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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.

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.

The color of active pharmaceutical ingredients (APIs) can be a critical quality attribute for pharmaceutical products. Color variation can be indicative of contaminants, chemical impurities, solid-state form impurities, or degradation products. The color of the pharmaceutical materials is typically specified and determined using visual appearance testing. To avoid the inherent subjectivity of visual appearance testing, to understand the link between the color and the process parameters, and to facilitate quality agreements between customers and vendors of chemical starting materials, quantitative color measurements utilizing visible spectroscopic methods are increasingly needed. In this work, a systematic method development strategy (MDS) is described to assist with the development of robust and rugged quantitative color measurement methods based on a science- and risk-based approach aligned with quality-by-design principles. The MDS is illustrated using typical scenarios encountered in method development through several examples including a method developed for 2,3-dimethyl-2H-indazol-6-amine, a starting material in the commercial synthesis of pazopanib hydrochloride API. Flowcharts and examples are presented to illuminate key decision points in the MDS process including selection of (1) solution-state versus solid-state spectroscopic method, (2) optimal color space for reporting color measurement results, and (3) appropriate method risk assessment and control to ensure successful method implementation. General guidance is also provided to facilitate the discussion for setting quantitative color specifications.

Solid-state analysis with powder X-ray diffraction (PXRD), solid-state NMR (SSNMR), and other spectroscopic and physical methods can provide detailed structural information about organic and pharmaceutical cocrystals. In this study, a range of solid-state analysis methods are used to characterize co-crystallized solid solutions of 5-fluorouracil and thymine. 1H, 13C and 19F SSNMR and PXRD methods are used to study the structure and disorder present in a solid solution previously prepared by solution evaporation methods; here the solid solution is prepared over a wider stoichiometric range by solvent-drop grinding techniques. Long-range perturbations of key chemical shifts are detectable by SSNMR, indicating that the solid solution is not random. Cross-polarization and heteronuclear correlation SSNMR experiments between 1H, 13C, and 19F nuclei offer insight into the structure of this solid solution, and density functional theory (DFT) methods are applied to calculate lattice energies and NMR properties in order to understand the population of the two primary disordered sites in the crystal structure. In addition, a second solid solution of 5-fluorouracil and thymine is reported and analyzed. This solid solution, which was produced by solvent-drop grinding experiments and characterized by SSNMR and powder X-ray diffraction methods, is determined to be an isostructural phase to that of anhydrous thymine with the inclusion of 5-fluorouracil defects. A similar effect does not occur under excess 5-fluorouracil conditions; instead, phase-separated Form 1 of 5-fluorouracil and anhydrous thymine are obtained. DFT calculations are applied to offer a possible explanation for this disparity.

A scalable synthesis of a novel pleuromutilin-based antibiotic is reported. The synthesis features the scale-up of an interesting skeletal rearrangement of the pleuromutilin core and isolation of a highly purified product despite starting with relatively impure pleuromutilin. The use of Design of Experiment (DoE) and Principal Component Analysis (PCA) tools to achieve these goals is also discussed. Furthermore, the novel coupling of a carbamate and N-acyl-imidazole to produce the imidodicarbonate portion of the target molecule is described.

Solid-state NMR (SSNMR) is capable of providing detailed structural information about organic and pharmaceutical cocrystals and complexes. SSNMR nondestructively analyzes small amounts of powdered material and generally yields data with higher information content than vibrational spectroscopy and powder X-ray diffraction methods. These advantages can be utilized in the analysis of pharmaceutical cocrystals, which are often initially produced using solvent drop grinding techniques that do not lend themselves to single crystal growth for X-ray diffraction studies. In this work, several molecular complexes and cocrystals are examined to understand the capabilities of the SSNMR techniques, particularly their ability to prove or disprove molecular association and observe structural features such as hydrogen bonding. Dipolar correlation experiments between spin pairs such as 1H−1H, 1H−13C, and 19F−13C are applied to study hydrogen bonding, intermolecular contacts, and spin diffusion to link individual molecules...

An unusual pharmaceutical solid containing a pleuromutilin derivative, succinic acid and water is studied with a combination of physiochemical methods. The parent pleuromutilin derivative creates a host structure that contains large channels, which are occupied by variable amounts of both succinic acid and water. The inherent disorder of the system does not lend itself to detailed single-crystal X-ray diffraction studies; hence a combination of powder X-ray diffraction (PXRD) and solid-state NMR (SSNMR) techniques were used to characterize this system and understand its behavior. A variety of one and two-dimensional SSNMR experiments were used to understand the proton transfer and the hydrogen bonding network, including 1H−13C heteronuclear correlation experiments and measurements of the principal components of 13C chemical shift tensors. This crystal system can exist as two distinct phases; a hemisuccinate phase containing a doubly ionized succinate molecule with two cations of the pleuromutilin derivati...

