Scott L. Childs

The role of solvent in mechanochemical and sonochemical cocrystal formation: a solubility-based approach for predicting cocrystallisation outcome

Mechanochemical liquid-assisted grinding (LAG) and sonochemical (SonicSlurry) techniques have been compared as methods to construct four model pharmaceutical cocrystals involving theophylline and caffeine as pharmaceutical ingredients and L-malic or L-tartaric acid as pharmaceutical cocrystal formers. For these model systems, the results are interpreted using the parameter η, the ratio of solvent volume to sample weight. Each if the four cocrystals was studied in four different solvents using LAG at η = 0.25 and 10 µL mg−1, as well as SonicSlurry experiments at η = 2, 6 and 12 µL mg−1. The formation of the cocrystal is observed in all standard LAG experiments when η = 0.25 µL mg−1. Cocrystal formation by neat grinding, i.e. with no liquid added, was observed only for the cocrystal of theophylline and L-malic acid. LAG experiments at very low η values (below 0.5 µL mg−1) revealed that the rate of cocrystal formation depended on the choice of the liquid and increases with η. SonicSlurry experiments performed at higher η values of 2, 6 and 12 µL mg−1 provided three different outcomes: the pure cocrystal, a mixture of the cocrystal with a cocrystal component, or a single cocrystal component. LAG experiments at η = 10 µL mg−1 produced results consistent with the SonicSlurry experiments at η = 12 µL mg−1. Measuring approximate solubilities of individual cocrystal components revealed that product formation is not dictated by the specific processing method but by saturation levels of reactants. An experimental approach based on approximate solubilities of cocrystal components has been developed to qualitatively predict the outcome of cocrystallization experiments at different η values. As a general guideline, cocrystal formation is expected under conditions in which all cocrystal components remain saturated.

Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine

Four different screening techniques were used to form cocrystals of carbamazepine containing pharmaceutically acceptable carboxylic acids. Twenty-seven unique solid phases utilizing eighteen carboxylic acid coformers were generated in the screening experiments. Cocrystal formation and stability in water is reported. Phase solubility diagrams and triangular phase diagrams are used to illustrate how saturation of the reactants leads to supersaturation of the cocrystal.

A model for a solvent-free synthetic organic research laboratory: click-mechanosynthesis and structural characterization of thioureas without bulk solvents

The mechanochemical click coupling of isothiocyanates and amines has been used as a model reaction to demonstrate that the concept of a solvent-free research laboratory, which eliminates the use of bulk solvents for either chemical synthesis or structural characterization, is applicable to the synthesis of small organic molecules. Whereas the click coupling is achieved in high yields by simple manual grinding of reactants, the use of an electrical, digitally controllable laboratory mill provides a rapid, quantitative and general route to symmetrical and non-symmetrical aromatic or aromatic–aliphatic thioureas. The enhanced efficiency of electrical ball milling techniques, neat grinding or liquid-assisted grinding, over manual mortar-and-pestle synthesis is demonstrated in the synthesis of 49 different thiourea derivatives. Comparison of powder X-ray diffraction data of mechanochemical products with structural information found in the Cambridge Structural Database (CSD), or obtained herein through single crystal X-ray diffraction, indicates that the mechanochemically obtained thiourea derivatives are pure in a chemical sense, but can also demonstrate purity in a supramolecular sense, i.e. in all structurally explored cases the product consisted of a single polymorph. As an extension of our previous work on solvent-free synthesis of coordination polymers, it is now demonstrated that such polymorphic and chemical purity of selected thiourea derivatives, the latter being evidenced through quantitative reaction yields, can enable the direct solvent-free structural characterization of mechanochemical products through powder X-ray diffraction aided by solid-state NMR spectroscopy.

