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Hot melt extrusion is important for the development of advanced pharmaceutical dosage forms. In this study, the dehydration of nitrofurantoin monohydrate during melt extrusion below the expected dehydration temperature has been investigated. The influence of process time, temperature, and drug/polymer ratio on the solid form of the drug compound was studied using drug/polymer physical mixtures with thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction, rheometry, and hot-stage microscopy and compared with data generated from the extruded products. Extensive dehydration of nitrofurantoin monohydrate was surprisingly observed at extrusion temperatures as low as 70 °C in contrast with TGA and DSC analysis of the pure drug indicating dehydration onset at around 90 °C. This was related to shear induced solution-mediated transformation, where nitrofurantoin dissolved into the molten polymer and rapidly recrystallized as nitrofurantoin anhydrate, as well as simultane...

Crystallization in the presence of pharmaceutically accepted excipients as additives was investigated as a tool for morphological crystal engineering of active pharmaceutical ingredients. Recrystallization of a model drug substance, erythromycin A dihydrate, was carried out by a precipitation technique in the presence of varying amount of hydroxypropyl methylcellulose (HPMC). In contrast to the reference crystals, the crystals grown in the presence of HPMC exhibited regular shape, which varied with the concentration of the additive present, thus indicating that HPMC is an effective habit modifier for erythromycin A dihydrate. On the basis of the crystal surface chemistry, the mechanism responsible for the change in morphology is proposed. Finally, the effect of crystal habit modification on compaction behavior of erythromycin A dihydrate is demonstrated.

Approximately one-third of all drugs can form hydrates, and therefore an in-depth understanding of the factors affecting anhydrate-to-hydrate transformation kinetics in a variety of environments is of interest. In this work, real-time analytical methods, in the form of Raman spectroscopy and optical microscopy, were used to establish representative transformation profiles and growth kinetics for hydrate formation of several drug substances. By comparing and contrasting the behavior of these different hydrates in terms of their specific properties such as solubility, dissolution rate, and growth rate of hydrate phase, and the influence of external factors such as seeding and agitation conditions, an increased understanding of hydrate formation has been achieved. The overall transformation rate from anhydrous to hydrate form was found to be not only a function of compound-specific properties, but was also strongly affected by surface properties and external factors such as the presence of seeds and the degr...

In-line monitoring of solid-state properties in crystallization processes is of great significance in controlling the quality of crystalline active pharmaceutical ingredients. In this work, the solvent-mediated phase transformation of anhydrous to dihydrated carbamazepine in ethanol−water mixtures was studied using an in-line Raman immersion probe. The solute concentration profile was measured by off-line sampling. The transformation experiments were conducted with different operation parameters in terms of solvent composition and temperature. The transformation rate depends on both solvent composition and temperature. The mechanism of the transition was interpreted with the two-step polymorphic form transformation mechanism. It was observed that the crystallization of the stable form was the rate-controlling step. The influence of the operation parameters on the transformation rate can be interpreted as the effects of solvent and supersaturation on the crystallization kinetics. Another interpretation is ...

Thermal stress that pharmaceutical solids are exposed to during manufacturing can induce various phase transitions in bulk drug substances or excipients, resulting in altered dosage form performance. This paper reports on the thermally induced transformations of a macrolide antibiotic, erythromycin A dihydrate, investigated in situ by variable temperature powder X-ray diffractometry and hot-stage Raman spectroscopy. Erythromycin A dihydrate undergoes dehydration to isomorphic dehydrate, which then melts and recrystallizes to anhydrate. Raman spectroscopy was able to distinguish the two isomorphs of erythromycin A, the dihydrate and the dehydrate, thus offering a potential tool for in-process control of the drying process. The model fitting approach did not provide insight into the solid-state dehydration mechanism. However, the reaction mechanism was presented on the basis of crystal chemistry.