Solubility and Bioavailability Enhancement of Poorly Water Soluble APIs for Cost Effective Formulation

Abstract

The present research work attempted to improve the oral bioavailability of the antiviral drug Efavirenz (EFV) using a pharmaceutical cocrystallization technique. EFV comes under BCS II and has extremely low water solubility and results in low oral bioavailability. The Hansan solubility parameter, ∆pKa value, thermal method, and virtual interaction techniques were utilized for the screening of plausible coformer. During the screening stage, we evaluated coformers like malic acid, mannitol, caffeine, glutaric acid, tyrosine, arginine, and nicotinamide with various stoichiometric ratios. Amongst the tested coformer, we got the cocrystal with nicotinamide, caffeine, and glutaric acid. Based on the results of analytical characterization, solubility, and in- vitro dissolution studies NICO, a water-soluble, safe, non toxic vitamin B3 was selected for further study. The EFV and nicotinamide (NICO) were selected in a (1:1) stoichiometric ratio and efavirenz nicotinamide cocrystal (ENCOC) was prepared through the liquid-assisted grinding method (LAG) and spray drying techniques. The confirmation of the formation of a new solid phase was done through spectroscopic techniques like Fourier transmission infrared (FTIR), Raman, and 13C solid-state nuclear magnetic resonance (13C ssNMR). Thermal techniques like differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy (HSM) illustrated the thermal behavior and melting patterns of ENCOC, EFV, and NICO. The X-ray powder diffraction (XRPD) confirms the formation of a new crystalline phase in ENCOC and ENCOCSD. The Morphology was determined through scanning electron microscopy (FESEM). The results of saturated solubility studies and In-vitro drug release studies exhibited an 8.9-fold enhancement in solubility and a 2.56-fold enhancement in percentage cumulative drug release. The percentage drug content of ENCOC was found higher than 97% and cocrystal exhibits excellent accelerated stability. The oral bioavailability of EFV (Cmax-799.08 ng/mL) exhibited significant enhancement after cocrystallization (Cmax- 5597.09 ng/mL) than EFV and Efcure® -200 tab (2896.21 ng/mL). The current work investigates the scalable and cost-effective method for enhancement of physicochemical stability, solubility, and oral bioavailability of an antiviral agent EFV. In the spray drying method, EFV and plausible coformer nicotinamide (NICO) were selected in the specific stoichiometric ratio (1:1), dissolved in a mixture of methanol and ethanol (70:30 v/v) to prepare 4% w/v slurry, and sprayed through a spray drier to formulate cocrystal (ENCOCSD). The well-known quality by design (QbD) approach through Design expert® software was used to optimize the process and develop the response surface method (RSM) with a central composite design (CCD). The Inlet temperature, aspiration flow rate, and feed flow rate were selected as critical process parameters (CPP), whereas average particle size (APS), % yield, and aqueous solubility were selected as critical quality attributes (CQA). The full factorial CCD with 17 runs including 6 center points was optimised for CPP and evaluated for CQA. All the batches exhibited improved aqueous solubility ranging from 6.5 to 9.6-fold. The average particle size (APS) was observed in the range of 17.39 to 72.54 µm, and % yield was 70.07 to 82.34 %. The optimized batch was further evaluated with Fourier transmission infrared (FTIR) and Raman spectroscopy for the detection of the formation of hydrogen bonds. Thermal techniques like differential scanning calorimetry (DSC), TGA, and HSM reveal the thermal behavior, purity, and residual solvent for cocrystal formation. Inverse gas chromatography (GC) was used for the residual solvent detection and we observed that the optimized batch had 0 ppm residual methanol and ethanol. The microscopic techniques viz. optical microscopy and scanning electron microscopy (FESEM) exhibited the morphological changes and APS. The X-ray powder diffraction (XRPD) technique confirmed the formation of the crystalline phase. The ENCOCSD showed a 9.6-fold improvement in saturated solubility and a 3.42-fold enhancement in % cumulative drug release (% CDR). The prepared formulation exhibited excellent accelerated stability for the period of six months at 40°± 2° C and 75± 5 % RH. The in vivo pharmacokinetic study revealed 7.80 fold enhancement in oral bioavailability. The present research work explores the scalable method for solubility enhancement, physicochemical stability, and improved bioavailability of an antiviral agent efavirenz.