A series of tantalum oxyfluoride materials containing the [Ta4F16O4]4− and [Ta8F24O12]8− anion clusters have been synthesized and characterized using X-ray diffraction (XRD) and solid-state nuclear magnetic resonance (SSNMR) spectroscopy. The structure of both tantalum oxyfluoride materials display octahedrally bonded tantalum atoms with bridging oxygen and terminal fluoride atoms. The [Ta4F16O4]4− cluster is an eight-membered ring, whereas the [Ta8F24O12]8- cluster forms a cagelike structure. Solid-state dynamics of these clusters were explored by monitoring the impact of temperature on the one-dimensional (1D) 19F magic angle spinning (MAS) NMR, 13C cross-polarization (CP) MAS NMR, and two-dimensional (2D) double quantum (DQ) 19F MAS NMR spectra. The DQ 19F NMR correlation experiments allowed the through space connectivity between the different resolved fluorine environments to be determined, thus aiding in the spectral assignment and structural refinement of these materials. Ab initio 19F NMR chemical ...

Several cage-substituted hexaazaisowurtzitanes [2,4,6,8,10,12-hexabenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (HBIW); 2,6,8,12-tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (TADB); and 2,6,8,12-tetra-acetyl-4,10-diformyl-2,4,6,8,10,12-hexaazaisowurtzitane (TADF)] have been synthesized as intermediate steps in the synthesis of CL-20. The 1 5 N NMR isotropic and chemical shift tensor principal values have been obtained for these intermediates using CP/MAS and FIREMAT methods. Solid-state 1 5 N NMR offers unique advantages in the study of these materials, due to solubility issues and lack of high-quality X-ray crystallographic data. In addition, the caged structures possess unique electronic properties that can be useful in further refining theoretical methods. The effects of the different functional groups on the chemical shift tensor principal values of these caged amines have been evaluated and are shown to be reflected in the total anisotropy. The position of the amine within the cage is manifested in the δ 2 2 values. Nitrogen-15 NMR shielding calculations using the embedded ion method (EIM) to account for long-range intermolecular interactions show a good correlation, rmsd = 4 ppm, with the observed chemical shift tensor values.

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.

The 1 3 C chemical-shift tensor principal values were measured for p-aminosalicylic acid, pyrazinamide, and isoniazid. A moderate-strength hydrogen bond between adjacent p-aminosalicylic acid molecules in the crystal was simulated several different ways in attempts to find a reasonable model of the electrostatic interactions in the crystal. Crystal lattice effects on the calculated chemical-shift tensors are treated by application of the embedded ion method (EIM). Coupling between 1 4 N and several 1 3 C atoms was included in the data analysis to provide more accurate 1 3 C chemical-shift tensor principal values. The chemical-shift tensors are assigned with a permutative algorithm based upon the computed chemical shifts.

Thermogravimetry has been used to study the kinetics of the thermal dissociation of solid and liquid ammonium nitrate. Model-fitting and model-free kinetic methods have been applied to the sets of isothermal and nonisothermal measurements to derive kinetic characteristics of the processes. The application of the model-fitting method to the isothermal data has demonstrated that both solid- and liquid-phase kinetics are characterized by a single activation energy of ∼90 kJ mol-1 and by the model of a contracting cylinder. A model-free isoconversional method has also been applied to isothermal and nonisothermal data and has yielded an activation energy of ∼90 kJ mol-1, which is essentially independent of the extent of conversion. The obtained kinetic characteristics have been assigned to the process of dissociative sublimation/vaporization.

Solid-state NMR (SSNMR) spectroscopy has been found to be very useful technique for pharmaceutical development. This technique is currently applied for the study of pharmaceutical solids, ranging from detailed structural studies of active pharmaceutical ingredients (APIs) forms to analysis of complex drug products and formulations. The study suggests that solid-state structure of a pharmaceutical product can influence its properties, manufacturability, and stability. It is essential to regulate and control over solid-state structure and subsequent properties. The studies show that SSNMR is closely related to the widely used technique of solution-state NMR and possesses many of the same features. Further the study concludes that field of pharmaceutical SSNMR continues to advance at a rapid rate and will develop new molecular classes and new formulations and delivery modes in near future. Keywords: active pharmaceutical ingredients; vibrational spectroscopy; dipolar coupling; magic-angle coil spinning; polymorphism

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.

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.

A molecular-scale interpretation of interfacial processes is often downplayed in the analysis of traditional water treatment methods. However, such an approach is critical for the development of enhanced performance in traditional desalination and water treatments. Water confined between surfaces, within channels, or in pores is ubiquitous in technology and nature. Its physical and chemical properties in such environments are unpredictably different from bulk water. As a result, advances in water desalination and purification methods may be accomplished through an improved analysis of water behavior in these challenging environments using state-of-the-art microscopy, spectroscopy, experimental, and computational methods.

