Pharmaceutical Co-crystal of Antiviral Agent Efavirenz with Nicotinamide for the Enhancement of Solubility, Physicochemical Stability, and Oral Bioavailability.

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. 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). 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. The Morphology was determined through scanning electron microscopy (FESEM). The results of saturated solubility studies and in vitro drug release studies exhibited 8.9-fold enhancement in solubility and 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) exhibits significant enhancement after cocrystallization (Cmax, 5597.09 ng/mL) than EFV and Efcure®-200 tablet (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.

Improved pharmaceutical properties of ritonavir through co-crystallization approach with liquid-assisted grinding method.

Ritonavir is a BCS class II antiretroviral agent which shows poor aqueous solubility and low oral bioavailability. The cocrystallization approach was selected to overcome these problems and to improve the physicochemical and mechanical properties of Ritonavir. The novel pharmaceutical Ritonavir-L-tyrosine cocrystals (RTC at a molar ratio of 1:1) were synthesized using the liquid assisted grinding (LAG) method. The possibility of molecular interactions between drug and coformer were studied using Gold software version 5.2. The newly formed crystalline solid phase was characterized through Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform-infrared spectroscopy (FT-IR), Scanning electron microscopy (SEM), and Solid-State Nuclear magnetic resonance (SSNMR). The improved pharmaceutical properties were confirmed by solubility, dissolution, and powder compaction study. The prepared cocrystals 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. Tabletability and compaction behavior of the pure drug and cocrystal with added excipients assessed. The tabletability profile of cocrystals showed enhanced tabletting performance as compared to pure drug. The stability studies revealed that cocrystals were stable for at least one month when stored at 40 °C/75 % RH and 25 °C/60 % RH conditions. The cocrystallization approach was found to be very promising and showed an overall improved performance of Ritonavir.

Development, Characterization, and Optimization of a Novel Abiraterone Acetate Formulation to Improve Biopharmaceutical Attributes Aided by Pharmacokinetic Modelling.

Abiraterone acetate has very low bioavailability and drastic food effect to warrant a dosing regimen under fasting state only. Therefore, we aimed to develop and optimize a liquisolid compact formulation of abiraterone acetate to improve biopharmaceutical attributes aided by pharmacokinetic modelling and achieve dose reduction with no food effect on the formulation. Preliminary studies highlighted the importance of the selection of olive oil as a compatible vehicle. The pharmacokinetic model, integrated with gastrointestinal physiology, was used to predict fasted and fed state pharmacokinetic parameters. Optimization of the liquisolid formulation containing abiraterone acetate was carried at more than five times lower dose, i.e. 190 mg, compared to 1000 mg. A central composite design (CCD) was used to identify optimal levels of formulation factors, namely the amount of vehicle (olive oil), the amount of coating agent (silicon dioxide), and the amount of surfactant (polysorbate 80). Graphical optimization using the selected models in conjunction with maximization of the desirability was used to identify the optimized liquisolid formulation. The predicted pharmacokinetic parameters (fasted Cmax 901.83 ng/mL, fasted AUCinf 2723.82 ng·h/mL, fed Cmax 1024.34 ng/mL, and fed AUCinf 3041.83 ng·h/mL) of the optimized formulation were acceptable. Overall, the liquisolid compact formulation of abiraterone acetate was successfully developed and optimized. In vitro solubility and dissolution results aided by pharmacokinetic modelling also showed improved predicted bioavailability with greater than five times reduction in dose and elimination of food effect.

Drug solubility: importance and enhancement techniques.

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.