Exploring The Potential Of Pharmaceutical Co-Crystals And Charge Density Methods To Develop Novel Drug Formulations

Abstract

There are numerous formulation difficulties present in the modern pharmaceutical industry. Commonly, the active pharmaceutical ingredient (API) will dictate its medical application due to its physical and chemical properties such as solubility and stability. The high cost of lead compound research has spurred the scientific community to develop and refine methods of formulation to enhance such properties. This thesis will focus on the promising method of co-crystallisation and explain through charge density results, how any physical and/or chemical properties are enhanced. It will also cover the differences between co-crystallisation and the more commonly used methods at present such as salt formation. The co-crystallisation method involves an API being formulated with a non-active ingredient such as a sugar or non-toxic acid known as a coformer. The resulting co-crystal will exhibit the same medical application with an enhanced physical/chemical profile. For example, a higher bioavailability will lead to the same therapeutic result from a lower dose, which also means less severe side effects. This advanced formulation method can provide APIs with unfavourable side effects such as Theophylline a brighter future. Using charge density studies, it is possible to study non-covalent weak interactions within the co-crystal to observe their influence on physical properties. The experiment in this thesis investigate the charge density distribution in a new co-crystal complex of 1,3-dimethylxanthine (theophylline) and malonic acid. The molecules crystallise in the triclinic, centrosymmetric space group 𝑃̅1, with four independent molecules (Z=4) in the asymmetric unit [two pairs of molecules]. Several strong intermolecular hydrogen bonds (101.34 kJ mol-1) and π-π interactions (30.07 kJ mol-1) formed through co-crystallisation contribute towards the molecular geometry and overall potential lattice energy. High-resolution X-ray diffraction data formed the basis of a charge density refinement using a pseudoatomic multipolar expansion (Hansen-Coppens formalism) of low-temperature (T = 150K) single-crystal X-ray diffraction data. Numerous hydrogen bonding sites produced through the coformer addition facilitate the reduced susceptibility to hydration. Topological analysis of the electron density in these sites, identify the theophylline carbonyl groups having the greatest influence due to the electron redistribution. The improved stability of the theophylline co-crystal is further noted as the lattice potential energy is substantially greater (-397 kJ mol-1) than its individual components (theophylline -157.9 kJ mol-1 & malonic acid -145.1 kJ mol-1). Furthermore, the increased lattice potential energy of the co-crystal enhanced not only the stability of the theophylline, but the metastable polymorph formed during dissolution which can lead to increased solubility.