Travoprost
(trav' oh prost).
Click to View Image
C26H35F3O6 500.55

[1R-[1(Z),2(1E,3R*),3,5]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl ester.
Isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[(,,-trifluoro-m-tolyl)oxy]-1-butenyl]cyclopentyl]-5-heptenoate [157283-68-6].
» Travoprost contains not less than 96.0 percent and not more than 102.0 percent of C26H35F3O6, calculated on the anhydrous and solvent-free basis.
[Caution—Great care should be taken to avoid contact with the body. ]
Packaging and storage— Preserve at –25 to –15 in tight, light-resistant containers under a nitrogen atmosphere.
USP Reference standards 11
USP Travoprost RS Click to View Structure
Identification—
A: Thin-Layer Chromatographic Identification Test 201
Test solution— Use the Assay preparation.
Standard solution— Use USP Travoprost RS.
Developing solvent system: a mixture of ethyl acetate and ethanol (4:1).
Spray reagent: 20% solution of phosphomolybdic acid in ethanol.
Procedure— Separately apply 5 µL each of the Test solution and the Standard solution to a thin-layer chromatographic plate (see Chromatography 621) coated with silica gel that contains 20% silver nitrate. [note—To keep the spot size small, it is usually necessary to apply approximately 1 to 2 µL at a time, allowing the spot to dry between each application. ] Proceed as directed in the chapter. Spray the plate with Spray reagent, and heat it in an oven at 80 to 100. The travoprost will appear as black spots.
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.
Specific rotation 781S: from +52.0 to +58.0, at 365 nm.
Test solution: 20 mg per mL, in dehydrated alcohol.
Water, Method Ia 921: not more than 1.0%, determined on a 0.2-g specimen. Use a solvent mixture of acetonitrile and methanol (1:1) and a titrant for which 1 mL is equivalent to 2 mg of water.
Limit of ethyl acetate—
Standard solution— Dilute an accurately measured quantity of ethyl acetate in N,N-dimethylacetamide to obtain a solution having a known concentration of about 50 µg per mL.
Test solution— Dissolve an accurately weighed quantity of Travoprost in N,N-dimethylacetamide to obtain a solution having a concentration of about 20 mg per mL.
Chromatographic system (see Chromatography 621) The gas chromatograph is equipped with a flame-ionization detector and contains a 0.53-mm × 30-m column coated with a 1-µm film of liquid phase G16. The carrier gas is helium, flowing at a rate of 4 mL per minute. The chromatograph is programmed as follows. Initially the temperature of the column is maintained at 55 for 6 minutes, then the temperature is increased at a rate of 25 per minute to 240 and maintained at 240 for 20 minutes. The injection port temperature is maintained at 140, and the detector temperature is maintained at 240. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the retention time is about 2 to 5 minutes for ethyl acetate [note—For the purpose of the peak identification, the approximate retention time range of ethyl acetate is given. ] ; the resolution, R, between ethyl acetate and any adjacent peak is not less than 1.5; and the relative standard deviation for replicate injections is not more than 15.0%.
Procedure— Separately inject equal volumes (about 1 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the concentration, in ppm, of ethyl acetate in the portion of Travoprost taken by the formula:
(CS / CU) (rU / rS)
in which CS is the concentration, in µg per mL, of ethyl acetate in the Standard solution; CU is the concentration, in g per mL, of Travoprost in the Test solution; and rU and rS are the peak responses obtained from the Test solution and the Standard solution, respectively; not more than 5000 ppm of ethyl acetate is found.
Related compounds—
Buffer, Mobile phase, Standard preparation, and Chromatographic system— Proceed as directed in the Assay.
Test solution— Use the Assay preparation.
Procedure— Inject a volume (about 100 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 Travoprost taken by the formula:
100(1/F)(ri / rs)
in which F is the relative response factor for each impurity; ri is the individual peak response of each individual impurity; and rs is the sum of the responses of all the peaks. In addition to not exceeding the limits for each impurity in Table 1, not more than 0.1% of any other individual impurity is found, and not more than 4.0% of total impurities is found.
Table 1
Name Relative
Retention
Time
Relative
Response
Factor (F)
Limit
(%)
USP Travoprost Related Compound A RS about 0.11 1.0 0.2
Epoxide derivative1 about 0.55 1.0 0.4
15-epi Diastereomer2 about 0.90 1.1 0.1
5,6-trans Isomer3 about 1.16 1.0 3.5
15-Keto derivative4 about 1.45 1.6 0.3
1  (5Z)-(9S,11R,15S)-9,11,15-Trihydroxy-13,14-epoxy-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-5-prostadienoic acid, isopropyl ester.
2  (5Z,13E)-(9S,11R,15S)-9,11,15-Trihydroxy-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid, isopropyl ester.
3  (5E,13E)-(9S,11R,15R)-9,11,15-Trihydroxy-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid, isopropyl ester.
4  (5Z,13E)-(9S,11R)-9,11,-Dihydroxy-15-oxo-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid, isopropyl ester.
Assay—
Buffer— Add 2.0 mL of phosphoric acid to 1 L of water. Adjust with sodium hydroxide to a pH of 3.0.
Mobile phase— Prepare a filtered and degassed mixture of Buffer and acetonitrile (7:3). Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard preparation— Use USP Travopost RS without dilution (0.5 mg per mL).
Assay preparation— Transfer about 25 mg of Travoprost, accurately weighed, to a 50-mL volumetric flask, and dissolve in 15 mL of acetonitrile. Add 25 mL of water, mix, and wait until the solution reaches room temperature. Dilute with water to volume, and mix.
Chromatographic system (see Chromatography 621) The liquid chromatograph is equipped with a 220-nm detector and a 4.6-mm × 5-cm column that contains packing L1. The flow rate is about 3.0 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative retention times are about 1.0 for travoprost and 1.1 for 5,6-trans isomer; the resolution, R, between travoprost and the 5,6-trans isomer is not less than 1.5; the column efficiency is not less than 1500 theoretical plates; the tailing factor is not more than 2.0; and the relative standard deviation for replicate injections is not more than 2.0%. [note—USP Travoprost RS contains a small percentage of 5,6-trans isomer. ]
Procedure— Separately inject equal volumes (about 100 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 percentage of C26H35F3O6 in the portion of Travoprost taken by the formula:
100(CS / CU)(rU / rS)
in which CS is the concentration, in mg per mL, of travoprost in the Standard preparation; CU is the concentration of Travoprost in the Assay preparation; and rU and rS are the peak areas obtained from the Assay preparation and the Standard preparation, respectively.
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