Analytical methods for analyzing and determining impurities in dianhydrogalactitol
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Publication Number
US-10145824-B2
Publication Date
2018-12-04
Expiration Date
Abstract
An improved analytical method for analysis of dianhydrogalactitol preparations provides a method for determining the purity of dianhydrogalactitol and detecting impurities in preparations of dianhydrogalactitol, as well as identifying any such impurities. The method employs high performance liquid chromatography (HPLC), in particular, HPLC with refractive index (RI) detection; the HPLC can be followed by tandem mass spectroscopy. The method can further comprise the step of performing preparative HPLC collection of at least one specific substance peak present in a preparation of dianhydrogalactitol.
Core Innovation
The disclosed invention relates to an analytical method for analyzing the presence and quantity of impurities present in a preparation of dianhydrogalactitol. The method analyzes the preparation by high performance liquid chromatography using elution with a mobile phase gradient or an isocratic mobile phase to separate dianhydrogalactitol from dulcitol and other contaminants of the preparation, and evaluates one or more HPLC-resolved peaks representing compounds other than dianhydrogalactitol itself to determine their relative concentration.
The invention further provides impurity quantification using evaporative light scattering detection for relative concentration of the resolved peaks representing compounds other than dianhydrogalactitol itself. The evaporative light scattering detection includes post-column addition of a volatile solvent to enhance evaporation of a 100% aqueous mobile phase, supporting measurement of relative amounts of non-dianhydrogalactitol components resolved by HPLC, including dulcitol and other related peaks.
For identification of impurities and degradation products, the invention uses tandem mass spectrometry together with HPLC to obtain molecular ion information for observed impurities and degradation products, and to identify possible chemical structures whose molecular weight matches the molecular ion information. The disclosure also includes collection of impurity/degradation-related peaks by preparative HPLC and solid characterization of purified unknown material using standard analytical procedures such as NMR, FT-IR, elemental analysis, HPLC purity determination, and Karl Fischer water content.
Claims Coverage
The partial content shows three independent analytical-method claims that define an HPLC separation of dianhydrogalactitol from dulcitol and other contaminants, followed by quantification of HPLC-resolved peaks representing compounds other than dianhydrogalactitol. Two independent claims further require evaporative light scattering detection with a post-column volatile solvent for 100% aqueous mobile phases, while one independent claim uses an isocratic mobile phase. The overall coverage centers on HPLC-based impurity profiling and relative concentration determination, with optional mass-spectrometry and characterization workflows reflected in dependent claim content.
Gradient HPLC separation and relative peak concentration determination for non-dianhydrogalactitol compounds
Analyzing a preparation of dianhydrogalactitol by subjecting the preparation to high performance liquid chromatography using elution with a mobile phase gradient to separate dianhydrogalactitol from dulcitol and other contaminants of the preparation, and determining the relative concentration of one or more peaks resolved by high performance liquid chromatography that represent compounds other than dianhydrogalactitol itself.
HPLC with gradient separation and ELSD with post-column volatile-solvent enhancement
Analyzing a preparation of dianhydrogalactitol by subjecting the preparation to high performance liquid chromatography using elution with a mobile phase gradient to separate dianhydrogalactitol from dulcitol and other contaminants of the preparation, determining the relative concentration of one or more peaks resolved by high performance liquid chromatography that represent compounds other than dianhydrogalactitol itself, performing the determining step by evaporative light scattering detection, and performing the evaporative light scattering detection by post-column addition of a volatile solvent to enhance evaporation of the 100% aqueous mobile phase.
Isocratic HPLC separation and relative peak concentration determination for non-dianhydrogalactitol compounds
Analyzing a preparation of dianhydrogalactitol by subjecting the preparation to high performance liquid chromatography using elution with an isocratic mobile phase to separate dianhydrogalactitol from dulcitol and other contaminants of the preparation, and determining the relative concentration of one or more peaks resolved by high performance liquid chromatography that represent compounds other than dianhydrogalactitol itself.
Across the independent claims, the inventive coverage is directed to using HPLC, gradient or isocratic, to separate dianhydrogalactitol from dulcitol and other contaminants, and then determining the relative concentration of peaks for compounds other than dianhydrogalactitol itself. The dependent-claim content further ties ELSD to post-column volatile-solvent enhancement for 100% aqueous mobile phases and includes tandem MS molecular-ion-based identification and optional preparative HPLC peak collection with solid characterization.
Stated Advantages
Improved impurity/purity analysis for dianhydrogalactitol by resolving and quantifying non-dianhydrogalactitol peaks, including dulcitol and an unknown related substance.
Documented Applications
Impurity analysis and quantification in a preparation of dianhydrogalactitol, including separating dianhydrogalactitol from dulcitol and other contaminants.
Identification of unknown impurities and degradation products by obtaining molecular ion information using tandem MS and, optionally, collecting impurity/degradation-related peaks by preparative HPLC followed by solid characterization using NMR, FT-IR, elemental analysis, HPLC purity determination, and Karl Fischer water content.
Use of HPLC/RI to resolve dulcitol and an unknown related substance at RRT ~0.6 in stressed samples.
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