Method for the direct detection and/or quantification of at least one compound with a molecular weight of at least 200
Inventors
Perello Bestard, Joan • Maraschiello de Zuani, Ciriaco • Lentheric, Irene • Mendoza de las Heras, Paula • Tur Espinosa, Fernando • Tur Tur, Eva • Encabo Alarcon, Maximo • Martin Becerra, Eva • Benito Amengual, Maria de Mar • Isern Amengual, Bernat
Assignees
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Publication Number
US-11162958-B2
Publication Date
2021-11-02
Expiration Date
Abstract
The present invention relates to method for the direct detection and/or quantification of at least one compound with a molecular weight of at least 200, wherein the compound to be detected and/or quantified is a chemically complex molecule, wherein said chemically complex molecule is substituted with at least two groups R, wherein each R group means independently —OH, —OP(O)(OH)2 or —P(O)(OH)2, with the proviso that at least two R are independently selected from —P(O)(OH)2 and —OP(O)(OH)2, wherein the compound or compounds to be detected and/or quantified are within a biological matrix, wherein said biological matrix is a biological fluid, a biological tissue, stomach contents, intestine contents, stool sample or a culture cells, wherein the method comprises performing a chromatography and identifying the retention time and/or the intensity of the signal by means of a mass or radioactivity detector.
Core Innovation
The invention is directed to a method for analyzing a pharmaceutical composition that comprises at least one phosphorus containing compound having a molecular weight of at least 200 daltons. The phosphorus containing compound is present in the pharmaceutical compositions at above 70% by weight, and the method quantifies the phosphorus containing compound together with its impurities.
The method includes preparing at least one standard sample and preparing a test sample by at least partially or totally dissolving the pharmaceutical composition to form a solution or a slurry containing the compound, without any sample pretreatment apart from diluting the test sample. The standard and test samples are introduced, together or sequentially, into a stream of a polar solvent system comprising potassium hydroxide (KOH) or a solvent mixture comprising at least one polar solvent comprising KOH.
A single anion-exchange chromatography column containing particles of a polystyrene cross-linked with divinylbenzene polymer resin is used, with the column essentially filled of the cross-linked polymer particles in a stationary phase while maintaining the pressure between 5 and 1500 atm. The method identifies the retention time and/or quantifies the intensity of the signal of the phosphorus containing compound when the samples are eluted from the anion-exchange chromatography column.
Claims Coverage
The document provides one independent claim covering a method to analyze a pharmaceutical composition by quantifying a phosphorus-containing compound together with its impurities using a single anion-exchange chromatography column and retention time and/or signal intensity readout. Dependent claims further constrain solvent conditions, pressure, and compound selection, and specify a purity-based acceptance for batches.
Quantifying phosphorus compound with impurities in pharmaceutical composition
A method for analyzing a pharmaceutical composition comprising at least one phosphorus containing compound having a molecular weight of at least 200 daltons, wherein the amount of the at least one phosphorus containing compound in the pharmaceutical compositions is above 70% by weight, and wherein the method comprises quantifying the phosphorus containing compound together with its impurities.
Polar KOH-containing solvent and single anion-exchange chromatography column
Introducing the standard sample together or sequentially with the test sample into a stream of a solvent system comprising potassium hydroxide (KOH), and passing the samples through a single anion-exchange chromatography column containing particles of a polystyrene cross-linked with divinylbenzene polymer resin.
Pressure-controlled column operation
The column is essentially filled with the cross-linked polymer particles in a stationary phase while maintaining the pressure of the system between 5 and 1500 atm.
Retention time identification and/or signal intensity quantification
Identifying the retention time and/or quantifying the intensity of the signal of the phosphorus containing compound when the samples are eluted from the anion-exchange chromatography column.
Phosphorus-containing compound selection for the pharmaceutical composition
The at least one phosphorus containing compound is selected from a bisphosphonate or polyphosphonate; a hexametaphosphate; a C3-C7 cycloalkyl substituted compound with at least two —R group wherein each —R group is —OH, —OP(O)(OH)2 or —P(O)(OH)2; ions or salts thereof; or a combination thereof.
Independent claim 1 centers on quantifying a phosphorus-containing compound together with its impurities in a pharmaceutical composition using a single anion-exchange chromatography column with a KOH-containing polar solvent system and determining retention time and/or signal intensity on elution.
Stated Advantages
Documented Applications
Analyzing pharmaceutical compositions containing at least one phosphorus containing compound present above 70% by weight, including quantification together with impurities.
Measuring purity and using a purity threshold to include a batch only if the compound’s purity is above 70% by weight, wherein purity is determined by the method.
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