Injectable Formulations of Poorly Water-Soluble Drugs

Finding the Needle in the Haystack: Characterization of Trace Crystallinity in a Commercial Formulation of Paclitaxel Protein-Bound Particles by Raman Spectroscopy Enabled by Second Harmonic Generation Microscopy

“…For intravenous (IV) formulations, incomplete solubilization of the API introduces additional embolism risks associated with blood vessel occlusion by circulation of poorly soluble API particulates. Therefore, various different strategies to solubilize APIs are employed, including pH adjustment and/or the use of cosolvents, surfactants, or emulsifiers. − Unfortunately, additives used to solubilize drugs for IV formulations can exhibit toxicity, , in some cases fatal . Therefore, solubilization strategies that minimize the use of additives with undesirable side-effects are of great interest.…”

“…Quantification and detection of crystallinity at low levels within such an amorphous formulation is often a defining measurement for predicting the long-term success of the product. For IV formulations in particular, crystal formation is detrimental because it not only reduces the solubility advantage of the amorphous formulation, but the presence of large, insoluble particulates is problematic and hence subject to stringent regulations. ,, Unfortunately, for potent APIs at low loadings, accurate determination of crystallinity poses a significant measurement challenge. As the drug loading approaches the detection limits of conventional benchtop methods, even major differences in relative drug crystallinity become difficult to distinguish with statistical confidence.…”

“…In the present study, assessment of this SHG-guided analysis approach was performed for the amorphous IV formulation Abraxane (nanoparticle albumin bound paclitaxel for injectable suspension). Abraxane was the first nanosuspension approved for clinical use , and is indicated to contain 10% (w/w) PTX bound to nanoparticles of HSA. Abraxane has been shown to have increased efficacy compared to other PTX formulations (e.g., Taxol), particularly in the treatment of breast cancer, ,, nonsmall cell lung cancer, − and pancreatic carcinoma .…”

“…Abraxane has been shown to have increased efficacy compared to other PTX formulations (e.g., Taxol), particularly in the treatment of breast cancer, ,, nonsmall cell lung cancer, − and pancreatic carcinoma . PTX is generally regarded as exhibiting substantial solubility limitations, with crystalline PTX exhibiting poor bioavailability . In addition to the increased apparent solubility arising from an amorphous nanosuspension, it is thought that Abraxane achieves higher treatment specificity as a result of its HSA matrix, utilizing the known high protein uptake rate of tumors. ,− …”

“…49 PTX is generally regarded as exhibiting substantial solubility limitations, with crystalline PTX exhibiting poor bioavailability. 13 In addition to the increased apparent solubility arising from an amorphous nanosuspension, it is thought that Abraxane achieves higher treatment specificity as a result of its HSA matrix, utilizing the known high protein uptake rate of tumors. 20,50−52 ■ METHODS Abraxane samples were analyzed in their native (solid) form as obtained from the manufacturer.…”