Solubility Of Artemisinin Research Articles

Screening of alternative solvent ionic liquids for artemisinin: COSMO-RS prediction and experimental verification

Organic solvents are usually used to extract artemisinin from Artemisia annua L., and they can also be the solvents for the subsequent purification or derivatization to produce compounds with more efficient antimalarial effect. However, these solvents are volatile, explosive and toxic. The designable material ionic liquids (ILs) are alternative solvents to replace traditional ones. In this work, a reliable method for screening ILs with high solvation capability for artemisinin was developed. The infinite dilution activity coefficients of artemisinin in 903 ILs, composed by 43 cations and 21 anions, were calculated by COSMO-RS, and the results implied that the solubility of artemisinin in ILs mainly depends on the anions. Solubilities of artemisinin in 14 representative ILs were tested, and the results were in good accordance with those obtained in COSMO-RS calculation. The stability of artemisinin in some typical ILs was also studied, which indicated that this drug was stable in [EMIM][BF4], [EMIM][CF3Ac], [EMIM][NTF2], [BPY][NTF2], [EMIM][SCN], and [EMIM][Ac]. The excess enthalpy analysis demonstrated that artemisinin interacted with ILs mainly through hydrogen bond. Extraction of artemisinin using the optimal IL indicated that more artemisinin could be extracted from the leaves when compared with petroleum ether (254.73 mg/mol IL vs. 14.16 mg/mol solvent), further verifying accuracy of the simulation results. Therefore, structures of ILs with high solvation capacity for artemisinin can be obtained by the COSMO-RS method.

Investigation on the relationship between solubility of artemisinin and polyvinylpyrroli done addition by using DAOSD approach

In this work, we investigated the influence of polyvinylpyrrolidone (PVP) on the solubility of artemisinin in aqueous solution by using quantitative 1H NMR. Experimental results demonstrate that about 4 times of incremental increase occurs on the solubility of artemisinin upon introducing PVP. In addition, dipole-dipole interaction between the ester group of artemisinin and the amide group of N-methylpyrrolidone (NMP), a model compound of PVP, is characterized by two-dimensional (2D) correlation FTIR spectroscopy with the DAOSD (Double Asynchronous Orthogonal Sample Design) approach developed in our previous work. The observation of cross peaks in a pair of 2D asynchronous spectra suggests that dipole-dipole interaction indeed occurs between the ester group of artemisinin and amide group of NMP. Moreover, the pattern of cross peaks indicates that the carbonyl band of artemisinin undergoes blue-shift while the bandwidth and absorptivity increases via interaction with NMP, and the amide band of NMP undergoes blue-shift while the absorptivity increases via interaction with artemisinin. Dipole-dipole interaction, as one of the strongest intermolecular interaction between artemisinin and excipient, may play an important role in the enhancement of the solubility of artemisinin in aqueous solution.

Crystallization of Artemisinin from Chromatography Fractions of Artemisia annua Extract

Crystallization is an inevitable step in the purification of artemisinin either from the plant Artemisia annua or from reaction mixtures of semisynthetically produced artemisinin. Rational design of crystallization process requires knowledge about the solid–liquid equilibrium in a given solvent system and effect of impurities on it. In the present work, a crystallization process was designed to purify artemisinin from fractions of a flash chromatography column effluent collected after injecting extracts of Artemisia annua leaves. The fractions from chromatography containing artemisinin were combined together into one fraction, and the impurities present in this fraction were identified. The solubility of artemisinin in the mobile phase used for chromatography, i.e., n-hexane–ethyl acetate mixture of varying compositions, was measured at 25, 15, and 5 °C, respectively. The collective effect of impurities present in the combined fraction on the solid–liquid equilibrium of artemisinin was evaluated by measur...

Thermodynamic phase behavior of API/polymer solid dispersions.

To improve the bioavailability of poorly soluble active pharmaceutical ingredients (APIs), these materials are often integrated into a polymer matrix that acts as a carrier. The resulting mixture is called a solid dispersion. In this work, the phase behaviors of solid dispersions were investigated as a function of the API as well as of the type and molecular weight of the carrier polymer. Specifically, the solubility of artemisinin and indomethacin was measured in different poly(ethylene glycol)s (PEG 400, PEG 6000, and PEG 35000). The measured solubility data and the solubility of sulfonamides in poly(vinylpyrrolidone) (PVP) K10 and PEG 35000 were modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT). The results show that PC-SAFT predictions are in a good accordance with the experimental data, and PC-SAFT can be used to predict the whole phase diagram of an API/polymer solid dispersion as a function of the kind of API and polymer and of the polymer's molecular weight. This remarkably simplifies the screening process for suitable API/polymer combinations.

