Another Move towards Bicalutamide Dissolution and Permeability Improvement with Acetylated β-Cyclodextrin Solid Dispersion

Abstract

The complex formation of antiandrogen bicalutamide (BCL) with methylated (Me-β-CD) and acetylated (Ac-β-CD) β-cyclodextrins was investigated in buffer solution pH 6.8. A two-fold strongly binding of BCL to Ac-β-CD as compared to Me-β-CD was revealed. The solid dispersion of BCL with Ac-β-CD was prepared by the mechanical grinding procedure to obtain the complex in the solid state. The BCL/Ac-β-CD complex was characterized by DSC, XPRD, FTIR, and SEM techniques. The effect of Ac-β-CD in the BCL solid dispersions on the non-sink dissolution/permeation simultaneous processes was disclosed using the side-by-side diffusion cell with the help of the cellulose membrane. The elevated dissolution of the ground complex, as compared to the raw drug as well as the simple physical mixture, accompanied by the supersaturation was revealed. Two biopolymers-polyvinylpyrrolidone (PVP, M_n = 58,000) and hydroxypropylmethylcellulose (HPMC, M_n ~ 10,000)-were examined as the precipitation inhibitors and were shown to be useful in prolonging the supersaturation state. The BCL/Ac-β-CD complex has the fastest dissolution rate in the presence of HPMC. The maximal concentration of the complex was achieved at a time of 20, 30, and 90 min in the pure buffer, with PVP and with HPMC, respectively. The effectiveness of the BCL dissolution (release) processes (illustrated by the AUCC(t) parameter) was estimated to be 7.8-, 5.8-, 3.0-, and 1.8-fold higher for BCL/Ac-β-CD (HPMC), BCL/Ac-β-CD (PVP), BCL/Ac-β-CD (buffer), and the BCL/Ac-β-CD physical mixture, respectively, as compared to the BCL_raw sample. The excipient gain factor (EGF), calculated for the dissolution of the BCL complex, was shown to be 2.6 in the presence of HPMC, which is 1.3-fold greater as compared to PVP. From the experimental dissolution results, it can be concluded that the formation of BCL ground complex with Ac-β-CD enhances the dissolution rate of the compound. The permeation was also shown to be advantageous in the presence of the polymers, which was demonstrated by the elevated fluxes of BCL through the membrane. The comparison of the dissolution/permeation processes was illustrated and discussed. The conclusion was made that the presence of HPMC as a stabilizer of the supersaturation state is promising and seems to be a useful tool for the optimization of BCL pharmaceutical formulations manufacturing.

Keywords: complexation; dissolution; permeability; supersaturation; β-cyclodextrin derivatives.

Figure 1

Structures of bicalutamide (BCL) (a), methylated β-CD (Me-β-CD) (b), acetylated β-CD (Ac-β-CD) (c); *—means the substituent in the cyclodextrin molecule.

Figure 2

Phase solubility diagrams of BCL with Me-β- (a) and Ac-β- (b) cyclodextrins at different temperatures: 298.15 K—black, 303.15 K—green, 308.15 K—blue, and 313.15 K—red color.

Figure 2

Phase solubility diagrams of BCL with Me-β- (a) and Ac-β- (b) cyclodextrins at different temperatures: 298.15 K—black, 303.15 K—green, 308.15 K—blue, and 313.15 K—red color.

Figure 3

DSC profiles of BCL raw material (BCL_raw black solid line), BCL ground sample (BCL_gr black dash-dot line), BCL physical mixture with Ac-β-CD (BCL/Ac-β-CD _pm green solid line), BCL with Ac-β-CD ground sample (BCL/Ac-β-CD_gr red solid line), Ac-β-CD raw material (Ac-β-CD blue solid line).

Figure 4

Effect of grinding (1 h) on raw BCL crystallinity: BCL raw (1), BCL_gr (2), BCL/Ac-β-CD_pm (3), BCL/Ac-β-CD_gr (4). The % crystallinity is calculated by Equation (6).

Figure 5

PXRD patterns of BCL raw material (BCL_raw black solid line), BCL ground sample (BCL_gr black dash-dot line), BCL physical mixture with Ac-β-CD (BCL/Ac-β-CD_pm green solid line), BCL with Ac-β-CD ground sample (BCL/Ac-β-CD_gr red solid line), Ac-β-CD raw material (Ac-β-CD blue solid line).

Figure 6

FTIR spectra of BCL raw material (BCL_raw black line), BCL physical mixture with Ac-β-CD (BCL/Ac-β-CD_pm green line), BCL with Ac-β-CD ground sample (BCL/Ac-β-CD_gr red line), Ac-β-CD raw material (Ac-β-CD blue solid line).

Figure 7

SEM images of raw BCL (1a,1b,1c,1d), ground BCL (2a,2b,2c,2d), BCL/Ac-β-CD_pm (3a,3b,3c,3d), BCL/Ac-β-CD_gr (4a,4b,4c,4d), Ac-β-CD (5a,5b,5c,5d). Indexes (a), (b), (c), and (d) are referred to (×400), (×1300), (×5000) and (×24,000), respectively.

Figure 7

SEM images of raw BCL (1a,1b,1c,1d), ground BCL (2a,2b,2c,2d), BCL/Ac-β-CD_pm (3a,3b,3c,3d), BCL/Ac-β-CD_gr (4a,4b,4c,4d), Ac-β-CD (5a,5b,5c,5d). Indexes (a), (b), (c), and (d) are referred to (×400), (×1300), (×5000) and (×24,000), respectively.

Figure 8

The equilibrium solubility of the BCL solid samples in pH 6.8 buffer at 310.15 K. BCL_raw (1.05 × 10⁻⁵ M) = BCL_gr (1.01 × 10⁻⁵ M) < BCL/Ac-β-CD_pm (1.21 × 10⁻⁵ M) < BCL/Ac-β-CD_gr (1.45 × 10⁻⁵ M) ≤ BCL/Ac-β-CD_gr (PVP) (1.51 × 10⁻⁵ M) < BCL/Ac-β-CD_gr (HPMC) (2.72 × 10⁻⁵ M).

Figure 9

Dissolution (a) and permeation (b) profiles of the studied BCL samples using the combined dissolution/permeation setup at 310 K. The BCL amounts related to the equilibrium solubility in the respective conditions are indicated by the dotted lines.

Figure 10

(a) The steady-state fluxes in sink conditions (left grey columns) and permeability coefficients (right dashed columns) from the experiments in the Franz diffusion cell; (b) the steady-state fluxes in non-sink conditions from the solution (Franz diffusion cell) (left blue columns) and from the suspension (side-by-side cell) (right cyan columns) of BCL raw material (BCL_raw), BCL physical mixture (BCL/Ac-β-CD_pm) and BCL ground sample (BCL/Ac-β-CD_gr) (buffer pH 6.8, 310.15 K).