Method and device for separating metabolites or stereoisomers
Inventors
Kobold, Uwe • Thiele, Roland • Weiss, Noah • Brown, Lauren
Assignees
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Publication Number
US-11099154-B2
Publication Date
2021-08-24
Expiration Date
Abstract
A method of quantifying the amount of at least two analytes A1 and A2 involving (a) adding at least one salt (S) to at least a portion (P1) of the sample comprising the at least two analytes A1 and A2, (b) ionizing at least a portion of the sample according to (a) thereby forming an analyte flow comprising the analytes A1 and A2 in ionized form, (c) separating the ionized analytes A1 and A2 from each other by using at least one ion mobility separator (124), wherein the analyte flow according to (b) at least partially passes through the ion mobility separator (124), and (d) quantifying the amount of the separated ionized analytes obtained according to (c), wherein A1 is a pharmaceutically active compound C or derivative thereof and A2 is a metabolite or stereoisomer of C.
Core Innovation
The invention relates to an ion mobility spectrometry quantification approach for at least two analytes A1 and A2 comprised in a sample, where A1 is a pharmaceutically active compound C or derivative thereof and A2 is an epimer of C. The method addresses quantification of closely related metabolites or stereoisomers/epimers that are difficult to separate and quantify due to high structural similarity and similar physicochemical behavior.
A salt modifier S is added to at least a portion of the sample, where the salt provides a monovalent cation of an alkaline metal or a transition metal or of an organic compound selected from pyridine, pyrrolindin, imidazole and morpholin. The sample is ionized in the presence of the salt to form an analyte flow comprising the analytes in ionized form, and the ionized analytes are separated from each other by using at least one ion mobility separator.
The separated ionized analytes are then quantified, with the relationship between A1 and A2 maintained as an epimer relationship to pharmaceutically active compound C. The disclosed concept emphasizes quantification using ion mobility separation enabled by the salt modifier, and it further specifies log P constraints for A1, including greater than 0 and in related formulations a range from 0 to 12.
Claims Coverage
The independent claims cover a method of quantifying at least two analytes A1 and A2 in a sample using a monovalent-cation salt modifier, ionization to form an ionized analyte flow, separation by an ion mobility separator, and quantification of the separated ionized analytes. Across the independent claims, the inventive features are aligned around the A1/A2 epimer relationship and the salt-driven ion mobility separation, with log P and salt-cation specification as key differences. The independent claims identified are clm-00001, clm-00014, and clm-00021.
Salt-modified ion mobility quantification for an epimer pair
A method of quantifying the amount of at least two analytes A1 and A2 comprised in a sample by adding at least one salt (S) being a monovalent cation of an alkaline metal or a transition metal or of an organic compound selected from pyridine, pyrrolindin, imidazole and morpholin to at least a portion (P1) of the sample, ionizing in the presence of the at least one salt (S) thereby forming an analyte flow comprising the analytes A1 and A2 in ionized form, separating the ionized analytes A1 and A2 from each other by using at least one ion mobility separator, and quantifying the amount of the separated ionized analytes, wherein A1 is a pharmaceutically active compound C or derivative thereof and A2 is an epimer of C, and wherein A1 has a log P value of greater than 0.
Salt used as a modifier in an ion mobility spectrometry process for epimer quantification
A method of using at least one salt (S) as a modifier in a process for quantifying the amount of at least two analytes A1 and A2 comprised in a sample by ion mobility spectrometry by ionizing the sample in the presence of the at least one salt (S), wherein the salt is a monovalent cation of an alkaline metal or a transition metal or of an organic compound selected from pyridine, pyrrolindin, imidazole and morpholin, wherein A1 is a pharmaceutically active compound C or a derivative thereof and A2 is an epimer of C, and wherein A1 has a log P value of greater than 0.
Defined monovalent cation set and log P range for epimer quantification by ion mobility
A method of quantifying the amount of at least two analytes A1 and A2 comprised in a sample by adding at least one salt (S) being a monovalent cation selected from Li+, Na+, K+, Rb+, Cs+, Ag+, Cu+, Ni+, Mn+, pyridinium and combinations thereof to at least a portion (P1) of the sample, ionizing in the presence of the at least one salt (S) thereby forming an analyte flow comprising the analytes A1 and A2 in ionized form, separating the ionized analytes A1 and A2 from each other by using at least one ion mobility separator, wherein the analyte flow according to (b) at least partially passes through the ion mobility separator, and quantifying the amount of the separated ionized analytes, wherein A1 is a pharmaceutically active compound C or derivative thereof and A2 is an epimer of C, and wherein A1 has a log P value in the range of from 0 to 12.
Across the independent claims, the coverage centers on quantifying at least two closely related analytes defined as an epimer pair (A1 is a pharmaceutically active compound C or derivative and A2 is an epimer of C) using ion mobility spectrometry separation that is enabled by adding a monovalent-cation salt modifier prior to ionization. The claims additionally constrain the salt cation types and apply log P limitations to A1.
Stated Advantages
Enables quantification of closely related metabolites or stereoisomers/epimers, including vitamin D epimers, with baseline or improved separation/quantification despite high structural similarity.
Improves separation/quantification of analyte pairs such as 25-hydroxyvitamin D3 versus 3-epi-25-hydroxyvitamin D3 using salt adducts with an ion mobility separator.
Documented Applications
Quantifying vitamin D epimers, specifically 25-hydroxyvitamin D3 (A1) and 3-epi-25-hydroxyvitamin D3 (A2), using ion mobility spectrometry enabled by salt modifiers.
Quantifying amphetamine stereoisomers.
Quantifying corticosteroid-related analytes, including corticosterone and related steroids.
Quantifying vancomycin B isoforms (CDP1/CDPM/CDPm).
Quantifying folate oxidation products and folate vitamer oxidation isobars, including 4a-hydroxy-5-methylTHF, 5-methyltetrahydrofolate/5-formylTHF, and MeFox.
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