Simvastatin-Nicotinamide Co-Crystals: Formation, Pharmaceutical Characterization and in vivo Profile

• Published in: Drug design, development and therapy development and therapy, 2020-01, Vol.14, p.4303-4313
• Main Authors: Khan, Fahad Mehmood, Ahmad, Mahmood, Idrees, Hafiz Arfat
• Format: Article
• Language: English
• Subjects: Angle of repose; Animals; Antilipemic agents; Bioavailability; Caustic soda; co-crystal; Comparative analysis; Crystallization; Crystallography, X-Ray; Crystals; Cubes; Differential Thermal Analysis; Dissolution; Drug Compounding; Drug Liberation; Drug Stability; Dry grinding; Evaporation; Fourier transforms; Grinding; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; In vivo methods and tests; Infrared analysis; Infrared spectroscopy; Light; Light scattering; Methods; Morphology; Niacinamide; Niacinamide - chemistry; Niacinamide - pharmacokinetics; Niacinamide - pharmacology; Nicotinamide; Original Research; Particle Size; Particle size distribution; Pharmaceuticals; Pharmacokinetics; Pharmacy; Potassium; Properties (attributes); Rabbits; Scanning electron microscopy; Scattering, Radiation; Simvastatin; Simvastatin - chemistry; Simvastatin - pharmacokinetics; Simvastatin - pharmacology; Size distribution; Slurries; Solubility; solubility enhancement; Solvents; Spectroscopy; Spectroscopy, Fourier Transform Infrared; Spectrum analysis; Thermal stability; Vitamin B Complex - chemistry; Vitamin B Complex - pharmacokinetics; Vitamin B Complex - pharmacology; X ray powder diffraction; XPD protein
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S270742

To enhance the solubility and dissolution profile of simvastatin (SIM) through co-crystallization with varying ratios of nicotinamide (NIC) using various co-methods. Twelve SIM:NIC co-crystal formulations (F01-F12) were prepared using dry grinding, slurry, liquid-assisted grinding, and solvent-evaporation methods, and their properties compared. Optimized formulations were selected on the basis of dissolution profiles and solubility for in vivo studies. The angle of repose, Carr Index and Hausner ratio were calculated to evaluate flow properties. Differential light scattering (DLS) was used to estimate particle-size distribution. Scanning electron microscopy (SEM) was employed to evaluate surface morphology. Thermal analyses and Fourier-transform infrared (FTIR) spectroscopy were used to determine the ranges of thermal stability and physical interaction of formulated co-crystals. X-ray powder diffraction (XPD) spectroscopy was used to determine the crystalline nature. Solubility and dissolution studies were undertaken to determine in vitro drug-release behaviors. Micromeritic analyses revealed the good flow properties of formulated co-crystals. DLS showed the particle size of co-crystals to be in the nanometer range. SEM revealed that the co-crystals were regular cubes. Thermal studies showed the stability of co-crystals at >300°C. FTIR spectroscopy revealed minor shifts of various peaks. XPD spectroscopy demonstrated co-crystal formation. The formulations exhibited an improved dissolution profile with marked improvements in solubility. In vivo studies showed a 2.4-fold increase in C whereas total AUC was increased 4.75-fold as compared with that of SIM tablets. Co-crystallization with NIC improved the solubility and dissolution profile and, hence, the bioavailability of the poorly water-soluble drug SIM.