Pharmaceutical cocrystals of nitrofurantoin: screening, characterization and crystal structure analysis

The objective of this study was to screen and prepare cocrystals of the poorly soluble drug nitrofurantoin (NTF) with the aim of increasing its solubility. Screening for cocrystals of NTF using 47 coformers was performed by high-throughput (HT) screening using liquid assisted grinding (LAG) methods. Raman spectroscopy and powder X-ray diffraction (PXRD) were used as the primary analytical tools to identify the new crystalline solid forms. Manual LAG and reaction crystallization (RC) experiments were carried out to confirm and scale-up the hits. Seven hits were confirmed to be cocrystals. The cocrystals were characterized by PXRD, Raman and IR spectroscopy, thermal analysis (DSC and TGA) and liquid-state NMR or elemental analysis. The solution stability of the scaled-up cocrystals in water was tested by slurrying the cocrystals at 25 °C for one week. NTF forms cocrystals with a 1:1 stoichiometric ratio with urea (1), 4-hydroxybenzoic acid (2), nicotinamide (3), citric acid (4), L-proline (5) and vanillic acid (6). In addition, NTF forms a 1:2 cocrystal with vanillin (7). All but one of the NTF cocrystals transformed (dissociated) in water, resulting in NTF hydrate crystalline material or NTF hydrate plus the coformer, which indicates that the transforming cocrystals have a higher solubility than the NTF hydrate under these conditions. The crystal structures of 1:1 NTF-citric acid (4) and 1:2 NTF-vanillin (7) were solved by single-crystal X-ray diffraction. The crystal structures of these two cocrystals were analyzed in terms of their supramolecular synthons.

Cocrystals of chlorzoxazone with carboxylic acids

Two polymorphs of a chlorzoxazone:2,4-dihydroxybenzoic acid cocrystal and one form of a chlorzoxazone:4-hydroxybenzoic acid cocrystal are characterized and the crystal structure of chlorzoxazone:2,4-dihydroxybenzoic acid (form 1) is reported and analyzed, revealing an uncommon carbonyl–carbonyl interaction and a destabilizing C–H⋯Cl–C interaction.

New cocrystals of ezetimibe with L-proline and imidazole

The objectives of the study were to screen and prepare cocrystals of anti-cholesterol drug ezetimibe (EZT) with the aim of increasing its solubility and dissolution rate. Thermodynamic phase diagra ...

Cocrystal Solubilization in Biorelevant Media and its Prediction from Drug Solubilization

This work examines cocrystal solubility in biorelevant media (FeSSIF, fed-state simulated intestinal fluid), and develops a theoretical framework that allows for the simple and quantitative prediction of cocrystal solubilization from drug solubilization. The solubilities of four hydrophobic drugs and seven cocrystals containing these drugs were measured in FeSSIF and in acetate buffer at pH 5.00. In all cases, the cocrystal solubility (Scocrystal ) was higher than the drug solubility (Sdrug ) in both buffer and FeSSIF; however, the solubilization ratio of drug, SRdrug = (SFeSSIF /Sbuffer )drug , was not the same as the solubilization ratio of cocrystal, SRcocrystal = (SFeSSIF /Sbuffer )cocrystal , meaning drug and cocrystal were not solubilized to the same extent in FeSSIF. This highlights the potential risk of anticipating cocrystal behavior in biorelevant media based on solubility studies in water. Predictions of SRcocrystal from simple equations based only on SRdrug were in excellent agreement with measured values. For 1:1 cocrystals, the cocrystal solubilization ratio (SR) can be obtained from the square root of the drug SR. For 2:1 cocrystals, SRcocrystal is found from (SRdrug )(2/3) . The findings in FeSSIF can be generalized to describe cocrystal behavior in other systems involving preferential solubilization of a drug such as surfactants, lipids, and other drug solubilizing media.

A co-crystal containing Kemp's tri-acid and acetic acid: a 0D aggregate disrupts a thermodynamically preferred 1D rod motif

A supramolecular aggregate of two Kemps tri-acid (cis,cis-1,3,5-trimethylcyclohexane-1,3,5-tricarboxylic acid, KTA) and four acetic acid molecules is arranged in a centrosymmetric zero-dimensional (0D) motif (2). This unusual pairing of unlike carboxylic acids disrupts a 1D hydrogen-bonded rod motif that is thermodynamically preferred by KTA (1) under most conditions. The six-molecule 0D aggregate reported here behaves like a large molecule with excellent self-recognition properties. Efficient centrosymmetric packing leads to maximized van der Waals contact and multiple C–H⋯O interactions between aggregates. The synthesis and physical properties of the parent KTA rod structure (1) and the acetic acid co-crystal (2) are compared and discussed.