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Crystallographic disorder, whether static or dynamic, can be detrimental to the physical and chemical stability, ease of crystallization and dissolution rate of an active pharmaceutical ingredient. Disorder can result in a loss of manufacturing control leading to batch-to-batch variability and can lengthen the process of structural characterization. The range of NMR active nuclei makes solid-state NMR a unique technique for gaining nucleus-specific information about crystallographic disorder. Here, we explore the use of high-field 35 Cl solid-state NMR at 23.5 T to characterize both static and dynamic crystallographic disorder: specifically, dynamic disorder occurring in duloxetine hydrochloride (1), static disorder in promethazine hydrochloride (2), and trifluoperazine dihydrochloride (3). In all structures, the presence of crystallographic disorder was confirmed by 13 C cross-polarization magic-angle spinning (CPMAS) NMR and supported by GIPAW-DFT calculations, and in the case of 3, 1 H solid-state NMR provided additional confirmation. Applying 35 Cl solid-state NMR to these compounds, we show that higher magnetic fields are beneficial for resolving the crystallographic disorder in 1 and 3, while broad spectral features were observed in 2 even at higher fields. Combining the data obtained from 1 H, 13 C, and 35 Cl NMR, we show that 3 exhibits a unique case of disorder involving the + N-H hydrogen positions of the piperazinium ring, driving the chloride anions to occupy three distinct sites., (© 2022 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

During the racemization of a novel pharmaceutical spiro-cyclic imidazole-amine compound, namely, 6'-bromo- N -(6'-bromo-4-meth-oxy-4''-methyl-3' H -di-spiro[cyclo-hexane-1,2'-indene-1',2''-imidazol]-5''-yl)-4-meth-oxy-4''-methyl-3' H -di-spiro-[cyclo-hexane-1,2'-indene-1',2''-imidazol]-5''-imine, C 36 H 41 Br 2 N 5 O 2 , two impurities were isolated. These impurities were clearly dimers from mass spectroscopic analysis, however single-crystal diffraction characterization was required for the assignment of stereochemistry. The single-crystal diffraction results revealed subtly different structures to those proposed, due to an unexpected proton transfer. The dimers contain four stereocentres, but two of primary inter-est, and are centrosymmetric, so after careful structure refinement and close inspection it was possible to unambiguously assign the stereochemistry of both the homochiral [( S ),( S )- and ( R ),( R )-] and the heterochiral [( S ),( R )- and ( R ),( S )-] compounds., (© Blade et al. 2021.)

Amorphous solid dispersions (ASDs) are used to increase the solubility of oral medicines by kinetically stabilizing the more soluble amorphous phase of an active pharmaceutical ingredient with a suitable amorphous polymer. Low levels of a crystalline material in an ASD can negatively impact the desired dissolution properties of the drug. Characterization techniques such as powder X-ray diffraction (pXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) are often used to detect and measure any crystallinity within ASDs. These techniques are unable to detect or quantify very low levels because they have limits of detection typically in the order of 1-5%. Herein, an ASD of felodipine (FEL) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) prepared via a hot melt extrusion (HME) in a mass ratio of 30:70 was characterized using a range of techniques. No signs of residual crystallinity were found by pXRD, DSC, or FTIR. However, transmission electron microscopy (TEM) did identify two areas containing crystals at the edges of milled particles from a total of 55 examined. Both crystalline areas contained Cl Kα X-ray peaks when measured by energy-dispersive X-ray spectroscopy, confirming the presence of FEL (due to the presence of Cl atoms in FEL and not in PVP/VA). Further analysis was carried out by TEM using conical dark field (DF) imaging of a HME ASD of 50:50 FEL-PVP/VA to provide insights into the recrystallization process that occurs at the edges of particles during accelerated ageing conditions in an atmosphere of 75% relative humidity. Multiple metastable polymorphs of recrystallized FEL could be identified by selected area electron diffraction (SAED), predominately form II and the more stable form I. Conical DF imaging was also successful in spatially resolving and sizing crystals. This work highlights the potential for TEM-based techniques to improve the limit of detection of crystallinity in ASDs, while also providing insights into transformation pathways by identifying the location, size, and form of any crystallization that might occur on storage. This opens up the possibility of providing an enhanced understanding of a drug product's stability and performance.

During drug development control of polymorphism, particle properties and impurities are critical for ensuring a good quality, reproducible, and safe medicine. A wide variety of analytical techniques are employed in demonstrating the regulators control over the drug substance and product manufacturing, storage, and supply. Transmission electron microscopy (TEM) offers the opportunity to analyze in detail pharmaceutical systems at a length scale and limit of detection not readily achieved by many traditional techniques. However, the use of TEM as a characterization tool for drug development is uncommon due to possible damage caused by the electron beam. This work outlines the development of a model, using molecular descriptors, to predict the electron beam stability of active pharmaceutical ingredients (API). For a given set of conditions and a particular imaging or analytical mode, the total number of electrons per unit area, which causes observable damage to a sample in the TEM, can be defined as the critical fluence ( C F ). Here the C F of 20 poorly water-soluble APIs were measured using selected area electron diffraction. Principal component analysis was used to select the most influential molecular descriptors on C F , which were shown to be descriptors involving the degree of conjugation, the number of hydrogen bond donors and acceptors, and the number of rotatable bonds. These were used to generate several multiple linear regression models. The model that provided the best fit to the measured C F data included the ratio of the number of conjugated carbons to nonconjugated carbons, the ratio of the number of hydrogen bond donors to acceptors, and the ratio of the number of hydrogen bond acceptors to donors. Using this model, the C F of the majority of the compounds was predicted within ±2 e - /Å 2 . Molecules with no hydrogen bond acceptors did not fit the model accurately possibly due to the limited sample size or the influence of other parameters not included in this model, such as intermolecular bond energies. The model presented can be used to support pharmaceutical development by quickly assessing the stability of other poorly soluble drugs in TEM. Provided that the model suggests that the API is relatively stable to electron irradiation, TEM offers the prospect of determining the presence of crystalline material at low levels at length scales and limits of detection unobtainable by other techniques. This is particularly so for amorphous solid dispersions.