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

The effect of milling on the 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 the commercial form (FC) with catalytic amounts of solvent converts it to pure FIV or to mixtures of FI and FIV depending on the solvent used. Pure FIV can be easily prepared from FC by this method. The physical stability of nonmechanically activated pure sulfathiazole forms in the presence of different levels of relative humidity (RH) was also investigated. At low RH, all sulfathiazole forms are kinetically stable, but at RH levels above 70% FII, FC 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. Comilling FC with a range of excipients gave results that depended on the excipient used, and comilling with cellulose gave samples that had an amorphous content that was stable at 10% RH for at least nine months at ambient temperature

Demonstrating the Influence of Solvent Choice and Crystallization Conditions on Phenacetin Crystal Habit and Particle Size Distribution

Phenacetin was used as a model pharmaceutical compound to investigate the impact of solvent choice and crystallization conditions on the crystal habit and size distribution of the final crystallized product. The crystal habit of phenacetin was explored using crash-cooling crystallization (kinetically controlled) and slow evaporative crystallization (thermodynamically controlled) in a wide range of organic solvents. In general, a variety of needle-type shapes (needles, rods, or blades) were recovered from fast-cooling crystallizations, in contrast to hexagonal blocks obtained from slow evaporative crystallizations. The solubility of phenacetin was measured in five solvents from 10–70 °C to allow for the design of larger-scale crystallization experiments. Supersaturation and the nucleation temperature were independently controlled in isothermal desupersaturation experiments to investigate the impact of each on crystal habit and size. The crystal size (needle cross-sectional area) decreased with increasing supersaturation because of higher nucleation rates at higher supersaturation, and elongated needles were recovered. Increasing the nucleation temperature resulted in the production of larger crystals with decreased needle aspect ratios. Antisolvent phenacetin crystallizations were developed for three solvent/antisolvent systems using four different antisolvent addition rates to simultaneously probe the crystal habit and size of the final product. In general, increasing the antisolvent addition rate, associated with increased rate of generation of supersaturation, resulted in the production of shorter needle crystals