Characterization and Interconversion of Polymorphs of Premafloxacin, a New Quinolone Antibiotic

Abstract

The quinolone antibiotic premafloxacin crystallizes in at least five solid modifications, including three anhydrous phases (Forms I-III), a hydrate, and a methanolate. The anhydrous phases were studied by optical microscopy, X-ray powder diffraction, HPLC, hot-stage microscopy, dynamic moisture sorption gravimetry, differential scanning calorimetry, thermal gravimetry, and solution and isothermal calorimetry. Dry samples of Form I converted to Form II and ultimately to Form III through a sequence of melts and recrystallizations. Form III was stable to its melting temperature near 200 degrees C. Humidified samples of Form I converted directly to Form III via a moisture-mediated solid-state phase transformation at temperatures as low as 40 degrees C. The calorimetric and solubility data confirmed that Form III was lower in free energy and enthalpy than Form I at room temperature. Our investigation revealed that Form I was not crystallized directly from solution. Rather, Form I was the product of facile solid-state desolvation of the methanol solvate.

Solid state forms of 4-aminoquinaldine – from void structures with and without solvent inclusion to close packing

“…The formation of a specific solvate form may be the only route to an otherwise elusive phase, e.g. premofloxacin, 82 cinacalect HCl, 83 prilocaine HCl, 84 DB7 (3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid). 27 Thus, the formation of solvates not only expands the solid form landscape of a compound but also the possible screening techniques, i.e.…”

Trends in Solubility of Polymorphs

“…It can be seen that in the majority of cases the ratio was less than 2. In the case of premafloxacin, 11 the solubility ratio in ethyl acetate was unusually high (a factor of 23.1). The general trend is better reflected in Figure 1b, in which premafloxacin is excluded.…”

Solubility analysis of venlafaxine hydrochloride polymorphs by shake-flask method and real time monitoring

“…A general rule is that a polymorph having the lower lattice free energy is the more stable form and it has the lower solubility while that having higher energy is less stable but tends to dissolve faster and has higher solubility [1]. Based on litera-ture solubility data Pudipeddi and Serajuddin [12] published a survey that the ratio of metastable/ stable polymorph solubility is typically less than 2, though occasionally higher ratios can be observed as reported for sulindac (7x difference between From I and II) [13] and for premafloxacin (23x) [14], etc. Similar trend was found for anhydrate/hydrate solubility ratio (~2) with many exceptions, while the amorphous/crystalline forms solubility differs with factor ~10, generally.…”