A series of tantalum oxyfluoride materials containing the [Ta4F16O4]4− and [Ta8F24O12]8− anion clusters have been synthesized and characterized using X-ray diffraction (XRD) and solid-state nuclear magnetic resonance (SSNMR) spectroscopy. The structure of both tantalum oxyfluoride materials display octahedrally bonded tantalum atoms with bridging oxygen and terminal fluoride atoms. The [Ta4F16O4]4− cluster is an eight-membered ring, whereas the [Ta8F24O12]8- cluster forms a cagelike structure. Solid-state dynamics of these clusters were explored by monitoring the impact of temperature on the one-dimensional (1D) 19F magic angle spinning (MAS) NMR, 13C cross-polarization (CP) MAS NMR, and two-dimensional (2D) double quantum (DQ) 19F MAS NMR spectra. The DQ 19F NMR correlation experiments allowed the through space connectivity between the different resolved fluorine environments to be determined, thus aiding in the spectral assignment and structural refinement of these materials. Ab initio 19F NMR chemical ...

Hydrogen storage is a key enabling technology required for attaining a hydrogen-based economy. Fundamental research can reveal the underlying principles controlling hydrogen uptake and release by storage materials, and also aid in characterizing and designing novel storage materials. New ideas for hydrogen storage materials come from exploiting the properties of hydrophobic hydration, which refers to water s ability to stabilize, by its mode of association, specific structures under specific conditions. Although hydrogen was always considered too small to support the formation of solid clathrate hydrate structures, exciting new experiments show that water traps hydrogen molecules at conditions of low temperatures and moderate pressures. Hydrogen release is accomplished by simple warming. While these experiments lend credibility to the idea that water could form an environmentally attractive alternative storage compound for hydrogen fuel, which would advance our nation s goals of attaining a hydrogen-based economy, much work is yet required to understand and realize the full potential of clathrate hydrates for hydrogen storage. Here we undertake theoretical studies of hydrogen in water to establish a firm foundation for predictive work on clathrate hydrate H{sub 2} storage capabilities. Using molecular simulation and statistical mechanical theories based in part on quantum mechanical descriptions of molecular interactions, we characterize the interactions between hydrogen and liquid water in terms of structural and thermodynamic properties. In the process we validate classical force field models of hydrogen in water and discover new features of hydrophobic hydration that impact problems in both energy technology and biology. Finally, we predict hydrogen occupancy in the small and large cages of hydrogen clathrate hydrates, a property unresolved by previous experimental and theoretical work.

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.

Nanocrystal (NC) synthesis and self-assembly have received much attention due to unique size-dependent properties and new collective physical properties derived from ordered NC arrays. However to fully exploit these properties, nanocrystal functionalization is critical and essential. In general, the key to functionalize NCs is maintenance of the original physical properties of the NCs, and in many situations, it is necessary to develop flexible NC surface chemistry, allowing further, subsequent functionalization. To date, most work has focused on alkane chain functionalized/ stabilized NCs prepared using hot soap 1,2 or a two-phase approach. 3 These methods can effectively make high quality NCs (narrow size distribution, preferred shape and composition, large production). Unfortunately, the alkane chains are chemically inert, preventing further chemical functionalization. In addition, these NCs are hydrophobic, precluding their direct use in bioapplications. There is an urgent need for general NC functionalization methods. Here, we report a new synthetic route to functionalize NCs with organo-silane groups through encapsulation of monodisperse, hydrophobic gold nanocrystals within the core of silane precursor micelles. Octadecyldimethyl(3-trimethoxysilylpropyl)ammonium chloride (precursor 1) is an amphiphilic functional methoxysilane that self-assemble into micelles and liquid crystal mesophase. 4 After encapsulation, the nanocrystal micelles are monodisperse, hydrophilic, and can self-assemble into 3-D ordered arrays through silane headgroup cross-linking under acidic conditions. In comparison with the previous method concerning the preparation of hybrid silica with stabilized gold NCs, 5,6 this method is simple, general, and allows extensive further functionalization based on silane coupling chemistry. The synthesis of organo-silane functionalized gold NC micelles was based on our recently developed surfactant encapsulation techniques.7,8 In a typical nanocrystal micelle synthesis procedure, a concentrated monosized 1-dodecanethiol (DT)-stabilized gold NC chloroform solution was added to an aqueous solution of precursor 1 under vigorous stirring to create an oil-in-water microemulsion. The highly volatile chloroform was then evaporated during heating at 30 ° C( 10 min), which transfers the nanocrystals into the aqueous phase, forming NC micelles. To prevent the silane groups from extensive hydrolysis, the heating process was kept as fast as possible and the temperature was kept as low as possible (30 °C). The encapsulation was driven by the hydrophobic van der Waals interactions between the primary alkane of the stabilizing ligand and the secondary alkane of the surfactant, resulting in thermodynamically defined interdigitated “bilayer” structures (Scheme 1c), which have been used to stabilize rod- and cube-shaped nanocrystals. 9-12 The gold NC micelles are monodisperse, as suggested by UVvis spectra. Figure 1a shows the UV-vis spectra of DT-stabilized gold NCs in chloroform. The absorbance at 519 nm corresponds to the gold surface plasmon resonance band. By comparison of Figure 1a-e, we observe no difference in the positions and peak widths of the plasmon resonance band of the DT-stabilized gold NCs in chloroform, those of the corresponding water-soluble NC