Andrew J. Edwards

Analysis of Amorphous Solid Dispersions Using 2D Solid-State NMR and 1H T1 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.

Probing Hydrogen Bonding in Cocrystals and Amorphous Dispersions Using 14N–1H HMQC Solid-State NMR

Cocrystals and amorphous solid dispersions have generated interest in the pharmaceutical industry as an alternative to more established solid delivery forms. The identification of intermolecular hydrogen bonding interactions in a nicotinamide palmitic acid cocrystal and a 50% w/w acetaminophen-polyvinylpyrrolidone solid dispersion are reported using advanced solid-state magic-angle spinning (MAS) NMR methods. The application of a novel (14)N-(1)H HMQC experiment, where coherence transfer is achieved via through-space couplings, is shown to identify specific hydrogen bonding motifs. Additionally, (1)H isotropic chemical shifts and (14)N electric field gradient (EFG) parameters, both accessible from (14)N-(1)H HMQC experiments, are shown to be sensitive to changes in hydrogen bonding geometry. Numerous indicators of molecular association are accessible from this experiment, including NH cross-peaks occurring from intermolecular hydrogen bonds and changes in proton chemical shifts or electric field gradient parameters. First-principles calculations using the GIPAW approach that yield accurate estimates of isotropic chemical shifts, and EFG parameters were used to assist in assignment. It is envisaged that (14)N-(1)H HMQC solid state NMR experiments could become a valuable screening technique of solid delivery forms in the pharmaceutical industry.

Probing intermolecular interactions and nitrogen protonation in pharmaceuticals by novel 15N-edited and 2D 14N-1H solid-state NMR

We report the applications of two novel magic-angle spinning (MAS) solid-state NMR methods, 1J15N-1H spectral editing and 2D 14N-1H HMQC, to the characterisation of nitrogen functional groups in two pharmaceutical compounds, cimetidine and tenoxicam. The 1J15N-1H spectral editing method can readily differentiate the number of protons directly bonded to a nitrogen site and is not susceptible to motional effects. This enables confirmation of proton transfer, therefore proving or disproving amine salt formation, which is of high significance to the properties of a drug. The recently developed 2D 14N-1H HMQC method can demonstrate the presence of specific hydrogen bonding interactions and thus aid in identifying molecular association. First-principles calculations of NMR chemical shifts and quadrupolar parameters using the GIPAW method were combined with experimental data to assist with spectral assignment and the identification of the hydrogen bonding motifs.

Detection of low-level PTFE contamination: An application of solid-state NMR to structure elucidation in the pharmaceutical industry

We report a novel use of solid-state ¹⁹F nuclear magnetic resonance to detect and quantify polytetrafluoroethylene contamination from laboratory equipment, which due to low quantity (up to 1% w/w) and insolubility remained undetected by standard analytical techniques. Solid-state ¹⁹F NMR is shown to be highly sensitive to such fluoropolymers (detection limit 0.02% w/w), and is demonstrated as a useful analytical tool for structure elucidation of unknown solid materials.

A risk-based statistical investigation of the quantification of polymorphic purity of a pharmaceutical candidate by solid-state 19F NMR

The DMAIC (Define, Measure, Analyse, Improve and Control) framework and associated statistical tools have been applied to both identify and reduce variability observed in a quantitative (19)F solid-state NMR (SSNMR) analytical method. The method had been developed to quantify levels of an additional polymorph (Form 3) in batches of an active pharmaceutical ingredient (API), where Form 1 is the predominant polymorph. In order to validate analyses of the polymorphic form, a single batch of API was used as a standard each time the method was used. The level of Form 3 in this standard was observed to gradually increase over time, the effect not being immediately apparent due to method variability. In order to determine the cause of this unexpected increase and to reduce method variability, a risk-based statistical investigation was performed to identify potential factors which could be responsible for these effects. Factors identified by the risk assessment were investigated using a series of designed experiments to gain a greater understanding of the method. The increase of the level of Form 3 in the standard was primarily found to correlate with the number of repeat analyses, an effect not previously reported in SSNMR literature. Differences in data processing (phasing and linewidth) were found to be responsible for the variability in the method. After implementing corrective actions the variability was reduced such that the level of Form 3 was within an acceptable range of ±1% ww(-1) in fresh samples of API.

Managing emerging mutagenicity risks: Late stage mutagenic impurity control within the atovaquone second generation synthesis

ABSTRACT The mutagenic‐impurity control strategy for a second generation manufacturing route to the non‐mutagenic antipneumocystic agent atovaquone (2‐((1R,4R)‐4‐(4‐chlorophenyl)cyclohexyl)‐3‐hydroxynaphthalene‐1,4‐dione) 1 is described. Preliminary assessment highlighted multiple materials of concern which were largely discharged either through returning a negative bacterial mutagenicity assay or through confidence that the impurity would be purged during the downstream processing from when it was first introduced. Additional genotoxicity testing highlighted two materials of concern where initial assessment suggested that testing for these impurities at trace levels within the drug substance would be required. Following a thorough review of process purging detail, spiking and purging experimentation, and an understanding of the process parameters to which they were exposed an ICH M7 Option 4 approach could be justified for their control. The development of two 1H NMR spectroscopy methods for measurement of these impurities is also described as well as a proposed summary table for describing the underlying rationale for ICH M7 control rationales to regulators. This manuscript demonstrates that process purging of potential mutagenic impurities can be realised even when they are introduced in the later stages of a process and highlights the importance of scientific understanding rather than relying on a stage‐counting approach. Graphical abstract Figure. No caption available. HighlightsRetrospective ICH M7 assessment applied to second generation atovaquone process.Predicted versus measured impurity purge confirms conservatism of Teasdale approach.Robust science justifies ICH M7 Option 4 control for late introduced impurities.