No / We report on the templated growth of 2:1 benzoic acid/isonicotinamide co-crystal on a benzoic acid subphase. The molecular basis for the template, registry between the phases, is presented. The template growth of behavior of the title compound was contrasted with that from melt and solution. This approach may be applicable as a precursor for the synthesis of bulk composite crystals.

No / The formation of crystalline molecular complexes of benzoic acid and isonicotinamide with 1:1 and 2:1 compositions has been investigated through solution cocrystallization. The 1:1 complex was solely obtained from ethanol solutions, while either complex could be grown from aqueous and methanol solution by variation of the initial composition. The crystal structures of the 2:1 complex and a monohydrate of isonicotinamide were determined by single crystal X-ray diffraction. The intermolecular interactions in the crystal structure of the complex were compared with other published carboxylic acid:isonicotinamide molecular complexes, which highlights the robust nature of the acid · · · pyridine and acid · · · amide hydrogen bond, which exist in most cases. Complementary computational studies into the binding of pairs of these molecules by ab initio calculations were found to support the experimental observations and highlight the role of solvent in controlling the final crystalline form for multicomponent systems, through altering the hierarchy of intermolecular interactions.

Crystal Engineering is the design of crystalline material using non-covalent synthesis. Co-crystals are multi-component crystals which are constructed from complementary intermolecular interactions, they are also known as supramolecular complexes. Design of such materials utilises the synthon approach, this involves the understanding of common intermolecular interactions which occur in the crystal packing and is used to design new solids with desired physical properties and chemical properties. Primary amides form supramolecular heterosynthons, these synthons represent an opportunity for a design of multi-component crystals in which one molecule contains a primary amide and a second molecule which is complimentary to the primary amide, usually carboxylic acids. The progress with regards to the screening process for the determination of co-crystals is evident in the literature, In particular, high throughput solution growth methods and solvent drop grinding. The comparison of Isonicotinamide and Benzamide as a co-crystal component has been presented. This study was motivated by the observation that the CSD contains 24 Isonicotinamide and 1 Benzamide co-crystal. The interaction with carboxylic acids is the focus of the work, in particular those which form Isonicotinamide co-crystal are being screened with Benzamide. Our work utilises a ReactArray Microvate to carry out the low throughput solution growth on a matrix of carboxylic acid with Benzamide, this study has been coupled with the Kofler hot stage microscope method which visually aids to screen and view co-crystal phase formation. Crystallisation screens have resulted in the identification of known co-crystal phases of Isonicotinamide and Benzamide, additionally new co-crystal phases have also been identified with Fumaric, 3-hydroxybenzoic acid, Mandelic Acid, 4-Nitrobenzoic Acid and Tartaric Acid. Single crystal structures of the Fumaric and 4-Nitrobenzoic acid have been obtained. In order to develop an understanding of co-crystal formation in Isonicotinamide and Benzamide with our supramolecular library, packing landscape analysis is being undertaken using both the CSD and crystal structures we have obtained. This is undertaken as collaboration with Dr Andy Parkin and Professor Gilmore (University of Glasgow), we have identified that the dSNAP analysis is a way forward for the analysis of how co-crystals pack. The analysis highlighted the subtleties that were present in the packing motifs of the Isonicotinamide co-crystals. In particular the cis and trans orientation of the amide and acid carbonyl to each other and the planar and off planar layer assemblies. All of which are required to maximise the hydrogen bond usage of the components comprising the co-crystals. Further investigations have led to the collaborative project with Syngenta Ltd in the design of a co-crystal screen using a high through-put robot, Crissy® -Automation Platform by Zinsser Analytical, using an extended screen of 16 acid coformers with Isonicotinamide, Benzamide and Nicotinamide the sample have been characterised using a reflectance diffraction method, GADDS. Further analysis of this data involves the use of polySNAP, which has led to further collaboration with Professor Gilmore's group.

