Improvement of solubility and dissolution properties of clotrimazole by solid dispersions and inclusion complexes

Abstract

Solid dispersions of a slightly water-soluble drug, clotrimazole, were prepared in different weight ratios using polyethyleneglycol 4000 and different molecular weight polyvinyl pyrrolidones as carriers. Moreover, binary and ternary β-cyclodextrin complexes were prepared in different molar ratios. Both solid dispersions and β-cyclodextrin complexes were prepared by solvent evaporation technique. A phase solubility method was used to evaluate the effect of the tested carriers on the aqueous solubility of clotrimazole. The dissolution of all the preparations was tested using the USP paddle method. The selected solid dispersions and inclusion complexes were characterized by differential scanning calorimetry and X-ray powder diffractometry studies, and results clarified the role of the tested carriers in decreasing the crystallinity of clotrimazole and complexing abilities. Based on physical characters and in vitro drug release pattern, polyvinylpyrrolidone solid dispersions (1:1 weight ratio) and ternary cyclodextrin complexes (clotrimazole-β-cyclodextrin complexes with either polymer, 1:1 molar ratio) were selected as ideal batches for suppositories. Suppocire AM/50 mg carbopol 940, was chosen as a suppository base and the suppositories were prepared by molding technique. The prepared suppositories were characterized for weight variation, softening time and drug content. All these properties were found to be ideal. The in vitro drug release pattern was determined in citrate buffer (pH 4.5) containing 1% sodium lauryl sulfate. The in vitro release of clotrimazole from its solid dispersions and inclusion complexes incorporated suppositories was markedly improved when compared to the intact drug incorporated suppositories. Polyvinyl pyrrolidone solid dispersions incorporated suppositories were found to possess excellent antifungal activity.

Keywords: Clotrimazole; polyethyleneglycol; polyvinylpyrrolidone; suppository; β-cyclodextrin.

Fig. 1

DSC curves of clotrimazole and binary systems with different polyvinyl pyrrolidone polymers. A; CLOT, B; PVP, C; 1:1 physical mixture, D; 1:1 solid dispersion (PVP k-17), E; 1:1 solid dispersion (PVP k-25), F; 1:1 solid dispersion (PVP k-30)

Fig. 2

DSC curves of clotrimazole and binary systems with polyethylene glycol4000. A; CLOT, B; PEG4000, C; 1:5 physical mixture, D; 1:5 solid dispersion

Fig. 3

DSC curves of clotrimazole and its different systems with β-cyclodextrin. A; CLOT, B; β-CD, C; 1:1 physical mixture, D; 1:1 binary complex, E; 1:1 β-CD ternary complex with PVP, 1:1 β-CD ternary complex with PEG

Fig. 4

X-ray diffraction patterns of clotrimazole and binary systems with different polyvinyl pyrrolidone polymers. A; CLOT, B; PVP, C; 1:1 physical mixture, D; 1:1 solid dispersion (PVP k-17), E; 1:1 solid dispersion (PVP k-25), F; 1:1 solid dispersion (PVP k-30)

Fig. 5

X-ray diffraction patterns of clotrimazole and binary systems with polyethylene glycol4000. A; CLOT, B; PEG4000, C; 1:5 physical mixture, D; 1:5 solid dispersion

Fig. 6

X-ray diffraction patterns of clotrimazole and different systems with β-cyclodextrin. A; CLOT, B; β-CD, C; 1:1 physical mixture, D; 1:1 binary complex, E; 1:1 β-CD ternary complex with PVP, 1:1 β-CD ternary complex with PEG