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Dihydroartemisinin-cyclodextrin complexation: Solubility and stability

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  • Drug Development
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Abstract

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-β-cyclodextrin (HPβCD) 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-HPβCD 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 AL-type, indicating the formation of a 1:1 stoichiometric inclusion complex. The equilibrium solubility of DHA was enhanced as a function of HPβCD concentration. DHA-HPβCD complexes showed an 89-fold increase in solubility compared to DHA. Solubilities of complexes containing 275.1 mM HPβCD 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 HPβCD, and it was stronger in complexes prepared in water than in buffers. However, the ÄH values were higher in buffer than water. DHA-HPβCD complexes prepared using commercial (untreated) or recrystallized DHA (no detectable impurity) showed a 40% increase in thermal stability (50°C) and a 29-fold decrease in hydrolysis rates compared with DHA. The rank order of stability constants (Ks) was: water, acetate buffer (pH 3.0), phosphate buffer (pH 3.0), and phosphate buffer (pH 7.4). Thus, HPβCD complexation with recrystalized DHA increases DHA solubility and stability.

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Authors and Affiliations

  1. Department of Statistics, Bahauddin Zakariya University, Multan, Pakistan

    Ijaz Iqbal

  2. School of Pharmacy, Curtin University of Technology, Perth, Australia

    Vivian Bruce Sunderland

  3. Department of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan

    Muhammad Tayyab Ansari, Ijaz Iqbal & Vivian Bruce Sunderland

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  1. Muhammad Tayyab Ansari
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  2. Ijaz Iqbal
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Correspondence to Muhammad Tayyab Ansari.

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Ansari, M.T., Iqbal, I. & Sunderland, V.B. Dihydroartemisinin-cyclodextrin complexation: Solubility and stability. Arch. Pharm. Res. 32, 155–165 (2009). https://doi.org/10.1007/s12272-009-1130-4

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