betadex and artenimol

The purpose of this study was to simultaneously improve the solubility and stability of dihydroartemisinin (DHA) in aqueous solutions by a ternary cyclodextrin system comprised of DHA, hydroxypropyl-β-cyclodextrin (HP-β-CD) and a third auxiliary substance. Solubility and phase solubility studies were carried out to evaluate the solubilizing efficiency of HP-β-CD in association with various auxiliary substances. Then, the solid binary (DHA-HP-β-CD or DHA-lecithin) and ternary systems were prepared and characterized by Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and power X-ray diffraction (PXRD). The effect of the ternary system on the solubility, dissolution and stability of DHA in aqueous solutions was also investigated. As a result, the soybean lecithin was found to be the most promising third component in terms of solubility enhancement. For the solid characterization, the disappearance of the drug crystallinity indicated the formation of new solid phases, implicating the formation of the ternary system. The dissolution rate of the solid ternary system was much faster than that of the drug alone and binary systems. Importantly, compared with binary systems, the ternary system showed a significant improvement in the stability of DHA in Hank's balanced salt solutions (pH 7.4). The solubility and stability of DHA in aqueous solutions were simultaneously enhanced by the ternary system, which might be attributed to the possible formation of a ternary complex. For the ternary interactions, results of molecular docking studies further indicated that the lecithin covered the top of the wide rim of HP-β-CD and surrounded around the peroxide bridging of DHA, providing the possibility for the ternary complex formation. In summary, the ternary system prepared in our study, with simultaneous enhancement of DHA solubility and stability in aqueous solutions, might have an important pharmaceutical potential in the development of a better oral formulation of DHA.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Artemisinins; beta-Cyclodextrins; Calorimetry, Differential Scanning; Cyclodextrins; Drug Stability; Lecithins; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction

To optimize the preparation method of the complex of dihydroartemisinin (DHA) included by hydroxypropyl-beta-cyclodextrin (HP-beta-CD), the molar ratio of DHA and HP-beta-CD, inclusion temperature and inclusion time were optimized by the orthogonal design method with the inclusion drug yield and drug loading as the evaluation indexes. The IR spectrum, DSC and PXRD analyses were employed to characterize the complex and the molecular simulation was processed to investigate the tendency of complex formation. The optimized molar ratio of DHA and HP-beta-CD was 1 : 5, and the optimized preparation was performed under 50 degrees C for 1 h. The IR spectrum, DSC and PXRD analyses indicated the formation of the complex. The low binding free energy and the high solvent accessible surface obtained by molecular simulation showed that DHA could be included by HP-beta-CD and its solubility could be improved significantly. In conclusion, the optimized conditions for the preparation of DHA-HP-beta-CD complex provide a theoretical and experimental basis for further scale-up research.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Artemisinins; beta-Cyclodextrins; Calorimetry, Differential Scanning; Chromatography, High Pressure Liquid; Drug Compounding; Solubility; Spectroscopy, Fourier Transform Infrared; Surface Properties; Temperature; Time Factors; X-Ray Diffraction

Dihydroartemisinin (DHA) is a poorly water-soluble drug that displays low bioavailability after oral administration. Attempts have been made to improve the solubility of DHA. Yet, no information is available concerning improved bioavailability. This study aimed to improve the water solubility of DHA by two systems: solid dispersions with polyvinylpyrrolidone (PVPK30, PVPK25, PVPK15) and inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβCD), as well as improving the bioavailability of both systems. The phase transition of DHA with hydrophilic polymers was evaluated by X-ray diffraction (XRD) and differential scanning calorimetery (DSC). DHA became amorphous in DHA-HPβCD complexes and showed more amorphous behavior in XRD analyses with rise in molecular weight of PVP. Melting onset temperature of DHA decreased, while DSC thermograms revealed the peak area and enhanced enthalpy change (DH) in solid dispersions as well as inclusion complexes. DHA solubility was enhanced 84-fold in DHA-HPβCD complexes and 50-times in DHA-PVPK30. The improved solubility using the four polymers was in the following order: HPβCD > PVPK30 > PVPK25 > PVPK15. Values of area under curve (AUC) and half life (t(1/2)) of DHA-PVPK30 were highest followed by DHA-HPβCD, DHA-PVPK15 and DHA-PVPK25. V(d)/f of DHA-PVPK30 was 7-fold. DHA-HPβCD, DHA-PVPK15 and DHA-PVPK25 showed significantly different pharmacokinetic parameters compared with DHA solutions. The 95% confidence interval was meaningful in AUC and t(1/2). Pharmacokinetic parameters revealed that all four-test preparations were significantly more bioavailable than DHA alone.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antimalarials; Artemisinins; beta-Cyclodextrins; Biological Availability; Calorimetry, Differential Scanning; Drug Carriers; Drug Compounding; Half-Life; Hydrophobic and Hydrophilic Interactions; Metabolic Clearance Rate; Mice; Molecular Weight; Phase Transition; Povidone; Random Allocation; Solubility; Suspensions; Transition Temperature; X-Ray Diffraction

Dihydroartemisinin (DHA) is a major metabolite of artemisinin and its derivatives, including arteether, artemether, and artesunate. To improve the solubility and stability of poorly soluble DHA, we prepared inclusion complexes with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and recrystalized DHA to study its thermal stability. The complexes were characterized by differential scanning calorimetery (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction patterns (XRD), thermal stability, phase, and equilibrium solubility studies. Pure DHA was crystalline and remained crystalline after recrystallization, but its unit cell dimensions changed as exhibited by XRD. DHA-HPbetaCD complexes showed a phase transitions towards amorphous in DSC thermograms, FTIR spectra, and XRD patterns. The phase solubility profiles of complexes prepared in water, acetate buffer, and phosphate buffers were classified as A(L)-type, indicating the formation of a 1:1 stoichiometric inclusion complex. The equilibrium solubility of DHA was enhanced as a function of HPbetaCD concentration. DHA-HPbetaCD complexes showed an 89-fold increase in solubility compared to DHA. Solubilities of complexes containing 275.1 mM HPbetaCD in water, acetate buffer (pH 3.0), and phosphate buffer (pH 3.0 and 7.4) were 10.04, 7.96, 6.30, and 11.61 mg/ml, respectively. Hydrogen bonding was found between DHA and HPbetaCD, and it was stronger in complexes prepared in water than in buffers. However, the AH values were higher in buffer than water. DHA-HPbetaCD complexes prepared using commercial (untreated) or recrystallized DHA (no detectable impurity) showed a 40% increase in thermal stability (50 degrees C) and a 29-fold decrease in hydrolysis rates compared with DHA. The rank order of stability constants (K(s)) was: water, acetate buffer (pH 3.0), phosphate buffer (pH 3.0), and phosphate buffer (pH 7.4). Thus, HPbetaCD complexation with recrystalized DHA increases DHA solubility and stability.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Oral; Antimalarials; Artemisinins; beta-Cyclodextrins; Buffers; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Crystallography, X-Ray; Drug Stability; Hydrogen Bonding; Hydrogen-Ion Concentration; Hydrolysis; Injections, Intravenous; Models, Chemical; Solubility; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical; Temperature