Abstract
Though paclitaxel (PTX) and doxorubicin (DOX) are amongst the most widely used and investigated drug pair for combination chemotherapy but surprisingly, not a single validated HPLC-UV method is available to analyze PTX and DOX simultaneously. So, herein a HPLC-UV method is developed and validated for the same, filling an indispensable gap in the literature. As these two moieties have characteristically different polarities, resolving them under the common chromatographic conditions is a challenging task. Herein, the principle of ion pair chromatography is utilized to resolve these two moieties on a C18 column employing an isocratic mobile phase comprised of acetonitrile and octane sulfonic acid buffer (67 : 37) and detected simultaneously at 231 nm using a UV detector only. The retention time is 4.4 and 7.2 min for PTX and DOX, respectively, with a total analysis time of less than 10 minutes, suitable for the formulation development and research, while LOQ is less than 0.066 μg/ml for both the drugs, suitable for the therapeutic drug monitoring at preclinical and clinical research setup. To substantiate the applicability of the developed method, a nanoformulation coloaded with PTX and DOX was designed and analyzed using the developed protocol. The method is also applied successfully to study the plasma kinetic profile of both the moieties simultaneously in Balb/c mice. Further, the method is validated as per the ICH guidelines fulfilling the unmet need of a validated analytical tool to simultaneously estimate PTX and DOX. Moreover, the results suggest that the principal of common ion chromatography demonstrated here can also be applied further for the simultaneous chromatographic separation of other polar and nonpolar moieties too. Consequently, the reported method surely will advance the toolset required for the precision-based combination chemotherapy.
Highlights
Paclitaxel (PTX) and doxorubicin (DOX) are the first-line chemotherapeutics that are very frequently used and investigated for combination chemotherapy in different types of cancer management
PTX and DOX were received as a generous gift sample from Alembic Pharmaceuticals, Vadodara, India. 1-Octane sulfonic acid sodium salt (OSA), orthophosphoric acid (OPA), phosphatidyl choline, and cholesterol were procured from Sigma, USA
Chromatographic resolution was accomplished on a RP LiChrospher® C18 column (100, 250 mm × 4:6 mm, 5 μm; Merck), at 35°C of column temperature. Both the moieties eluted using an isocratic mobile phase comprised of aqueous buffer (0.025% w/v OSA; pH adjusted to 3.0 with OPA) and ACN mixed in a ratio of 37 : 63 parts, respectively
Summary
Paclitaxel (PTX) and doxorubicin (DOX) are the first-line chemotherapeutics that are very frequently used and investigated for combination chemotherapy in different types of cancer management. An efficient analytical tool for the simultaneous estimation of PTX and DOX is an unmet need. Researchers working on combinational use of PTX and DOX have to analyze them individually employing different dedicated analytical techniques for each drug [3, 6, 9–15]. Pharmacokinetic study reported by Gianni et al employed two different HPLC methods for the estimation of PTX and DOX, respectively [14]. Analytical methods reported by Ahmed et al and Markovsky et al employed fluorescence spectroscopy for the analysis of DOX and HPLC separately for the analysis of PTX [10, 15]. Due to unavailability of a validated HPLC method, LC-MS is another analytical tool that is frequently employed for the coestimation of PTX and DOX [1, 17]. The application of the developed method is further applied to study the plasma pharmacokinetic of the PTX and DOX coadministered to Balb/c mice via developed nanoformulation
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