The Degradation Chemistry of GSK2879552: Salt Selection and Microenvironmental pH Modulation to Stabilize a Cyclopropyl Amine.

The cyclopropyl amine moiety in GSK2879552 (1) degrades hydrolytically in high pH conditions. This degradation pathway was observed during long-term stability studies and impacted the shelf life of the drug product. This article describes the work to identify the degradation impurities, elucidate the degradation mechanism, and design a stable drug product. It was found that salt selection and control of the microenvironmental pH of the drug product formulation blend significantly improved the chemical stability of the molecule in the solid state.

Analysis of unstable degradation impurities of a benzodiazepine and their quantification without isolation using multiple linear regression.

This manuscript presents a novel methodology for calculating the relative response factors (RRFs) of unstable degradation impurities of molibresib (1). The degradation impurities were observed by HPLC during stress testing and were accompanied by large mass balance deficits. However, the impurities could not be isolated for traditional RRF determination due to their instability. The RRFs of two degradation impurities were determined without isolation by multiple linear regression analysis of HPLC-UV data. The results permitted accurate quantification of the degradants. The benefits and drawbacks of the approach are discussed, including suggested validation acceptance criteria.

One-phase crystal disorder in pharmaceutical solids and its implication for solid-state stability.

Solid-state disorders of active pharmaceutical ingredients have been characterized by means of X-ray diffraction techniques and solid-state nuclear magnetic resonance spectroscopy. The results determined that the pleuromutilin-derivative, I, displays a unique continuous conformational disorder while retaining its long-range crystalline structure. The propionic acid (PA) version of this compound displayed partial crystalline order and site disorder of PA, depending on the quantity of PA incorporated in the structure. Thus, I is a unique example of one-phase crystalline-amorphous model. Physical and chemical stability data was acquired on these disordered systems and discussed in relation with the characterized disorder present in the crystal systems. Analysis of the results showed that in contrast to phase-separated amorphous, restrained disorders do not influence the stability.

Analysis of amorphous solid dispersions using 2D solid-state NMR and (1)H T(1) relaxation measurements.

Solid-state NMR (SSNMR) can provide detailed structural information about amorphous solid dispersions of pharmaceutical small molecules. In this study, the ability of SSNMR experiments based on dipolar correlation, spin diffusion, and relaxation measurements to characterize the structure of solid dispersions is explored. Observation of spin diffusion effects using the 2D (1)H-(13)C cross-polarization heteronuclear correlation (CP-HETCOR) experiment is shown to be a useful probe of association between the amorphous drug and polymer that is capable of directly proving glass solution formation. Dispersions of acetaminophen and indomethacin in different polymers are examined using this approach, as well as (1)H double-quantum correlation experiments to probe additional structural features. (1)H-(19)F CP-HETCOR serves a similar role for fluorinated drug molecules such as diflunisal in dispersions, providing a rapid means to prove the formation of a glass solution. Phase separation is detected using (13)C, (19)F, and (23)Na-detected (1)H T(1) experiments in crystalline and amorphous solid dispersions that contain small domains. (1)H T(1) measurements of amorphous nanosuspensions of trehalose and dextran illustrate the ability of SSNMR to detect domain size effects in dispersions that are not glass solutions via spin diffusion effects. Two previously unreported amorphous solid dispersions involving up to three components and containing voriconazole and telithromycin are analyzed using these experiments to demonstrate the general applicability of the approach.

Magnetic alignment of aqueous CTAB in nematic and hexagonal liquid crystalline phases investigated by spin-1 NMR.

Spin-1 NMR has been used to characterize the magnetically aligned nematic and hexagonal liquid crystalline phases of aqueous cetyltrimethylammonium bromide (CTAB). A nematic/hexagonal biphasic region has been identified for the first time in this system. The nematic phase is characterized by an order parameter of smaller magnitude and greater temperature dependence. Magnetic alignment kinetic rates of the two phases differ greatly, with the nematic phase showing magnetic alignment much faster than the hexagonal phase. Equilibration has been monitored over time by measuring the change in quadrupole splitting as a function of temperature. As the sample equilibrates the temperature dependence of the splitting decreases logarithmically. This work also demonstrates how the phase and order of the liquid crystal can be manipulated during the early part of equilibration.

Synthesis of organo-silane functionalized nanocrystal micelles and their self-assembly.

We report a general method to synthesize gold nanocrystal micelles with organo-silane headgroups. The method involves encapsulation of monodisperse, hydrophobic gold nanocrystals within the core of a micelle of an amphiphilic silane precursor. Formation and stability of monodisperse gold NC micelles have been confirmed using UV-visible spectroscopy and transmission electron microscopy. Self-assembly of such nanocrystal micelles through siloxane hydrolysis and cross-linking leads to an ordered array with a face-centered-cubic mesostructure.

Ring-chain tautomerism in solid-phase erythromycin A: evidence by solid-state NMR.

Chemical shift modeling, utilizing the DFT B3LYP/D95** method, provides the spectral assignment of the 35 visible 13C resonances from the solid-phase erythromycin A dihydrate. A new resonance at 110.8ppm is observed in the high-resolution 13C CP/MAS spectrum upon the application of heat or sample desiccation. With the use of the dipolar-dephasing spectral editing technique, this resonance is identified as a hemiketal carbon and the alternative hypothesis, a conformational change to the anomeric carbon of the desosamine sugar, is ruled out. Hence, the formation of a cyclic hemiketal in erythromycin A while in the solid phase is proven by solid-state NMR. The principal components of the 13C chemical-shift tensor corresponding to this hemiketal are reported. This is the first measurement of hemiketal 13C principal values. The delta11 and delta22 components are unique compared to anomeric carbon values reported in the literature.