Noncovalent dimerization of paclitaxel in solution: Evidence from electrospray ionization mass spectrometry

Lorenz, Sarah A.; Bigwarfe, Paul M.; Balasubramanian, Sathyamangalam V.; Fetterly, Gerald J.; Straubinger, Robert M.; Wood, Troy D.

doi:10.1002/jps.10194

Cited by 16 publications

(8 citation statements)

References 36 publications

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“…Although the discovery of electrospray techniques contributed a great deal to the development of new drug candidates, identification of molecular ions of trace level impurities could not be conclusive, due to alkali metal ion adduct formation. Earlier reports on paclitaxel impurity analysis by the electrospray ionization (ESI) mechanism showed predominant formation of alkali metal ion adducts 18, 19. Formation of alkali metal ion adducts is difficult to control due to its ubiquitous presence in glassware, tubing and impure solvents.…”

Section: Components Of Taxus Brevifolia Extract10mentioning

confidence: 99%

Identification of isocephalomannine in the presence of cephalomannine isomers and alkali metal ion adducts in a paclitaxel active pharmaceutical ingredient using electrospray tandem mass spectrometry

Kannan¹,

Swamy²,

Prasad³

et al. 2006

Rapid Comm Mass Spectrometry

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A strategy is developed for the identification of isocephalomannine in the presence of alkali metal ion adducts and other cephalomannine isomers in a paclitaxel active pharmaceutical ingredient. Intact molecular ion analyses and a sub-structural study have been performed for the differentiation of isocephalomannine (2-debenzoylpaclitaxel-2-pentenoate) from cephalomannine and 7-epi-cephalomannine. A comparative study of the cephalomannine isomers was carried out using molecular ions (MS) and fragmentation patterns (MS/MS) for sub-structural analysis. An attempt has been made to identify isocephalomannine in Cremophor(R) EL formulations.

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Section: Components Of Taxus Brevifolia Extract10mentioning

confidence: 99%

Identification of isocephalomannine in the presence of cephalomannine isomers and alkali metal ion adducts in a paclitaxel active pharmaceutical ingredient using electrospray tandem mass spectrometry

Kannan¹,

Swamy²,

Prasad³

et al. 2006

Rapid Comm Mass Spectrometry

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“…Hydrogen/deuterium (H/ D) exchange combined with mass spectrometry is a valuable tool to study protein-ligand interaction and protein-protein interactions (Nabuchi et al, 2004;Zhu et al, 2004). Recently, Lorenz and co-workers applied this approach to demonstrate the non-covalent dimerization of paclitaxel in solution and to investigate a drug-drug complex as being formed in solution or in the gas phase (Lorenz et al, 2001(Lorenz et al, , 2002. This study applied a H/D exchange experiment to investigate the involvement of hydrogen bonds in the non-covalent complex formed with octylamine.…”

Section: Introductionmentioning

confidence: 98%

The effect of alkylamine additives on the sensitivity of detection for paclitaxel and docetaxel and analysis in plasma of paclitaxel by liquid chromatography–tandem mass spectrometry

Gao

Zhang

Edinboro

et al. 2006

Biomed. Chromatogr.

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The formation of multiple molecular ions, especially due to sodium adduct ion formation, is commonly observed in electrospray mass spectrometry and may make reproducible and sensitive quantitation difficult. The objective of this work was to investigate the underlying mechanism involved in the suppression of multiple molecular ion formation and to improve the sensitivity of detection for the two anti-neoplastic agents paclitaxel and docetaxel. The results showed that alkylamine additives could significantly improve the detection of paclitaxel and docetaxel by suppression of multiple molecular ions through preferential formation of a predominant alkylamine adduct ion. Possible binding sites, binding interactions and binding competition were investigated for the sodium adduct and alkylamine adduct ions using various experimental techniques. The formation of a predominant amine adduct ion may be due to increased surface activity in the droplet. The optimal alkylamine for both analytes was octylamine, which increased peak heights of paclitaxel and docetaxel 4.8 and 3.7-fold (n = 3), respectively. The precision of the signals for the analytes was also improved 5.7-fold. A quantitative assay in plasma for paclitaxel was partially validated for the calibration range 1.0-1000 ng/mL (r = 0.9977) when using 0.05% octylamine as a reconstitution solution additive. The limit of detection (LOD) and limit of quantitation (LOQ) were 0.5 and 0.9 ng/mL, respectively. Acceptable precision, accuracy, specificity and sample stability were demonstrated for this assay. This approach may prove useful for other analytes with similar binding sites.

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“…Hydrogen bonding between the hydroxyl groups of PTX is important to generate the PTX crystal [32]. On the other hand, it was reported that the best stability of non-covalent PTX dimer was achieved in acetonitrile/acetic acid mixture rather than methanol/acetic acid mixture [33]. In that experiment, the acetic acid (p K a =4.7) was used to provide an appropriate pH to prevent PTX degradation.…”

Section: Resultsmentioning

confidence: 99%

Hydrotropic polymer micelles containing acrylic acid moieties for oral delivery of paclitaxel

Kim

Huh

et al. 2008

Journal of Controlled Release

118

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Hydrotropic polymers (HPs) and their micelles have been recently developed as vehicles for delivery of poorly water-soluble drugs, such as paclitaxel (PTX), by oral administration. The release of PTX from HP micelles, however, was slow and it took more than a day for complete release of the loaded PTX. Since the gastrointestinal (GI) transit time is known to be only several hours, pH-sensitive HP micelles were prepared for fast release of the loaded PTX responding to pH changes along the GI tract. Acrylic acid (AA) was introduced, as a release modulator, into HPs by copolymerization with 4-(2-vinylbenzyloxy)-N,N-(diethylnicotinamide) (VBODENA). The AA content was varied from 0% to 50 % (in the molar ratio to VBODENA). HPs spontaneously produced micelles in water, and their critical micelle concentrations (CMCs) ranged from 31 μg/mL to 86 μg/mL. Fluorescence probe study using pyrene showed that blank HP micelles possessed a good pH-sensitivity, which was clearly observed at relatively high AA contents and pH > 6. The pH sensitivity also affected the PTX loading property. Above pH 5, the PTX loading content and loading efficiency in HP micelles were significantly reduced. Although this may be primarily due to the AA moieties, other factors may include PTX degradation and polymer aggregation. The PTX release from HP micelles with more than 20% (mol) AA contents was completed within 12 h in a simulated intestinal fluid (SIF, pH=6.5). The HP micelles without any AA moiety showed very slow release profiles. In the simulated gastric fluid (SGF, pH=1.6), severe degradation of the released PTX was observed. The pH-dependent release of PTX from HP micelles can be used to increase the bioavailability of PTX upon oral delivery.

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Noncovalent dimerization of paclitaxel in solution: Evidence from electrospray ionization mass spectrometry

Cited by 16 publications

References 36 publications

Identification of isocephalomannine in the presence of cephalomannine isomers and alkali metal ion adducts in a paclitaxel active pharmaceutical ingredient using electrospray tandem mass spectrometry

Identification of isocephalomannine in the presence of cephalomannine isomers and alkali metal ion adducts in a paclitaxel active pharmaceutical ingredient using electrospray tandem mass spectrometry

The effect of alkylamine additives on the sensitivity of detection for paclitaxel and docetaxel and analysis in plasma of paclitaxel by liquid chromatography–tandem mass spectrometry

Hydrotropic polymer micelles containing acrylic acid moieties for oral delivery of paclitaxel

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