• Impact of mixed solvent on co-crystal solubility, ternary diagrams and crystallisation scale-up. Crystallisations of Isonicotinamide ¿Benzoic Acid Co-crystals from Ethanol ¿Water Co-solvent System.

      Blagden, Nicholas; Munshi, Tasnim; Redha, Batul H. (University of BradfordSchool of Pharmacy, 2013-11-20)
      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 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.