Development of solid dispersions of artemisinin for transdermal delivery

Solid dispersions of the poorly soluble drug artemisinin were developed using polymer blends of polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) with the aim of enhancing solubility and in vitro permeation of artemisinin through skin. Formulations were characterised using a combination of molecular dynamics (MD) simulations, differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR). Solubility of artemisinin was determined in two solvents: de-ionised water and phosphate buffered saline (PBS; pH 7.4), while in vitro drug permeation studies were carried out using rabbit skin as a model membrane. MD simulations revealed miscibility between the drug and polymers. DSC confirmed the molecular dispersion of the drug in the polymer blend. Decrease in crystallinity of artemisinin with respect to polymer content and the absence of specific drug-polymer interactions were confirmed using XRD and FT-IR, respectively. The solubility of artemisinin was dramatically enhanced for the solid dispersions, as was the permeation of artemisinin from saturated solid-dispersion vehicles relative to that from saturated solutions of the pure drug. The study suggests that high energy solid forms of artemisinin could possibly enable transdermal delivery of artemisinin.

Purification of artemisinin from quercetin by anti-solvent crystallization

In the present work, anti-solvent crystallization of artemisinin from four different organic solvents (methanol, ethanol, acetonitrile, and acetone) was studied. Water was used as anti-solvent. The effect of an impurity (quercetin) on the performance of anti-solvent crystallization of artemisinin was investigated. The fundamental process data such as solubility of artemisinin in pure organic solvents and their binary mixtures with varying composition water were measured at room temperature. The solubility of quercetin was measured only in pure organic solvents at room temperature. Anti-solvent crystallization experiments were designed based on the fundamental process data determined. Firstly, the anti-solvent crystallization of artemisinin without impurity was performed from all four organic solvents and then the experiments were repeated with addition of an impurity (quercetin) while keeping all other process parameters constant. Two different concentrations of impurity, i.e., 10% and 50% of its solubility, in the respective organic solvents at room temperature were used. The effect of impurity on performance of anti-solvent crystallization was evaluated by comparing the yield and purity of the artemisinin obtained with those in the absence of impurity. Results of the present work demonstrated that the presence of quercetin in the solution does not affect the final yield of artemisinin from the solution of each of four organic solvents used. However, the purity of artemisinin crystals were reduced when quercetin concentration was 50% of its solubility in all solvents studied.

Chromatography‐Crystallization Hybrid Process for Artemisinin Purification from Artemisia annua

AbstractThe feasibility of using a chromatography‐crystallization hybrid separation process for isolation and purification of artemisinin from the herbal plant Artemisia annua was studied. After separating the crude extracts of Artemisia annua by flash column chromatography, a two‐step antisolvent crystallization process was used for further isolation and purification. The two‐step antisolvent crystallization process was designed based on the solubility of artemisinin in different solvents and solvent mixtures. The first step crystallization process was to remove impurities from the solution and the second step to isolate artemisinin. The crystallization behavior of the two polymorphs of artemisinin during the antisolvent crystallization process was also studied by performing crystallization in solutions of artemisinin in acetonitrile and acetone, respectively. It was observed that the formation of the two polymorphs of artemisinin in acetone solution follows the Ostwald's rule of stages. Fast feeding of the antisolvent (water) resulted in crystallization of the metastable triclinic form which then transformed to the stable orthorhombic form through a solvent‐mediated transformation mechanism. The stable orthorhombic form crystallized out when water was fed slowly. Crystallization from acetonitrile always yielded the stable orthorhombic form regardless of the feeding rate of the antisolvent. Finally, a chromatography‐crystallization hybrid separation process was proposed and tested. The results of the present work demonstrated the feasibility of combining the advantages of column chromatography and crystallization to improve efficiency of the isolation of artemisinin from Artemisia annua.

Solubility of Artemisinin in Seven Different Pure Solvents from (283.15 to 323.15) K

The solubility of artemisinin in pure methanol, ethyl acetate, acetone, acetonitrile, cyclohexane, toluene, and chloroform was measured by a synthetic method over the temperature range from (283.15 to 323.15) K at atmospheric pressure. The results show that the solubility of artemisinin increases with increasing temperature in all seven solvents. The experimental data were correlated using the modified Apelblat model, and the agreement with the experimental data was very good.

Solubility of Artemisinin in Ethanol + Water from (278.2 to 343.2) K

The solubility of artemisinin in ethanol + water was measured at several concentrations and over the temperature range of (278.2 to 343.2) K. The solubility of artemisinin in ethanol and water mixture increases with the increase in temperature and with ethanol concentration. The solubility data were correlated with a modified Apelblat equation.