Developing Multi-Component Crystal Forms of Artemisinin and Apigenin for Bioavailability Improvement

Background: Several experiments are usually required before novel cocrystals are successfully discovered. Screening of appropriate coformers is a significant challenge throughout the development of cocrystals. Using computational methods of Molecular Complementarity (MC), Hydrogen Bond Propensity (HBP) and Hydrogen Bond Energy (HBE) in combination can narrow the choice of potential coformers and the experimental search can be significantly optimised. Apigenin (APG) has several possible medicinal advantages like anti-cancer, but its low aqueous solubility limits its medical claims. Artemisinin (ART) is utilised to treat multi-drug resistant strains of malaria. Additionally, it is in the initial stages of development as an anti-cancer drug. On the other hand, the usage of ART is restricted because of its low aqueous solubility.

Aim: The purpose is to determine new cocrystals of APG and ART which increase solubility and dissolution. This was accomplished via cocrystal screening using computational and experimental methods; cocrystal preparation using solvent evaporation and inspection of cocrystal solubility and dissolution in contrast to pure APG and ART.

Method: Polymorphism screening using different solvents to recrystallise APG and ART and then characterise using Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Determinate the structure of pure APG by growing single crystals using melt crystallisation. Cocrystal screening using computational methods of MC, HBP and HBE to rank 80 coformers. Experimental screening utilising Neat and Liquid Assisted Grinding (using different solvents). Solvent evaporation to grow single crystals for structure determination. Cocrystal characterisation using PXRD, Single crystal X-ray Diffraction, DSC, Hot Stage Microscope, TGA and Fourier-transform infrared spectroscopy. Cocrystal solubility and dissolution were analysed using High-performance liquid chromatography.

Result: A novel 2:1 artemisinin-acetylenedicarboxylic acid cocrystal (ART2-ACA CO) was discovered from large-scale cocrystal screening using both computational methods (MC and HBE) and experimental screening. ART2-ACA CO solubility was 6.34-fold greater than the solubility of ART. ART2-ACA CO dissolution rate indicated a 16% improvement in its Dissolution Performance Parameter (DPP) in contrast to raw ART. APG crystallise as needles from melt crystallisation. Seven APG cocrystals were discovered which are apigenin-carbamazepine hydrate 1:1:1 cocrystal (APG-CBZ-H2O CO), apigenin-1,2-di(pyridin-4-yl)ethane hydrate 1:1:1 cocrystal, apigenin-valerolactam 1:2 cocrystal, apigenin-DL proline 1:2 cocrystal, apigenin-D proline/ L proline 1:1 cocrystal and apigenin-3-aminopyridine 1:2 cocrystal were discovered using three computational methods (MC, HBP and HBE) and experimental screening. The APG-CBZ-H2O CO displayed the best improvement in dissolution performance with a 9.19-fold improvement of its DPP in contrast to raw APG.

Conclusion: It is invaluable to state that the preliminary computational screening might be challenging and contradictive, depending on the methods applied. Hence, experimental screening is always necessary to find new cocrystals. To the best of our understanding, this is the first ART cocrystal with a carboxylic acid which might assist in the breakthrough of further ART cocrystals with carboxylic acids in the forthcoming medicinal treatments. However, the APG cocrystals with coformers of Carbamazepine, D-Proline, L-Proline, DL-Proline, and Valerolactam can be made into drug formulations without concern for the toxicity issue of the coformers.