Solvent-drop Grinding Research Articles

Co-crystallization experiments of thiocarbamides with bipyridine-type molecules

Co-crystallization experiments conducted between thiocarbamide derivatives, (E)-O-alkyl N-aryl-thiocarbamide, ROC(S)N(H)R′, for R = Me, Et and iPr, and R′ = Ph and PhNO2-4, containing a pharmaceutically active chromophorei.e. –C(S)–N(H)–, and the bipyridine-type molecules, 4,4′-bipyridine, trans-1,2-bis(4-pyridyl)ethene and 1,2-bis(4-pyridyl)ethane, showed the formation of stable 2 : 1 co-crystals, i.e. {[ROC(S)N(H)R′]2(bipyridine-type molecule)}. Novel species were formed by grinding and solvent drop grinding methods, and characterized by powder X-ray diffraction. Five 2 : 1 co-crystals were isolated as single crystals by slow evaporation methods and fully characterized by spectroscopic and X-ray crystallographic methods. Uniformly, trimeric aggregates were formed where each pyridine-nitrogen was connected to an amide-H via a Npyridine⋯H–Namide hydrogen bond. This study shows that the eight-membered {⋯H–N–CS}2 homosynthon found in the parent thiocarbamides is readily disrupted in the presence of bipyridine-type molecules to enable the formation of the stable heterosynthon, {N⋯H–N}.

Solid-State NMR Analysis of Organic Cocrystals and Complexes

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 together in a crystal structure and quickly prove molecular association. Analysis of the principal components of chemical shift tensors is also utilized where relevant, as these are more sensitive to structural effects than the isotropic chemical shift alone. In addition, 1H T1 relaxation measurements are also demonstrated as a means to prove phase separation of components. On the basis of these results, a general experimental approach to cocrystal analysis by SSNMR is suggested.

An Alternate Crystal Form of Gabapentin: A Cocrystal with Oxalic Acid

A cocrystal of gabapentin and oxalic acid has been prepared employing a strategy based on a hydrogen-bonded synthon described by the graph set notation R42(8). High throughput techniques and solvent drop grinding were used along with traditional crystallization methods, including crystallization in aqueous solutions at various pH. A number of new solid forms have been detected. The cocrystal of gabapentin and oxalic acid was fully characterized including single crystal structure analysis, which revealed the R42(8) synthon.

Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement

AbstractPharmaceutical cocrystals are crystalline molecular complexes containing therapeutic molecules. They represent an emerging class of pharmaceutical materials offering the prospect of optimized physical properties. This article highlights important opportunities and challenges associated with the design and synthesis of pharmaceutical cocrystals. Cocrystallization is first placed into context with the more established approaches to physical property optimization of polymorph, hydrate, and salt selection. A directed, intermolecular-interaction-based approach to cocrystal design is described. The enhancement of specific physical properties, such as dissolution rate and physical stability, is illustrated by summarizing several recent reports. Synthetic approaches to cocrystallization are considered; in particular, the selectivity and screening-related opportunities afforded by solid-state grinding and solvent-drop grinding methods are discussed. Finally, an outlook on future developments summarizes the growth potential in this field, especially with regard to targeted, informatics-driven cocrystal screening approaches.

Screening for crystalline salts via mechanochemistry

Neat grinding and solvent-drop grinding methods are found to be effective screening tools for indicating the potential for crystalline salt formation involving a given acid-base pair, as demonstrated with two model pharmaceuticals.

Selective polymorph transformation of anthranilic acid via solvent-drop grinding

Selective polymorph transformation of anthranilic acid via solvent-drop grinding

Selective polymorph transformation via solvent-drop grinding

A method of inducing specific polymorph transformations is exemplified with two single-component systems, whereby a given crystal form undergoes conversion when subjected to solid state grinding in the presence of a minor quantity of a certain solvent.