Analysis method of 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, treatment for amyotrophic lateral sclerosis, inhibition of progression of amyotrophic lateral sclerosis, and method of producing drug containing 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug

Abstract

This method of analyzing the phenylhydrazine content in a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug involves: obtaining a first measured value by measuring the phenylhydrazine content of a standard solution that contains phenylhydrazine or a salt thereof, a first acidic water and a first water-soluble organic solvent, and that exhibits a phenylhydrazine concentration of 0.01 μg/mL to 10 μg/mL; obtaining a second measured value by measuring the phenylhydrazine content in a sample solution that contains a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, a second acidic water and a second water-soluble organic solvent; and detecting the phenylhydrazine content in the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug on the basis of the first measured value and the second measured value. The first acidic water is at least one type selected from hydrochloric acid, an aqueous acetic acid solution, and the like, the first water-soluble organic solvent is at least one type selected from acetonitrile and methanol, the second acidic water is at least one type selected from hydrochloric acid, an aqueous acetic acid solution, and the like, and the second water-soluble organic solvent is at least one type selected from acetonitrile, and methanol.

1 . A method of analyzing the phenylhydrazine content in a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, which comprises:
 obtaining a first measured value by measuring the phenylhydrazine content in a phenylhydrazine standard solution that contains phenylhydrazine or a salt thereof, a first acidic water and a first water-soluble organic solvent, and that exhibits a phenylhydrazine concentration of 0.01 μg/mL to 10 μg/mL,   obtaining a second measured value by measuring the phenylhydrazine content in a 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution that contains a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, a second acidic water and a second water-soluble organic solvent, and   detecting the phenylhydrazine content in the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug on the basis of the first measured value and the second measured value,   wherein the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the first water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the first water-soluble organic solvent is methanol, the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution, and   wherein the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the second water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the second water-soluble organic solvent is methanol, the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution.   
     
     
         2 . The method according to  claim 1 , which further comprises:
 preparing the phenylhydrazine standard solution that contains phenylhydrazine or the salt thereof, the first acidic water and the first water-soluble organic solvent, and   preparing the 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution that contains the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, the second acidic water and the second water-soluble organic solvent.   
     
     
         3 . The method according to  claim 1 , wherein the first measured value is a value obtained by measuring the phenylhydrazine content in the phenylhydrazine standard solution using high performance liquid chromatography, and the second measured value is a value obtained by measuring the phenylhydrazine content in the 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution using high performance liquid chromatography. 
     
     
         4 . The method according to  claim 1 , wherein the first acidic water contains 0.01 mol/L to 5 mol/L hydrochloric acid, and the second acidic water contains 0.01 mol/L to 5 mol/L hydrochloric acid. 
     
     
         5 . The method according to  claim 1 , wherein the volume ratio of the first acidic water and the first water-soluble organic solvent contained in the phenylhydrazine standard solution is in the range of 3:1 to 4:5, and the volume ratio of the second acidic water and the second water-soluble organic solvent contained in the 3-methyl-1-phenyl-2-pyrazoline-5-one sample solution is in the range of 3:1 to 4:5. 
     
     
         6 . A method of treating amyotrophic lateral sclerosis, which comprises:
 obtaining a first measured value by measuring the phenylhydrazine content in a phenylhydrazine standard solution that contains phenylhydrazine or a salt thereof, a first acidic water and a first water-soluble organic solvent, and that exhibits a phenylhydrazine concentration of 0.01 μg/mL to 10 μg/mL,   obtaining a second measured value by measuring the phenylhydrazine content in a 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution that contains a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, a second acidic water and a second water-soluble organic solvent,   detecting the phenylhydrazine content in the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug on the basis of the first measured value and the second measured value, to determine that the phenylhydrazine content is 20 ppm or less, and   administering a drug containing the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug to a patient in need,   wherein the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the first water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the first water-soluble organic solvent is methanol, the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution, and   wherein the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the second water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the second water-soluble organic solvent is methanol, the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution.   
     
     
         7 . The method according to  claim 6 , which further comprises:
 preparing the phenylhydrazine standard solution that contains phenylhydrazine or the salt thereof, the first acidic water and the first water-soluble organic solvent, and   preparing the 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution that contains the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, the second acidic water and the second water-soluble organic solvent.   
     
     
         8 . The method according to  claim 6 , wherein the first measured value is a value obtained by measuring the phenylhydrazine content in the phenylhydrazine standard solution using high performance liquid chromatography, and the second measured value is a value obtained by measuring the phenylhydrazine content in the 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution using high performance liquid chromatography. 
     
     
         9 . The method according to  claim 6 , wherein the first acidic water contains 0.01 mol/L to 5 mol/L hydrochloric acid, and the second acidic water contains 0.01 mol/L to 5 mol/L hydrochloric acid. 
     
