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» Valproic Acid contains not less than 98.0 percent and not more than 102.0 percent of C8H16O2, calculated on the anhydrous basis.
Packaging and storage Preserve in tight, glass, stainless steel or polyethylene (HDPE) containers.
USP Reference standards 11
B: The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
Water, Method I 921: not more than 1.0%.
Residue on ignition 281: not more than 0.1%.
Heavy metals, Method II 231: 0.002%.
System suitability solution Mix suitable quantities of butyric acid, valeric acid, and USP Valproic Acid Related Compound A RS in Valproic Acid to obtain a solution containing about 1.0 µL per mL, 1.0 µL per mL, and 0.1 µL per mL, respectively.
Test solution Use Valproic Acid.
Chromatographic system (see Chromatography 621) The gas chromatograph is equipped with a flame-ionization detector and a 0.32-mm × 60-m column coated with a 0.3-µm film of phase G25. Helium is used as the carrier gas with a total flow rate of about 150 mL per minute with a split flow ratio of 100:1. The injection port and detector temperatures are maintained at 240 and 260, respectively. The chromatograph is programmed as follows. Initially the temperature of the column is equilibrated at 145 for 48 minutes, then the temperature is linearly increased at a rate of 5 per minute to 190, and maintained at 190. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the relative retention times are about 0.38 for butyric acid, 0.52 for valeric acid, 1.64 for related compound A, and 1.0 for valproic acid; the resolution, R, between butyric acid and valeric acid is not less than 23.0; the column efficiency determined from valeric acid is not less than 100,000 theoretical plates; and the tailing factor for the valeric acid peak is not more than 1.5. The related compound A peak must elute between 41 and 50 minutes and must have a peak area of not less than 0.01% relative to the valproic acid peak.
Procedure Inject a volume (about 0.5 µL) of the Test solution into the chromatograph, record the chromatogram, and measure the peak responses. Calculate the percentage of each impurity in the portion of Valproic Acid taken by the formula:
100(ri / rs)in which ri is the peak response for each impurity; and rs is the sum of the responses for all the peaks: not more than 0.1% of any individual impurity is found; and not more than 0.3% of total impurities is found.
Internal standard solution Transfer about 1.2 g of nonanoic acid to a 100-mL volumetric flask, and dissolve in and dilute with heptane to volume.
Standard preparation Dilute an accurately weighed quantity of USP Valproic Acid RS with heptane to obtain a solution having a known concentration of about 10.0 mg per mL. Transfer 5.0 mL of this solution to a 50-mL volumetric flask, add 5.0 mL of Internal standard solution, dilute with heptane to volume, and mix.
Assay preparation Transfer about 100 mg of Valproic Acid, accurately weighed, to a 10-mL volumetric flask, dilute with heptane to volume, and mix. Transfer 5.0 mL of this solution to a 50-mL volumetric flask, add 5.0 mL of Internal standard solution, dilute with heptane to volume, and mix.
Chromatographic system (see Chromatography 621) The gas chromatograph is equipped with a flame-ionization detector and a 2.0-mm × 1.8-m column packed with 10% phase G34 on 80- to 100-mesh support S1A. The carrier gas is helium. The flow rate is about 35 mL per minute. The column, injection port, and detector temperatures are maintained at 175, 275, and 300, respectively. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative retention times are about 1.0 for valproic acid and 2.0 for nonanoic acid; the resolution, R, between valproic acid and nonanoic acid is not less than 7.0; and the relative standard deviation for replicate injections is not more than 1.5%.
Procedure Separately inject equal volumes (about 3 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of C8H16O2 in the portion of Valproic Acid taken by the formula:
100C(RU / RS)in which C is the concentration, in mg per mL, of USP Valproic Acid RS in the Standard preparation; and RU and RS are the peak response ratios of valproic acid to the internal standard obtained from the Assay preparation and the Standard preparation, respectively.
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USP35NF30 Page 4992Pharmacopeial Forum: Volume No. 29(3) Page 673