Studies Towards Cocrystal Formation, Characterization and Stability of Anti-Retroviral Agents

Abstract

Acquired immunodeficiency syndrome (AIDS) affects the immune system and makes people vulnerable to disease and infection. AIDS has gained attention due to its profound effect on the medical, social, and economic virtue that it causes. There are currently no therapies available to cure AIDS, and research in this area is underway. Even though current antiretroviral medications (ARVs) have been efficient in limiting the fatal Human Immunodeficiency virus (HIV) to chronic illness and lowering mortality, several limitations negatively impacted treatment outcomes. Also, most of the drugs show poor pharmacokinetics and drug resistance. Therefore, patient compliance suffers dramatically with high and frequent dosage administrations and concomitant adverse effects. The cocrystallization strategy has been prevalent among all solubility enhancement techniques in the present decade besides its capability to modify the drug's physicochemical and mechanical attributes without disturbing its molecular structure. This study aimed to prioritize a suitable coformer with virtual cocrystal screening tools for cocrystallization of ritonavir and drug-drug cocrystals of darunavir-ritonavir and lopinavir-ritonavir to enhance the solubility, dissolution, mechanical properties, and oral bioavailability. Ritonavir is a poorly soluble API and belongs to the HIV protease inhibitor category that binds to the plasma proteins and acts as a substrate for P-gp efflux transporter, limiting their absorption into target locations. For a selection of appropriate coformer based on prior knowledge and HSPs calculations twelve coformers were selected, and molecular modeling-based virtual cocrystal screening (MMVCS) was performed. Based on the rank ordering, Nicotinamide and L-Tyrosine was rank-ordered as the top-most coformers based on MMVCS. RNC and RTC in the stoichiometric ratio of 1:1 were synthesized using the liquid assisted grinding method and characterized for FTIR, PXRD, DSC, SSNMR, HSM, and SEM. Mechanical properties were evaluated by calculating tensile strength, and a tabletability study was performed at pre-determined compaction pressures. Pharmaceutical properties like in-vitro dissolution study, aqueous solubility, and pharmacokinetic parameters were also evaluated. The results showed that cocrystals exhibited higher tabletability as compared to pure drug. The RNC’s solubility was approximately 18-fold compared to a pure drug and the dissolution studies exhibited > 70% at 15 min and > 95% of % drug release at 60 min time point. The prepared RTC exhibited an 11.24-fold increase in solubility and a 3.73-fold increase in % of drug release at 1 h compared to pure drug. Notably, a pharmacokinetic study presented a rise in Cmax and in AUC0-24. Cocrystals were stable for at least for one months during stability testing when performed as per ICH guidelines. The cocrystallization approach was found to be very promising and showed an overall improved performance of Ritonavir. Drug-drug or Multi-drug Cocrystals of antiretroviral agents, Darunavir and Ritonavir were developed and evaluated similar to RNCs and RTCs. As per literature, Ritonavir in low doses improves the oral bioavailability of Darunavir. In the present study, wet grinding and solvent evaporation methods were used to synthesize cocrystals. A computational study using GOLD software 5.3 was performed to predict the molecular interactions and hydrogen bonding. From the results, prepared cocrystals exhibited improved solubility, dissolution, stability, and powder tabletability compared to pure drugs. The solubility of cocrystals prepared by wet grinding (DRCWG) and solvent evaporation (DRCSE) was improved to 7.5-fold and 7.2-fold in 0.1N HCl after 48 h. Similarly, cocrystals prepared via wet grinding exhibited 95 %, and the solvent evaporation method showed 90 % of drug release at 60 min. Both cocrystals exhibited a superior pharmacokinetic profile than pure drugs. The increase in Cmax and AUC0-24 value of DRCWG and DRCSE revealed the improved oral bioavailability of cocrystals. The prepared cocrystals were stable for six months at standard conditions of temperature and relative humidity of 25°C ± 60% RH and 40°C ± 75% RH as per ICH guidelines. Drug-drug cocrystals of Lopinavir and Ritonavir were designed and characterized. In view of literature, Ritonavir increases the oral bioavailability of Lopinavir in low dosage. A computational study using GOLD software 5.3 was performed to predict the molecular interactions and hydrogen bonding. The present research aimed to improve the solubility, dissolution, and oral bioavailability of Lopinavir through a cocrystallization approach using Ritonavir as a coformer. Cocrystallization was carried out using wet grinding and solvent evaporation methods. Prepared Cocrystals were examined and evaluated similar to RNCs and RTCs. Developed cocrystals showed superior solubility and dissolution as compared to pure drug. After 48 h, aqueous solubility of Lopinavir and Ritonavir co-amorphous formulation (LRCWG) was increased 3.7-fold in the wet grinding method, while Lopinavir and Ritonavir cocrystals prepared by solvent evaporation method (LRCSE) indicated 5.9-fold increase compared to pure drug. The co-amorphous formulation was developed using wet grinding showed 86 % drug release at 60 min, and cocrystals synthesized through solvent evaporation method showed 94 % of drug release. The increase in Cmax and AUC0-24 value of LRCWG and LRCSE revealed the improved oral bioavailability of cocrystals. Cocrystals produced using solvent evaporation approach were stable and showed excellent physicochemical characteristics. The study concluded that the cocrystallization approach would prove to be a successful method to improve physicochemical and mechanical properties.