Influence of Polyvinylpyrrolidone Molecular Weight and Concentration on the Precipitation Inhibition of Supersaturated Solutions of Poorly Soluble Drugs

Abstract

Supersaturating drug delivery systems such as solid dispersions of a drug in a polymer are frequently used in pharmaceutical development to enable oral delivery of poorly soluble drugs. In this study, the influence of the concentration and molecular weight of polyvinylpyrrolidone (PVP) on the precipitation inhibition of the poorly soluble drugs albendazole, ketoconazole and tadalafil is investigated to expand the understanding of the mechanism of PVP as a polymeric precipitation inhibitor. A three-level full-factorial design was used to delineate the influence of polymer concentration and viscosity of the dissolution medium on precipitation inhibition. Solutions of PVP K15, K30, K60 or K120 at concentrations of 0.1, 0.5 and 1% (w/v), as well as isoviscous solutions of PVP of increasing molecular weight, were prepared. Supersaturation of the three model drugs was induced by the use of a solvent-shift method. Precipitation of the three model drugs from supersaturated solutions in the absence and presence of polymer was investigated by the use of a solvent-shift method. Time-concentration profiles of the respective drugs in the absence and presence of polymer pre-dissolved in the dissolution medium were obtained by the use of a μDISS Profiler™ to determine the onset of nucleation and the precipitation rate. Multiple linear regression was used to evaluate the hypothesis that precipitation inhibition is influenced by the PVP concentration (i.e., the number of repeat units of the polymer) and the medium viscosity of the polymer for the three model drugs. This study showed that an increased concentration of PVP (i.e., an increased concentration of the PVP repeat units, independent of the molecular weight of the polymer) in solution increased the onset of nucleation and decreased the precipitation rate of the respective drugs during supersaturation, which can be explained by an increase in molecular interactions between the drug and polymer with increasing concentrations of polymer. In contrast, the medium viscosity had no significant influence on the onset of the nucleation and precipitation rate of the drugs, which can be explained by solution viscosity having a negligible effect on the rate of drug diffusion from bulk solution to the crystal nuclei. In conclusion, the precipitation inhibition of the respective drugs is influenced by the concentration of PVP, i.e., by molecular interactions between the drug and polymer. In contrast, the molecular mobility of the drug in solution, i.e., the medium viscosity, has no influence on the precipitation inhibition of the drugs.

Keywords: crystal growth; nucleation; polymer; precipitation inhibitor; solvent-shift method; supersaturation.

Figure A1

Standard curves for determination of the equilibrium solubility of the albendazole R² = 0.997 (A), tadalafil R² = 0.999 (B) and ketoconazole R² = 0.989 (C) (n = 3) (mean ± SD).

Figure A2

Viscograms of the solutions of PVP K15 at the concentrations of 0.1, 0.5 and 1% (w/v) (n = 3) (mean ± SD).

Figure A3

Viscogram of water (n = 3) (mean ± SD).

Figure A4

Time–concentration profiles of supersaturated solutions of albendazole (A), tadalafil (B) and ketoconazole (C) in phosphate buffer (n = 8) (mean ± SD).

Figure A5

Time–concentration profiles of supersaturated solutions of albendazole in solutions of PVP K15 (A), K30 (B), K60 (C) and K120 (D) at the concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

Figure A6

Time–concentration profiles of supersaturated solutions of tadalafil in solutions of PVP K15 (A), K30 (B), K60 (C) and K120 (D) at the concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

Figure A7

Time–concentration profiles of supersaturated solutions of ketoconazole in solutions of PVP K15 (A), K30 (B), K60 (C) and K120 (D) at the concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

Figure 1

Molecular structures of (a) albendazole, (b) tadalafil and (c) ketoconazole.

Figure 2

Equilibrium solubility of albendazole (A), tadalafil (B) and ketoconazole (C) in absence and presence of solutions of 0.1, 0.5 and 1% (w/v) PVP K15, K30, K60 and K120 (n = 3) (mean ± SD). Asterisk (*) indicating statistically significant differences (p < 0.05).

Figure 3

Viscosities of the solutions of PVP K15, K30, K60 and K120 at concentrations of 0.1, 0.5 and 1% (w/v) at a shear rate of 631 s⁻¹ (n = 3) (mean ± SD).

Figure 4

Induction time (t_ind) of the time–concentration profiles of albendazole (A), tadalafil (B) and (C) ketoconazole in absence and presence of aqueous solutions of PVP K15, K30, K60 and K120 at concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

Figure 5

Time–concentration profiles of albendazole (A), tadalafil (B) and ketoconazole (C) in aqueous solutions PVP K15, K30, K60 and K120 at a concentration of 0.1% (w/v) (n = 8) (mean ± SD).

Figure 6

Precipitation rates of the time–concentration profiles of albendazole (A), tadalafil (B) and ketoconazole (C) in absence and presence of solutions of PVP K15, K30, K60 and K120 at concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

Figure 7

Coefficient plot generated from MODDE11 pro showing the influence of solution viscosity and PVP concentration on the t_ind and precipitation rate of albendazole, tadalafil and ketoconazole.

Figure 8

Precipitation rates of the time–concentration profiles of albendazole (A), tadalafil (B) and ketoconazole (C) in ~1 mPa.s isoviscous solutions of PVP K15, K30, K60 and K120 (n = 8) mean ± SD.