Determination of paclitaxel solubility in the presence of intravenous excipients

Abstract

The formulation of Taxol contains 50:50 (v/v) of ethanol and Cremophor EL as vehicle. Cremophor EL is responsible for many adverse effects which the most important of them is hypersensitivity reactions. Furthermore, it leaches diethylhexyl phthalate from polyvinylchloride containers. Aim: This research sets out to determine the solubility of paclitaxel in intravenous excipients. Material and methods: Solubility of paclitaxel was measured in PEG 400, ethanol, miglyol 812, octanoic acid and oleic acid using the shake flask method. The supernatant fluid was filtered and the concentration of paclitaxel was analyzed with HPLC. Two excipients in which paclitaxel had most solubility were used to prepare a vehicle of 50:50 (v/v). Citric acid monohydrate was added to enhance stability of paclitaxel. The compositions were kept under ambient and accelerated stability study for 3 months. 1 ml of the prepared compositions was added to 1, 5, 10, 25 and 50 ml of normal saline and stirred for 5 minutes. All dilutions were centrifuged at 5000 rpm for 10 minutes. Precipitation was observed in all of them optically. Supernatant fluid of 1:50 dilution was analyzed using HPLC. Results: Paclitaxel is most soluble in PEG 400 because they are similar in polarity and hydrophobic and hydrophilic balance. Co-solvents disturb the hydrogen bonding structure of water and reduce the dielectric constant of the resulting solvent system. The similarity of drug and solvent in polarity leads to smaller decomposition rate of the substance. Adjusting pH into the range 3 to 6 by addition of acid citric monohydrate improved stability. Dilution of co-solvent with aqueous media can cause drug precipitation. Conclusion: Paclitaxel showed the highest solubility in PEG 400 and ethanol. 50:50 (v/v) mixture of PEG 400 and ethanol containing citric acid monohydrate were chemically stable. Paclitaxel precipitates upon introduction of the prepared compositions to aqueous media.