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Timolol Maleate
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C13H24N4O3S·C4H4O4 432.49

2-Propanol, 1-(1,1-dimethylethyl)amino-3-[[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-, (S)-, (Z)-2-butenedioate (1:1) (salt).
()-1-(tert-Butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt) [26921-17-5].
» Timolol Maleate contains not less than 98.0 percent and not more than 101.0 percent of C13H24N4O3S·C4H4O4, calculated on the dried basis.
Packaging and storage— Preserve in well-closed containers.
Identification—
B: Ultraviolet Absorption 197U—
Solution: 25 µg per mL.
Medium: 0.12 N hydrochloric acid.
Absorptivities at 294 nm, calculated on the dried basis, do not differ by more than 3.0%.
Specific rotation 781S: between 11.7 and 12.5 (= 405 nm).
Test solution: 50 mg per mL, in 1.0 N hydrochloric acid.
pH 791: between 3.8 and 4.3, in a solution containing 20 mg per mL.
Loss on drying 731— Dry it in vacuum at 100 to constant weight: it loses not more than 0.5% of its weight.
Residue on ignition 281: not more than 0.1%.
Heavy metals, Method II 231: 0.002%.
Chromatographic purity— Dissolve 500 mg in methanol to obtain 10.0 mL of test solution. Dissolve an accurately weighed quantity of USP Timolol Maleate RS in methanol, and dilute quantitatively and stepwise with methanol to obtain Standard solutions having the following compositions:
Standard
solution		 Concentration
(µg RS
per mL)		 Percentage (%,
for comparison
with test
specimen)
A 200 0.4
B 100 0.2
C 50 0.1
Separately apply 10-µL portions of the solutions to a suitable thin-layer chromatographic plate (see Chromatography 621) coated with a 0.25-mm layer of chromatographic silica gel mixture. Allow the spots to dry, and develop the chromatogram in a solvent system consisting of a mixture of chloroform, methanol, and ammonium hydroxide (80:20:1) until the solvent front has moved about three-fourths of the length of the plate. Remove the plate from the developing chamber, mark the solvent front, and allow the solvent to evaporate. Expose the plate to iodine vapors for 2 hours, and locate the spots on the plate by examination under short-wavelength UV light. Compare the intensities of any secondary spots observed in the chromatogram of the test solution, excluding the origin spot due to the maleate anion, with those of the principal spots in the chromatograms of the Standard solutions: no secondary spot is more intense than the principal spot obtained from Standard solution A (0.4%), and the sum of the intensities of all secondary spots, excluding any having intensities less than the principal spot obtained from Standard solution C, does not exceed 1.0%.
Organic volatile impurities, Method I 467: meets the requirements.
Residual solvents 467: meets the requirements.
(Official January 1, 2007)
Assay— Dissolve about 800 mg of Timolol Maleate, accurately weighed, in about 90 mL of glacial acetic acid, and titrate with 0.1 N perchloric acid VS, determining the endpoint potentiometrically, using a platinum electrode and a sleeve-type calomel electrode containing 0.1 N lithium perchlorate in acetic anhydride (see Titrimetry 541). Perform a blank determination, and make any necessary correction. Each mL of 0.1 N perchloric acid is equivalent to 43.25 mg of C13H24N4O3S·C4H4O4.
Auxiliary Information— Staff Liaison : Andrzej Wilk, Ph.D., Senior Scientific Associate
Expert Committee : (MDCV05) Monograph Development-Cardiovascular
USP29–NF24 Page 2152
Phone Number : 1-301-816-8305