Crystal Engineering is the design of crystalline material using non-covalent synthesis. Co-crystals are multi-component crystals which are constructed from complementary intermolecular interactions, they are also known as supramolecular complexes. Design of such materials utilises the synthon approach, this involves the understanding of common intermolecular interactions which occur in the crystal packing and is used to design new solids with desired physical properties and chemical properties. Primary amides form supramolecular heterosynthons, these synthons represent an opportunity for a design of multi-component crystals in which one molecule contains a primary amide and a second molecule which is complimentary to the primary amide, usually carboxylic acids. The progress with regards to the screening process for the determination of co-crystals is evident in the literature, In particular, high throughput solution growth methods and solvent drop grinding. The comparison of Isonicotinamide and Benzamide as a co-crystal component has been presented. This study was motivated by the observation that the CSD contains 24 Isonicotinamide and 1 Benzamide co-crystal. The interaction with carboxylic acids is the focus of the work, in particular those which form Isonicotinamide co-crystal are being screened with Benzamide. Our work utilises a ReactArray Microvate to carry out the low throughput solution growth on a matrix of carboxylic acid with Benzamide, this study has been coupled with the Kofler hot stage microscope method which visually aids to screen and view co-crystal phase formation. Crystallisation screens have resulted in the identification of known co-crystal phases of Isonicotinamide and Benzamide, additionally new co-crystal phases have also been identified with Fumaric, 3-hydroxybenzoic acid, Mandelic Acid, 4-Nitrobenzoic Acid and Tartaric Acid. Single crystal structures of the Fumaric and 4-Nitrobenzoic acid have been obtained. In order to develop an understanding of co-crystal formation in Isonicotinamide and Benzamide with our supramolecular library, packing landscape analysis is being undertaken using both the CSD and crystal structures we have obtained. This is undertaken as collaboration with Dr Andy Parkin and Professor Gilmore (University of Glasgow), we have identified that the dSNAP analysis is a way forward for the analysis of how co-crystals pack. The analysis highlighted the subtleties that were present in the packing motifs of the Isonicotinamide co-crystals. In particular the cis and trans orientation of the amide and acid carbonyl to each other and the planar and off planar layer assemblies. All of which are required to maximise the hydrogen bond usage of the components comprising the co-crystals. Further investigations have led to the collaborative project with Syngenta Ltd in the design of a co-crystal screen using a high through-put robot, Crissy® -Automation Platform by Zinsser Analytical, using an extended screen of 16 acid coformers with Isonicotinamide, Benzamide and Nicotinamide the sample have been characterised using a reflectance diffraction method, GADDS. Further analysis of this data involves the use of polySNAP, which has led to further collaboration with Professor Gilmore¿s group. / Syngenta

The production of stable solid crystalline material is an important issue in the pharmaceutical industry and the challenge to control the desired active pharmaceutical ingredient (API) with the specific chemical and physical properties has led to more development in the drug industry. Increasing the solubility and the dissolution of the drug will increase its bioavailability; therefore the solubility can be improved with the change in the preparation method. The formation of co-crystals has emerged as a new alternate to the salts, hydrates and solvate methods since the molecules that cannot be formed by the usual methods might crystallise in the form of co-crystals. Co-crystals are multicomponent crystals which can be known as supramolecules and are constructed by the non covalent bonds between the desired former and co-former. Therefore the synthon approach was utilised to design co-crystals with the specific properties, this involves the understanding of the intermolecular interactions between these synthons. These interaction forces can be directed to control the crystal packing in the design of the new crystalline solid with the desired chemical and physical properties. The most familiar synthon was the amide group with its complementary carboxylic group, in this work isonicotinamide and benzoic acid were chosen to design co-crystal and much literature exist that introduce the determination of co-crystal growth from these two compounds. The growth of co-crystals was carried out in water, ethanol and ethanol / water mixed solvent (30 - 90 % ethanol) by utilising the Cryo-Compact circulator. Co-crystals (1:1) and (2:1) were grown in ethanol and water respectively and a mixture of both phases were grown in the mixed solvent. All the phases were examined by powder X-ray diffraction (PXRD), Raman, Infrared and 1H-NMR spectroscopy. The solubility of isonicotinamide, benzoic acid, co-crystals (1:1) and (2:1) in water, ethanol and ethanol/water mixed solvent (30 - 90 % ethanol) were determined at 25 °C, 35 °C and 40 °C by utilising the React-Array Microvate. It was important to understand some of the thermodynamic factors which control the formation of these polymorphs such as the change in the enthalpy and the change in the entropy. Also it was important to study the pH behaviour during dissolution of the former, co-former and co-crystals in water, ethanol and ethanol/water mixed solvent (30 - 90 % ethanol) in-order to examine the affect of the solvent composition on the solubility and to identify if some ions were formed during the dissociation and how this could affects the formation of co-crystals. A discussion has been introduced in this research of how similar solubility of the compounds maps the formation of the typical ternary phase diagram of the mixture of 1:1 while compounds with different solubility maps the formation of skewed phase diagram as shown in section 1.6.2.3. In this project an isotherm ternary phase diagram at 20 °C and 40 °C was constructed to map the behaviour of benzoic acid and isonicotinamide and to show all possible phases formed and the regions where all phases are represented in the ternary phase diagram were determined by the slurry method. The ternary phase diagram was used to design a drawn out and cooling crystallisation at 100 cm3 solution of 50 % ethanol / water mixed solvent and a study of the impact of seeds of co-crystals 1:1 on the cooling crystallisation method.