Butorphanol Tartrate Nasal Solution
» Butorphanol Tartrate Nasal Solution is an aqueous solution of butorphanol tartrate for administration as a metered spray to the nasal mucosa. It contains the equivalent of not less than 90.0 percent and not more than 110.0 percent of the labeled amount of butorphanol tartrate (C21H29NO2·C4H6O6).
Packaging and storage— Preserve in tight containers at controlled room temperature. Store at 25, excursions permitted between 15 and 30.
USP Reference standards 11
USP Butorphanol Tartrate RS Click to View Structure
Identification—
A: 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.
B: Thin-Layer Chromatographic Identification Test 201
Test solution— Prepare a composite solution by pooling the contents of three containers of Nasal Solution into a suitable vessel. Transfer 1.0 mL of pooled sample to a 10-mL volumetric flask, and dilute with methanol to volume.
Standard solution— Dissolve an accurately weighed quantity of USP Butorphanol Tartrate RS in methanol to obtain a solution having a known concentration of about 1.0 mg per mL.
Developing solvent system— Prepare a mixture of chloroform, methanol, benzene, and ammonium hydroxide (17:5:4:1). Mix thoroughly. [Caution—Prepare in a hood while wearing appropriate safety gloves, lab coat, and protective eyewear. ]
Spray reagent— Prepare a 1 in 10 solution of chloroplatinic acid in water. To 0.5 mL of this solution, add 33 mL of water and 1 g of potassium iodide. Prepare fresh daily.
Procedure— Proceed as directed in the chapter, except to spray the plate with Spray reagent. The typical RF value is about 0.7 for butorphanol tartrate.
Osmolality 785: between 252 and 292 mOsmol per kg.
Microbial enumeration tests 61 and Tests for specified microorganisms 62 The total aerobic microbial count does not exceed 1000 cfu per g or mL, and the total combined molds and yeasts count does not exceed 100 cfu per g or mL. It meets the requirements of the tests for absence of Staphylococcus aureus and Pseudomonas aeruginosa.
pH 791: between 4.0 and 6.0.
Related compounds—
Phosphate buffer (0.025 M)— Prepare as directed in the Assay.
Mobile phase— Prepare a filtered and degassed mixture of phosphate buffer, acetonitrile, and triethylamine (85:15:5.1). Mix thoroughly, and adjust with 85.0% phosphoric acid to a pH of 3.0 ± 0.1. Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard solution— Dissolve an accurately weighed quantity of USP Butorphanol Tartrate RS in water, and dilute quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 0.005 mg per mL.
Sensitivity solution— Transfer 2.5 mL of the Standard solution to a 50-mL volumetric flask, dilute with water to volume, and mix. Do not filter.
Test solution— Prepare a composite solution by pooling a minimum of four containers of Nasal Solution into a suitable glass vessel. Transfer the equivalent of 50 mg of butorphanol tartrate to a 50-mL volumetric flask. Dilute with water to volume, and mix. Do not filter.
Chromatographic system (see Chromatography 621) The liquid chromatograph is equipped with a 280-nm detector, a 4.6-mm × 25-cm column that contains 5-µm packing L11, and a 4.6-mm × 1-cm guard column packed with 5-µm packing L11. The column temperature is maintained at 40. The flow rate is about 2.0 mL per minute. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the relative standard deviation for six replicate injections is not more than 10.0%. Chromatograph the Sensitivity solution, and record the peak responses as directed for Procedure: the peak height for butorphanol tartrate is greater than or equal to three times the baseline noise.
Procedure— Separately inject equal volumes (about 60 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the responses for the butorphanol tartrate peak in the Standard solution and for all known and unknown related compounds in the Test solution. The chromatographic run time is about 40 minutes. Calculate the percentage of each related compound (see Table 1) and each unknown impurity in the portion of Nasal Solution taken by the formula:
5000(C/VLA)(ri / rS)
in which C is the concentration, in mg per mL, of USP Butorphanol Tartrate RS in the Standard solution; V is the volume of sample taken; LA is the labeled amount, in mg per mL, of butorphanol tartrate in the sample; ri is the peak response of each known or unknown related compound in the Test solution; and rS is the peak response of butorphanol tartrate in the Standard solution: the impurities meet the requirements specified in Table 1.
Table 1
Compound Relative
Retention
Time
Limit (%)
3,14-Dihydroxymorphinan 0.3 0.3
D6-Butorphanol 0.7 0.5
Butorphanol tartrate 1.0
Unknown impurity 0.3
Total impurities 1.0
Assay—
Phosphate buffer (0.025 M)— Transfer 3.4 g of monobasic potassium phosphate into a 1000-mL volumetric flask. Dilute with water to volume, and filter.
Mobile phase— Prepare a filtered and degassed mixture of phosphate buffer, acetonitrile, and triethylamine (85:15:2). Mix thoroughly, and adjust with 85.0% phosphoric acid to a pH of 3.0 ± 0.1. Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard preparation— Dissolve an accurately weighed quantity of USP Butorphanol Tartrate RS in Mobile phase to obtain a solution having a known concentration of 0.2 mg per mL. Mix, and filter, discarding the first 2 mL of the filtrate. The Standard preparation is stable for at least 108 hours.
Assay preparation— Prepare a composite solution by pooling a minimum of four containers of Nasal Solution into a suitable glass vessel. Transfer the equivalent of 20 mg of butorphanol tartrate to a 100-mL volumetric flask. Dilute with Mobile phase to volume, mix, and filter, discarding the first 2 mL of the filtrate.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 280-nm detector, a 4.6-mm × 15-cm column that contains 5-µm packing L11, and a 4.6-mm × 1-cm guard column that contains 5-µm packing L11. The column temperature is maintained at 30. The flow rate is about 2.0 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the tailing factor for the butorphanol tartrate peak is not more than 2.0; and the relative standard deviation for five replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the butorphanol tartrate peak. Calculate the quantity, in mg, of butorphanol tartrate (C21H29NO2·C4H6O6) in the portion of Nasal Solution taken by the formula:
100C(rU / rS)
in which C is the concentration, in mg per mL, of USP Butorphanol Tartrate RS in the Standard preparation; and rU and rS are the peak responses for butorphanol tartrate obtained from the Assay preparation and the Standard preparation, respectively.
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