Ijaz Iqbal

Dihydroartemisinin-cyclodextrin complexation: Solubility and stability

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.

Circular Strongly Balanced Repeated Measurements Designs

Magda (1980) and Hedayat (1981) first considered the construction of circular strongly balanced repeated measurements designs. Sen and Mukerjee (1987) and Roy (1988) considered the optimality and existence of circular strongly balanced repeated measurements designs based on the method of differences and Hamiltonian decomposition of lexicographic product of two graphs. In this article, we consider the construction of circular strongly balanced repeated measurements designs using the newly proposed method called cyclic shifts, and propose some new designs for p < v.

Circular First- and Second-Order Balanced Repeated Measurements Designs

Sharma (1977) and Aggarwal et al. (2006) considered non circular construction of first- and second-order balanced repeated measurements designs. Sharma et al. (2002) constructed circular first- and second-order balanced repeated measurements designs only for a class with parameters (v, p = 3n, n = v 2) and also showed its universal optimality. In this article, we consider circular construction of first- and second-order balanced repeated measurements designs and strongly balanced repeated measurements designs by using the method of cyclic shifts. Some new circular designs with parameters (v, p, n) for cases p = v, p < v and p > v are given.

Efficient Repeated Measurements Designs with Equal and Unequal Period Sizes

Abstract We describe a general method of constructing repeated measurements designs using sets of cyclic shifts. Efficient designs for t treatments in p periods, where t ⩽10 and p ⩽8, are given. In addition, efficient strongly balanced designs and designs that are balanced for first- and second-order residual effects are given. Finally, some efficient designs with two different period sizes are given. The designs extend and fill in gaps in previously published tables.

Improving the Solubility and Bioavailability of Dihydroartemisinin by Solid Dispersions and Inclusion Complexes

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 (t1/2) of DHA-PVPK30 were highest followed by DHA-HPβCD, DHA-PVPK15 and DHA-PVPK25. Vd/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 t1/2. Pharmacokinetic parameters revealed that all four-test preparations were significantly more bioavailable than DHA alone.

Universally Optimal Designs Balanced for Neighbor Effects

The performance of a treatment is affected by the treatments applied to its adjacent plots, especially in the experiments of agriculture, horticulture, forestry, serology and industry. Neighbor designs ensure that treatment comparisons are least affected by neighbor effects, therefore, this is a rich field of investigation. In this paper, criterion for construction of universally optimal neighbor balanced designs is discussed.

Cyclic Polygonal Designs with Block Size 3 and Joint Distance α = 2

Polygonal designs are useful in survey sampling in terms of balanced sampling plans excluding contiguous units (BSECs) and balanced sampling plans excluding adjacent units (BSAs). In this article, the method of cyclic shifts has been used for the construction of cyclic polygonal designs (in terms of BSAs) with block size k = 3 and λ = 1, 2, 3, 4, 6, 12 for joint distance α = 2 and 51 new designs for treatments v ≤ 100 are given.

Cyclic Polygonal Designs with Block Size 3 and λ = 1 for Joint Distance α = 6 to 16

Stufken (1993) first introduced cyclic polygonal designs (CPDs) (in terms of cyclic balanced sampling plans excluding adjacent units (CBSAs)) for joint distance α ≥ 2. Wei (2002) first suggested the use of Langford sequence for the existence and construction of CPDs with block size k = 3 and λ = 1 for arbitrary α. Zhang and Chang (2005b) used Langford and extended Langford sequence, and constructed CPDs (in terms of CBSAs) with block size k = 3 and λ = 1 for joint distance α = 2; 3. Zhang and Chang (2006) also constructed CPDs by using Langford sequence with k = 3 and λ = 1 for joint distance α = 4. Mandal, Parsad and Gupta (2008a) used symmetrically repeated differences and linear programming approach and gave a catalog of CPDs with k = 3, and λ = 1 for joint distance α = 2;3;4 and for some ν. In this paper, we use the method of cyclic shifts and constructed CPDs with k = 3 and λ = 1 for joint distance α = 6 to 16. A catalog of non-fractional and fractional (or smaller) CPDs for λ ≤ 100 treatments is compiled.