Surface Engineering of the Mechanical Properties of Molecular Crystals via an Atomistic Model for Computing the Facet Stress Response of Solids.

Dynamic molecular crystals are an emerging class of crystalline materials that can respond to mechanical stress by dissipating internal strain in a number of ways. Given the serendipitous nature of the discovery of such crystals, progress in the field requires advances in computational methods for the accurate and high-throughput computation of the nanomechanical properties of crystals on specific facets which are exposed to mechanical stress. Here, we develop and apply a new atomistic model for computing the surface elastic moduli of crystals on any set of facets of interest using dispersion-corrected density functional theory (DFT-D) methods. The model was benchmarked against a total of 24 reported nanoindentation measurements from a diverse set of molecular crystals and was found to be generally reliable. Using only the experimental crystal structure of the dietary supplement, L-aspartic acid, the model was subsequently applied under blind test conditions, to correctly predict the growth morphology, facet and nanomechanical properties of L-aspartic acid to within the accuracy of the measured elastic stiffness of the crystal, 24.53±0.56 GPa. This work paves the way for the computational design and experimental realization of other functional molecular crystals with tailor-made mechanical properties.

A strategy to optimize precompression pressure for tablet manufacturing based on in-die elastic recovery.

A precompression pressure optimization strategy using in-die elastic recovery was developed to effectively address tablet lamination caused by air entrapment. This strategy involves exacerbating the air entrapment issue using high tableting speeds and main compaction pressures and collecting in-die elastic recovery data as a function of precompression pressure. The optimized precompression pressure, which corresponds to the minimum elastic recovery, is most effective at eliminating air from the powder bed prior to the main compression. When the optimized precompression pressure was employed, intact tablets of a model blend prone to lamination due to air entrapment could be produced over a wide range of high main compaction pressures, while tablets without precompression laminated immediately after ejection at equivalent main compaction pressures. This optimization strategy is effective for addressing lamination issues due to air entrapment using precompression. An advantage of this strategy is that intact tablets are not required to identify an optimized precompression pressure since elastic recovery measurements occur in-die.

Crystal structure-mechanical property relationship in succinic acid and L- alanine probed by nanoindentation.

Establishing structure-mechanical property relationships is crucial for understanding and engineering the performance of pharmaceutical molecular crystals. In this study, we employed nanoindentation, a powerful technique that can probe mechanical properties at the nanoscale, to investigate the hardness and elastic modulus of single crystals of succinic acid and L-alanine. Nanoindentation results reveal distinct mechanical behaviors between the two compounds, with L-alanine exhibiting significantly higher hardness and elastic modulus compared to succinic acid. These differences are attributed to the underlying variations in molecular crystal structures - the three-dimensional bonding network and high intermolecular interaction energies of L-alanine molecules leads to its stiffness compared to the layered and weakly bonded crystal structure of succinic acid. Furthermore, the anisotropic nature of succinic acid is reflected in the directional dependence of the mechanical responses where it has been found that the (111) plane is more resistant to indentation than (100). By directly correlating the nanomechanical properties obtained from nanoindentation with the detailed crystal structures, this study provides important insights into how differences in molecular arrangements can translate into different macroscopic mechanical performance. These findings have implications on the selection of molecular crystals for optimized drug manufacturability.

Enabling direct compression tablet formulation of celecoxib by simultaneously eliminating punch sticking, improving manufacturability, and enhancing dissolution through co-processing with a mesoporous carrier.

The development of a high quality tablet of Celecoxib (CEL) is challenged by poor dissolution, poor flowability, and high punch sticking propensity of CEL. In this work, we demonstrate a particle engineering approach, by loading a solution of CEL in an organic solvent into a mesoporous carrier to form a coprocessed composite, to enable the development of tablet formulations up to 40% (w/w) of CEL loading with excellent flowability and tabletability, negligible punch sticking propensity, and a 3-fold increase in in vitro dissolution compared to a standard formulation of crystalline CEL. CEL is amorphous in the drug-carrier composite and remained physically stable after 6 months under accelerated stability conditions when the CEL loading in the composite was ≤ 20% (w/w). However, crystallization of CEL to different extents from the composites was observed under the same stability condition when CEL loading was 30-50% (w/w). The success with CEL encourages broader exploration of this particle engineering approach in enabling direct compression tablet formulations for other challenging active pharmaceutical ingredients.

Magnesium stearate surface coverage on tablets and drug crystals: Insights from SEM-EDS elemental mapping.

Scanning electron microscopy-based energy dispersive X-ray spectroscopy (SEM-EDS) is proposed as a versatile tool for quantifying surface area coverage (SAC) by magnesium stearate (MgSt) on pharmaceutical tablets and particles. Our approach involved fast elemental mapping and subsequent SAC quantitation by image analysis. The study was conducted using a multi-component system, but the particle-level mapping was limited to active pharmaceutical ingredient (API) crystals. For both tablets and API particles, the calculated SAC against MgSt loading afforded a positive linear correlation over the range of MgSt levels examined in this work. On the tablet surface, MgSt was found to be preferentially concentrated at or in the close vicinity of grain boundaries, supporting the idea of compression-driven migration and relocation of MgSt within the tablet. On the particle surface, only discrete aggregates of MgSt were observed, as opposed to the widely accepted phenomenon of the formation of a thin lubricant film around host particles. The selection of proper SEM-EDS operating conditions and the challenges confronted in particle surface mapping are discussed in detail.

Effects of thermal binders on chemical stabilities and tabletability of gabapentin granules prepared by twin-screw melt granulation.

The effect of thermal binders on the physicochemical properties of gabapentin, a thermally labile drug, in granules prepared using twin-screw melt granulation was investigated in this study. Hydroxypropyl cellulose (HPC), a thermoplastic high molecular-weight binder, was compared against conventional low molecular-weight semi-crystalline thermal binders PEG 8000 and Compritol. Both the chemical degradation and polymorph form change of gabapentin were analyzed. The effects of particle size and molecular weight of HPC on the properties of granules were also studied. To overcome the high melt viscosity of HPC, higher barrel temperatures and higher specific mechanical energy were required to attain suitable granules. As a result, higher levels of gabapentin degradant were observed in HPC-based formulations. However, gabapentin form change was not observed in all formulations. Smaller particle size and lower molecular weight of HPC led to faster granule growth. The tabletability of granules was insensitive to the variations in particle size and molecular weight of HPC. Gabapentin crystal size reduction, HPC size reduction, and HPC enrichment on granule surface were observed for HPC-based granules.

Solid-state characterization of optically pure (+)Dihydromyricetin extracted from Ampelopsis grossedentata leaves.

Dihydromyricetin (DMY) is a natural flavanol compound isolated from a traditional Chinese medicine, Ampelopsis grossedentata. Despite that optically pure (+)DMY is desired for treating chronic pharyngitis and alcohol use disorders, only DMY racemate is commercially available due to prolonged exposure time to high temperature and the presence of metal ions during industrial extraction, which cause racemization of the homochiral (+)DMY. We have developed an extraction method for successfully obtain optically pure (+)DMY. We have further assessed the physicochemical properties of the two phases using PXRD, DSC, TGA, FTIR, and moisture sorption. Among them, PXRD and FT-IR are suitable for quickly distinguishing homochiral (+)DMY from racemic (±)DMY. Lastly, with the aid of cocrystallization with theophylline, the absolute configuration of homochiral (+)DMY was identified to be (2R, 3R).