     
         10 . The method according to  claim 6 , wherein the volume ratio of the first acidic water and the first water-soluble organic solvent contained in the phenylhydrazine standard solution is in the range of 3:1 to 4:5, and the volume ratio of the second acidic water and the second water-soluble organic solvent contained in the 3-methyl-1-phenyl-2-pyrazoline-5-one sample solution is in the range of 3:1 to 4:5. 
     
     
         11 . A method of suppressing progress of amyotrophic lateral sclerosis, which comprises:
 obtaining a first measured value by measuring the phenylhydrazine content in a phenylhydrazine standard solution that contains phenylhydrazine or a salt thereof, a first acidic water and a first water-soluble organic solvent, and that exhibits a phenylhydrazine concentration of 0.01 μg/mL to 10 μg/mL,   obtaining a second measured value by measuring the phenylhydrazine content in a 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution that contains a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, a second acidic water and a second water-soluble organic solvent,   detecting the phenylhydrazine content in the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug on the basis of the first measured value and the second measured value, to determine that the phenylhydrazine content is 20 ppm or less, and   administering a drug containing the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug to a patient in need,   wherein the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the first water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the first water-soluble organic solvent is methanol, the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution, and   wherein the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the second water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the second water-soluble organic solvent is methanol, the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution.   
     
     
         12 . The method according to  claim 11 , which further comprises:
 preparing the phenylhydrazine standard solution that contains phenylhydrazine or the salt thereof, the first acidic water and the first water-soluble organic solvent, and   preparing the 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution that contains the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, the second acidic water and the second water-soluble organic solvent.   
     
     
         13 . The method according to  claim 11 , wherein the first measured value is a value obtained by measuring the phenylhydrazine content in the phenylhydrazine standard solution using high performance liquid chromatography, and the second measured value is a value obtained by measuring the phenylhydrazine content in the 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution using high performance liquid chromatography. 
     
     
         14 . The method according to  claim 11 , wherein the first acidic water contains 0.01 mol/L to 5 mol/L hydrochloric acid, and the second acidic water contains 0.01 mol/L to 5 mol/L hydrochloric acid. 
     
     
         15 . The method according to  claim 11 , wherein the volume ratio of the first acidic water and the first water-soluble organic solvent contained in the phenylhydrazine standard solution is in the range of 3:1 to 4:5, and the volume ratio of the second acidic water and the second water-soluble organic solvent contained in the 3-methyl-1-phenyl-2-pyrazoline-5-one sample solution is in the range of 3:1 to 4:5. 
     
     
         16 . A method of producing a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug having a phenylhydrazine content of 20 ppm or less, which comprises:
 obtaining a first measured value by measuring the phenylhydrazine content in a phenylhydrazine standard solution that contains phenylhydrazine or a salt thereof, a first acidic water and a first water-soluble organic solvent, and that exhibits a phenylhydrazine concentration of 0.01 μg/mL to 10 μg/mL,   obtaining a second measured value by measuring the phenylhydrazine content in a 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution that contains a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, a second acidic water and a second water-soluble organic solvent, and   detecting the phenylhydrazine content in the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug on the basis of the first measured value and the second measured value, to determine that the phenylhydrazine content is 20 ppm or less,   wherein the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the first water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the first water-soluble organic solvent is methanol, the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution, and   wherein the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the second water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the second water-soluble organic solvent is methanol, the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution.   
     
     
         17 . A method of producing a drug containing a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug having a phenylhydrazine content of 20 ppm or less, which comprises:
 obtaining a first measured value by measuring the phenylhydrazine content in a phenylhydrazine standard solution that contains phenylhydrazine or a salt thereof, a first acidic water and a first water-soluble organic solvent, and that exhibits a phenylhydrazine concentration of 0.01 μg/mL to 10 μg/mL,   obtaining a second measured value by measuring the phenylhydrazine content in a 3-methyl-1-phenyl-2-pyrazolin-5-one sample solution that contains a 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, a second acidic water and a second water-soluble organic solvent,   detecting the phenylhydrazine content in the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug on the basis of the first measured value and the second measured value, to determine that the phenylhydrazine content is 20 ppm or less, and   mixing the 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug with at least one pharmacologically and pharmaceutically acceptable additive,   wherein the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the first water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the first water-soluble organic solvent is methanol, the first acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution, and   wherein the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution, an aqueous phosphoric acid solution and an aqueous perchloric acid solution, and the second water-soluble organic solvent is at least one type selected from the group consisting of acetonitrile and methanol, provided that, when the second water-soluble organic solvent is methanol, the second acidic water is at least one type selected from the group consisting of hydrochloric acid, an aqueous acetic acid solution, an aqueous trifluoroacetic acid solution, an aqueous formic acid solution and an aqueous perchloric acid solution.   
     
     
         18 . A drug for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, which is produced by the method according to  claim 17 . 
     
     
         19 . A 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug obtained by the method according to  claim 16 .