New Solid Forms of Griseofulvin: A Solvate and a Relict Polymorph Related to Reported Solvates.

This work presents two new solid forms, a polymorph and a solvate, of the antifungal active pharmaceutical ingredient griseofulvin (GSF). The novel forms were characterized by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, and their crystal structures were determined by single-crystal X-ray diffraction. The new polymorphic form (GSF Form VI) was obtained upon drying at room temperature the GSF-acetonitrile solvate. GSF Form VI is a relict structure related to reported solvates of GSF. Thermal stability studies show that Form VI is metastable and monotropically related to the stable GSF Form I. The new GSF-n-butyl acetate solvate was obtained by crystallization from an n-butyl acetate solution. The stoichiometry of the n-butyl acetate solvate is 1:0.5. The solvate loses the solvent from the crystal lattice at a temperature between 363.15 and 374.15 K.

Impact of Additives on Drug Particles during Liquid Antisolvent Crystallization and Subsequent Freeze-Drying.

The impact of single or combinations of additives on the generation of nanosuspensions of two poorly water-soluble active pharmaceutical ingredients (APIs), fenofibrate (FF) and dalcetrapib (DCP), and their isolation to the dry state via antisolvent (AS) crystallization followed by freeze-drying was explored in this work. Combinations of polymeric and surfactant additives such as poly(vinyl alcohol) or hydroxypropyl methyl cellulose and sodium docusate were required to stabilize nanoparticles (∼200-300 nm) of both APIs in suspension before isolation to dryness. For both FF and DCP, multiple additives generated the narrowest, most-stable particle size distribution, with the smallest particles in suspension, compared with using a single additive. An industrially recognized freeze-drying process was used for the isolation of these nanoparticles to dryness. When processed by the liquid AS crystallization followed by freeze-drying in the presence of multiple additives, a purer monomorphic powder for FF resulted than when processed in the absence of any additive or in the presence of a single additive. It was noted that all nanoparticles freeze-dried in the presence of additives had a flat, flaky habit resulting in large surface areas. Agglomeration occurred during freeze-drying, resulting in micron-size particles. However, after freeze-drying, powders produced with single or multiple additives showed similar dissolution profiles, irrespective of aging time before drying, thus attenuating the advantage of multiple additives in terms of size observed before the freeze-drying process.

Quantitative insights into noncovalent interactions involving halogen and tetrel bonds in 2,4,6-trimethylpyrylium tetrafluoroborate.

The crystal and molecular structure of an organic salt, in which a 2,4,6-trimethylpyrylium cation forms a salt with a tetrafluoroborate anion, namely, 2,4,6-trimethylpyrylium tetrafluoroborate, C8H11O+·BF4-, has been experimentally realized. The compound crystallizes in the orthorhombic centrosymmetric space group Pnma. The crystal packing is stabilized via a subtle interplay of [F3-B-F]-...O+-C fluorine/oxygen-centred halogen/chalcogen bonds and Cδ+...Fδ- tetrel-bonded contacts. Although the O centre has a formal charge of +1, the estimation of the partial negative charges on O is in accordance with electronegativity considerations. Hirshfeld surface analysis, which also includes an analysis of the three-dimensional deformation density, along with molecular electrostatic potential (MESP) calculations, provides quantitative insights into the nature of the intermolecular interactions. The topological analysis of the electron-density distribution has been performed using AIMAll and TOPOND, and unequivocally establishes the bonding character associated with the different noncovalent interactions. In addition, NBO analysis and polarizability calculations using PolaBer render deeper physical insights into the electronic characteristics of these noncovalent interactions.

The mechanism of bending in a plastically flexible crystal.

Mechanically adaptable molecular crystals have potential applications in flexible smart materials and devices. Here, we report the mechanism of plastic deformation in single crystals of a small organic molecule (N-(4-ethynylphenyl)-3-fluoro-4-(trifluoromethyl)benzamide) that can be repeatedly irreversibly bent and returned to its original shape without concomitant delamination or loss of integrity. Along with the quantification of the crystals' local and bulk mechanical properties (hardness, indentation modulus and Young's modulus), micro-focus synchrotron X-ray diffraction mapping show that upon deformation, molecular layers lined with trifluoromethyl groups cooperatively slip past one another resulting in their impressive plastic malleability.