Crystal engineering and protein binding studies on selected antibacterials in Silico and experimental investigations

Abstract

In relation to pharmaceutical development, it is apparently clear that there is a necessity for better understanding and control of different crystalline phases. The approach of crystal engineering is poised to tackle such issues and has developed into a paradigm for the supramolecular synthesis of new compounds with modulated physicochemical properties. These include sets of polymorphs and multicomponent forms, such as solvates, salts, eutectics and cocrystals. The antibacterial agents i.e. ciprofloxacin, linezolid and nitrofurantoin selected for the present study belongs to the Class II and Class IV of BCS which is having the APIs with low aqueous solubility s. The ideal solution to overcome drawbacks associated with these poorly water soluble antibacterial drugs without covalent modification involves alteration of crystal lattice by crystal engineering. This work thus focuses on the crystal engineering of various crystal forms of selected antibacterials, in particular pharmaceutical cocrystals, polymorphs, eutectics and salts via in silico and experimental means. It addresses: (i) rational designing of various crystal forms with high success rate using CSD data mining, (ii) predicting the crystal structure landscape of the selected API, (iv) crystal structure determination of the prepared multicomponents from PXRD data and further validating the determined structure using NMR crystallography method. (v) ascertaining the physicochemical, pharmacokinetic and antibacterial profile of prepared forms which are discussed in the subsequent chapters. Moreover, the work also incorporates interaction studies of the selected antibacterials with HSA using molecular modelling as well as calorimetry and to compare the calculated binding parameters with experimentally determined thermodynamic parameters