Developing multi-component crystal forms of Daidzein and Luteolin for Bioavailability improvement

The intention of this study is to discover novel cocrystals of Daidzein (DAI) and Luteolin (LUT) that possess increased water solubility and dissolution. This will be achieved through cocrystal screening, preparation via solution methods and investigation of solubility and dissolution against DAI and LUT. This research was divided into four main parts: (1) Characterise raw DAI and LUT and their recrystallisations: DAI was recrystallised in acetonitrile (ACN), ethanol (EtOH) and methanol (MeOH) and LUT was recrystallised in ACN, EtOH, MeOH, ethyl acetate (EtAC), isopropanol (IPA) and tetrahydrofuran (THF). The characterisation of DAI revealed it was form II with a low solubility and it was not affected by recrystallisation. On the other hand, LUT was affected by the different solvents and produced varying x-ray diffraction (XRD) patterns and differential scanning calorimetry (DSC) thermograms. It was also determined the measured solubility was affected by equilibration length with 48 hours providing the more consistent solubility. (2) Compare DAI cocrystal formation with a structurally similar nutraceutical: Genistein (GEN) was determined to be structurally similar during a Cambridge structural database (CSD) search. Comparison of DAI and GEN structures using Mercury showed they were similar in 3D structure and angles but differed in torsions, packing and morphology. Screening the coformers of GEN cocrystals with DAI, successfully produced a novel 1:1 Daidzein-4,4’-bipyridine cocrystal (DAI-BIP CO) that crystallised in the same space group and through the same intermolecular hydrogen bonds (H-bonds) as genistein-4,4’-bipyridine cocrystal (GEN-BIP CO). The structural differences observed in pure DAI and GEN were overcome through the cocrystallisation with 4,4’-bipyridine (BIP). (3) Screen for DAI cocrystals and evaluate solubility and dissolution: Improving the solubility and dissolution of DAI through discovery of novel DAI cocrystals was investigated. The combination of computational and experimental screening of DAI with potential coformers successfully formed four novel cocrystals including DAI-BIP CO and 1:2 Daidzein-Piperazine cocrystal (DAI-PIP CO). Both DAI-PIP CO and DAI-BIP CO increased the solubility (208.099 and 1.122 mM respectively) and concentration of DAI released during dissolution compared to pure DAI. The improvement observed in DAI-PIP CO was much greater compared to DAI-BIP CO. (4) Screen for LUT cocrystals and evaluate solubility and dissolution: Novel cocrystals for LUT to increase solubility and dissolution of LUT were explored. Seven novel cocrystals of LUT were successfully produced, six were formed through experimental grinding including 1:1 Luteolin-4,4’-bipyridine (LUT-BIP CO) and a 1:1 luteolin-4,4’-bipyridine cocrystal solvate (LUT-BIP CO solvate) was formed through solvent evaporation (SE). LUT-BIP CO improved the solubility of LUT (0.239 mM) whilst both LUT-BIP CO and LUT-BIP CO solvate experienced improved dissolution.