Characterization, selection, and development of an orally dosed drug polymorph from an enantiotropically related system.

Solid-state characterization methods are used to study a dimorphic pharmaceutical compound and select a form for development. Polymorph screening found that [4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl] acetic acid can crystallize into two non-solvated polymorphs designated Forms 1 and 2. Physical methods including vibrational spectroscopy, X-ray powder diffraction, solid-state NMR (SSNMR), thermal analysis, and gravimetric water vapor sorption are used to fully characterize the two polymorphs. Temperature-dependent competitive ripening experiments and solubility measurements indicated that the polymorphs in this system exhibit enantiotropy with a thermodynamic transition temperature of 35+/-3 degrees C. This complicates the selection of a polymorph to progress in drug development. Both forms had undesirable qualities; however, a particular drawback of Form 1 was found in its tendency to convert to Form 2 upon milling. Combining this effect and the desired formulation approach with physical property results led to a rationale for the choice of Form 2 for further development. Because this form is thermodynamically metastable at room temperature, analytical approaches were developed to ensure its exclusive presence, including a quantitative infrared spectroscopic method for drug substance and (13)C and (19)F solid-state NMR limit tests for the undesired form in drug product at drug loads of 8.3% (w/w).

A study of variable hydration states in topotecan hydrochloride.

Topotecan hydrochloride, a pharmaceutical compound developed as a treatment for cancer, exhibits variable hydration states in a crystalline solid form chosen for manufacturing. This variability requires additional controls for successful development, and presents a characterization and detection challenge for analytical methods. In this study, overall water content was determined by Karl Fischer titration and thermogravimetric analysis (TGA) on topotecan HCl equilibrated at different relative humidity levels. These results, when combined with information obtained from dynamic water vapor sorption and differential scanning calorimetry (DSC), indicate that this form of topotecan HCl contains 3 mol of water integral to the crystalline structure and up to two additional moles of water depending on the relative humidity. Powder X-ray diffraction experiments did not detect significant differences in topotecan HCl samples equilibrated at trihydrate and pentahydrate states, and showed that the crystal lattice dimensions are not affected unless the form is dried below the trihydrate state. This behavior is typical of crystal structures with channels that can accommodate additional loosely bound water. To study the role of the loosely bound water in the crystal structure in more detail, solid-state (13)C and (15)N nuclear magnetic resonance (NMR) were used to examine the differences between the hydration states. Both the trihydrate and pentahydrate states yielded similar solid-state NMR spectra, consistent with the lack of change in the crystal lattice. However, minor but readily detectable differences in the (13)C spectra are observed with changes in water content. Interpretation of this data suggests that the loosely bound channel water is hydrogen-bonding to specific portions of the topotecan parent molecule. Topotecan HCl trihydrate was hydrated with D(2)O vapor to confirm the nature and location of the channel water using (13)C and (2)H solid-state NMR. Despite the detectable association of the channel water with hydrogen bonding sites on the topotecan molecule, (2)H quadrupolar echo experiments indicate that the channel water is highly mobile at room temperature and at -60 degrees C.

Rearrangement of epoxynitriles: a convenient homologation of acyclic and cyclic ketones to carboxylic acids.

A convenient two-step homologation of both aliphatic and aromatic ketones to the corresponding carboxylic acid has been developed. First ketones were converted to epoxynitriles with the Darzens reaction. Second, a Lewis acid mediated rearrangement of these epoxynitriles with lithium bromide was achieved to give homologated secondary alkanoic acids (as well as aryl-alkanoic) in good yields. The mechanism and the scope of the rearrangement reaction were investigated. This strategy constitutes a two-step homologation of ketones to secondary carboxylic acids.