Poor mechanical properties of paracetamol are improved through the strategy of cocrystal formation. Mechanochemical screening by liquid-assisted grinding generated four cocrystals of paracetamol that readily form tablets by direct compression. Computational studies reveal the mechanical properties can be related to structural features, before all the formation of hydrogen-bonded layers

The formation of cocrystal hydrates represents a potential route to achieve molecular materials with improved properties, particularly stability under conditions of high relative humidity. We describe the use of neat and liquid-assisted grinding for screening for hydrated forms of pharmaceutical cocrystals. In the case of liquid-assisted grinding, water is present in the reaction mixture as a liquid, whereas in the case of neat grinding, it is introduced by employing crystalline hydrates as reactants. The ability to form a cocrystal hydrate by either of the two methods appears to be variable, depending on the choice of cocrystal components. Theophylline readily forms a cocrystal hydrate with citric acid. This contrasts with the behavior of caffeine, which provides only an anhydrous cocrystal ("caffeine citrate") even when both reactants are crystalline hydrates. The preference of theophylline to form a cocrystal hydrate is qualitatively explained by similarity between crystal structures of the products and reactant hydrates. Overall, liquid-assisted grinding is less sensitive to the form of the reactant (i.e., hydrate or anhydrate) than neat grinding. For that reason liquid-assisted grinding appears to be a more efficient method of screening for cocrystal hydrates, and it is also applicable to screening for hydrates of APIs.

Images reproduced with permission of Tomislav Friscic (left) and Reiko Kuroda (right) Papers published in this issue include: Mechanochemistry: the varied applications of mechanical bond-breaking

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Amorphous solid dispersions (ASDs) are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs. Various approaches have been employed to produce ASDs and novel techniques are emerging. This review provides an updated overview of manufacturing techniques for preparing ASDs. As physical stability is a critical quality attribute for ASD, the impact of formulation, equipment, and process variables, together with the downstream processing on physical stability of ASDs have been discussed. Selection strategies are proposed to identify suitable manufacturing methods, which may aid in the development of ASDs with satisfactory physical stability.

We demonstrate that crystal structure prediction calculations can be used to predict both the stoichiometry and structure of multicomponent molecular crystals. The methods are used here to determine the structure of a recently discovered acetic acid solvate of theobromine.

Isotope effects were determined for the oxidative demethylation of the substituted N-methyl-N-(trideuteriomethy1)anilines la-d, and the corresponding N,N-bis(dideuteriomethy1)anilines 2 a 4 , by microsomal cytochrome P-450. The pairs ofp-cyano-andp-nitro-N,N-dimethylanilines were found to have the same intramolecular isotope effects, while the unsubstituted and p-chloro derivatives had different isotope effects. It is concluded that, in general, intramolecular isotope effects measured for the enzymatic oxidations of N-methyl-N-(trideuteriomethy1)anilines are susceptible to masking. The isotope effect for the hydrogen (deuterium) atom abstractions from PhN(CH& vs PhN(CD3)z by the tert-butoxy radical was found to be 2.5. Interestingly, this is the same as the isotope effect measured for the cytochrome P-450 oxidation of N,N-bis(dideuteriomethy1)aniline (2a). These results are discussed with respect to the use of isotope effects for distinguishing the oxidative dealkylation mechanisms of amines by cytochrome P-450 and by related enzymes.

The current level of laboratory instrumentation and computational resources allows X-ray powder diffraction to be implemented into the toolbox of organic chemists, providing a means for rapid (i.e., within a day) structural characterization of organic solids, without the need for single crystals. We illustrate such use of powder diffraction using two case studies of molecular cocrystals of trifluoroacetic acid and malonic acid, involving theobromine, a model active pharmaceutical ingredient. We also report on a previously unobserved conformation of malonic acid in the solid state.