflectance infrared (ATR-IR) and near-infrared (NIR) spectroscopy. Sulfathiazole forms FII-FV undergo a transformation toward the metastable FI, which involves an intermediate amorphous stage upon milling at ambient temperature. Milling FIII with catalytic amounts of solvent converts FIII to FIV or to mixtures of FI and FIV depending on the solvent used. Pure FIV can be easily prepared from FIII by this method. The physical stability of pure sulfathiazole forms in the presence of different levels of relative humidity (RH) was also investigated. At low RH all sulfathiazole forms are stable but at RH levels above 70% FII, FIII and FIV remain stable while FI and FV transform to mixtures of FII and FIV without any apparent change in the external form of the crystals. Co-milling FIII with a range of excipients gave results which depended on the excipient used and co-milling with cellulose gave samples which had an amorphous content that was stable at 10% RH for at least nine months at ambient temperature.

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“…There is no indication of polymorphic conversion on the timescale of the stability studies. The extreme slowness of the FI → FII transformation has been pointed out by Zhang et al The observation that the recrystallization of the amorphized samples does not follow Ostwald's Rule when stored under vacuum has also been made by us in the case of sulfathiazole …”

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“…8. According to the study of Hu et al [26], the regions of greatest interest in IR spectra of sulfathiazole is 3200-3500 cm -1 . As shown in Fig.…”

Near-Infrared Spectroscopy: Effective Tool for Screening of Polymorphs in Pharmaceuticals

“…Therefore, understanding the effect of milling on the stability of desired forms is highly valuable. Hu et al (29) studied the solid-state transformation of sulfathiazole polymorphs by examining the effect of milling (neat and solvent assisted), relative humidity, and range of pharmaceutical excipients. The spectra were preprocessed using SNV and a second derivative and calibration model were developed using principal component analysis (PCA).…”