Local Structural Effects Due to Micronization and Amorphization on an HIV Treatment Active Pharmaceutical Ingredient.

Processing procedures for inducing domain size reduction and/or amorphous phase generation can be crucial for enhancing the bioavailability of active pharmaceutical ingredients (APIs). It is important to quantify these reduced coherence phases and to detect and characterize associated structural changes, to ensure that no deleterious effects on safety, function, or stability occur. Here, X-ray powder diffraction (XRPD), total scattering pair distribution function (TSPDF) analysis, and solid-state nuclear magnetic resonance spectroscopy (SSNMR) have been performed on samples of GSK2838232B, an investigational drug for the treatment of human immunodeficiency virus (HIV). Preparations were obtained through different mechanical treatments resulting in varying extents of domain size reduction and amorphous phase generation. Completely amorphous formulations could be prepared by milling and microfluidic injection processes. Microfluidic injection was shown to result in a different local structure due to dispersion with dichloromethane (DCM). Implications of combined TSPDF and SSNMR studies to characterize molecular compounds are also discussed, in particular, the possibility to obtain a thorough structural understanding of disordered samples from different processes.

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).

Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: crystal structures and multinuclear solid-state NMR.

Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a thermodynamic transition temperature of 35 +/- 3 degrees C. The crystal structure of Form 1, which is thermodynamically more stable at lower temperatures, was determined by SCXRD. The crystal structure of Form 2 was determined using PXRD structure solution methods that were assisted using two types of SSNMR experiments, dipolar connectivity experiments and chemical shift measurements. These experiments determined certain aspects of local conformation and intermolecular packing in Form 2 in comparison to Form 1, and provided qualitative knowledge that assisted in obtaining the best possible powder structure solution from the X-ray data. NMR chemical shifts for 1H, 13C, 15N, and 19F nuclei in Forms 1 and 2 are sensitive to hydrogen-bonding behavior, molecular conformation, and aromatic pi-stacking interactions. Density functional theory (DFT) geometry optimizations were used in tandem with Rietveld refinement and NMR chemical shielding calculations to improve and verify the Form 2 structure. The energy balance of the system and other properties relevant to drug development are predicted and discussed.