title: Design of novel multi-component cocrystals with a special focus on the use of green methods
Creators: name: Alaa Eldin Refat, Lamis
Publisher: name: University of Galway
Year: 2025
Subjects: subject: Crystal engineering
subject: pharmaceutical cocrystals
subject: Green methods
subject: Chemistry
subject: Biological and Chemical Sciences

description: With the introduction of cocrystals into the pharmaceutical market and increasing reliance on cocrystals for improving the physicochemical properties of drug compounds, there is a need for efficient and sustainable methods of cocrystal production. A key objective towards successful formulation of higher order cocrystals is the identification of new synthons and understanding their preferences, with the aim of enhancing the functionality and performance of pharmaceutical materials. This thesis investigates the design and synthesis of higher-order multicomponent pharmaceutical cocrystals, addressing the increasing demand for innovative, environmentally friendly methods in the pharmaceutical industry. The focus of the first study was on two key Active Pharmaceutical Ingredients (APIs), trimethoprim (tmp) and pyrimethamine (pyr), both known for their therapeutic applications in the treatment of bacterial and parasitic infections. Both APIs share a 2,4-diaminopyrimidine ring, a structure that offers multiple hydrogen bonding sites, mainly a Donor-Acceptor (DA) and a Donor-Acceptor-Donor (DAD) binding site, making them excellent candidates for cocrystal formation. Through extensive screening of the two APIs with a range of dicarboxylic acids and sulfa drug coformers, distinct synthon preferences and hydrogen bonding motifs were identified, highlighting the variability in cocrystal formation despite structural similarities between the APIs. This revealed that tmp and pyr interact differently with coformers, even when their chemical properties are nearly identical. The versatility of tmp and pyr in forming multicomponent cocrystals was demonstrated in the second study, highlighting the role of coformers such as trimesic acid in facilitating robust synthon interactions. Binary, ternary, and quaternary cocrystals were successfully synthesized, revealing complex interactions and binding site behaviours in higher-order systems. In addition to solution crystallization, which is considered the most common method of forming cocrystals, liquid-assisted grinding was explored as a greener and more efficient alternative. This method allowed for the reliable synthesis of higher-order cocrystals in a controlled stoichiometric manner. Notably, six ternary and three quaternary salt cocrystals involving tmp, pyr, and various bipyridine and trimesic acid coformers were successfully prepared, with mechanochemistry consistently yielding phase-pure products. Detailed investigation of synthon interactions and hydrogen bonding patterns in the cocrystals of 2,4-diaminopyrimidines showed that, despite the presence of two distinct hydrogen bonding sites in the APIs, simultaneous interaction with two different coformers at both sites proved to be unfavourable. This prompted investigating how proton transfer affects synthon preferences at the second binding site of tmp. A detailed screening experiment led to the formation of ternary molecular ionic cocrystals with tmp and two carboxylic acid coformers, one of which was a Non-Steroidal Anti-inflammatory Drug (NSAID). Computational analysis, including Molecular Electrostatic Potential (MEP) surface analysis and Density Functional Theory (DFT) calculations, confirmed that upon salt formation, the hydrogen bond donor ability of tmp's donor groups increased while the acceptor strength sharply decreased. This explained the difficulty of accommodating two coformers at both sites, with further support from Hunter’s interaction site pairing energy calculations and Hirshfeld surface analysis. Finally, sublimation was investigated as a green, solvent-free method for both crystal growth and thermal transformation reactions. This technique was expanded beyond traditional crystal growth to include one-step thermal transformations, leading to the synthesis of key pharmaceutical intermediates such as organosulfones. Through sublimation of bis(arylsulfone) triene and its derivatives, phenylsulfinic acid elimination was achieved, resulting in the crystallization of 4-(phenylsulfonyl)biphenyl. Pixel analysis, coupled with DSC and TGA data, revealed that the transformations occurred in the gas phase and that sublimation is kinetically and energetically feasible for such reactions.