Dorzolamide Hydrochloride

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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C₁₀H₁₆N₂O₄S₃ · HCl                  360.90

4H-Thieno[2,3-b]thiopyran-2-sulfonamide, 4-(ethylamino)-5,6-dihydro-6-methyl-, 7,7-dioxide, monohydrochloride, (4S-trans)-;(4S,6S)-4-(Ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide, monohydrochloride CAS RN: 130693-82-2; UNII: QZO5366EW7.

1 DEFINITION

Dorzolamide Hydrochloride contains NLT 99.0% and NMT 101.0% of dorzolamide hydrochloride (C₁₀H₁₆N₂O₄S₃ · HCl), calculated on the anhydrous basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197M

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

C. IDENTIFICATION TESTS GENERAL, Chloride (191)

3 ASSAY

PROCEDURE

Buffer: 3.7 g/L of monobasic potassium phosphate in water

Solution A: Acetonitrile and Buffer (6.5:94)

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Standard solution: 0.6 mg/mL of USP Dorzolamide Hydrochloride RS in Solution A

Sample solution: 0.6 mg/mL of Dorzolamide Hydrochloride in Solution A

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 25-cm; packing L1

Column temperature: 35°

Flow rate: 1.5 mL/min

System suitability

Sample: Standard solution

Suitability requirements

Column eciency: NLT 6500 theoretical plates

Tailing factor: 0.6–1.2

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of dorzolamide hydrochloride (C₁₀H₁₆N₂O₄S₃ · HCl) in the portion of Dorzolamide Hydrochloride taken:

Result = (r_u /r_s ) × (C_s /C_u ) × 100

r_u = peak area of the Sample solution

r_s = peak area of the Standard solution

C_s = concentration of USP Dorzolamide Hydrochloride RS in the Standard solution (mg/mL)

C_u = concentration of Dorzolamide Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 99.0%–101.0% on the anhydrous basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%, an ignition temperature of 600° being used

4.1 Organic Impurities

Solution A, Solution B, Mobile phase, Sample solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Analysis

Sample: Sample solution

Calculate the percentage of each individual impurity in the portion of Dorzolamide Hydrochloride taken:

Result = (r_U /r_T ) × 100

r_U = peak area of each individual impurity from the Sample solution

r_T = sum of all the peak areas from the Sample solution

Acceptance criteria

Any individual impurity: NMT 0.1%

Total impurities: NMT 0.5%

4.2 Limit of Dorzolamide Hydrochloride Related Compound A

Mobile phase: tert-Butyl methyl ether, chromatographic n-heptane, acetonitrile, and water (63:35:2:0.2)

System suitability solution: Transfer 18 mg of USP Dorzolamide Hydrochloride RS and 2 mg of USP Dorzolamide Hydrochloride Related Compound A RS, each, to a 15-mL centrifuge tube. Dissolve in 4 mL of 0.5 N ammonium hydroxide, and add 4 mL of ethyl acetate. Separate the ethyl acetate layer, and transfer to a 15-ml centrifuge tube. Add 4 mL of ethyl acetate to the aqueous layer, and mix. Separate the ethyl acetate layer, and combine it with the first extract. Evaporate the combined organic layers to dryness on a water bath maintained at 50° under a stream of nitrogen. Dissolve the residue in 3 mL of acetonitrile, add 3 drops of (S)-(-)-a-methylbenzyl isocyanate (discard the reagent if it is colored), and allow to react for 5 min on a water bath maintained at 50". Evaporate the mixture to dryness on a water bath maintained at 50° under a stream of nitrogen. Dissolve the residue in 10 mL of a mixture of tert-butyl methyl ether, glacial acetic acid, and acetonitrile (87:10:3).

Sample solution: Transfer 20 mg of Dorzolamide Hydrochloride to a 15-ml centrifuge tube, dissolve in 4 ml. of 0.5 N ammonium hydroxide, and add 4 mL of ethyl acetate. Separate the ethyl acetate layer, and transfer to a 15-mL centrifuge tube. Add 4 mL of ethyl acetate to the aqueous layer, and mix. Separate the ethyl acetate layer, and combine it with the first extract. Evaporate the combined organic layers to dryness on a water bath maintained at 50° under a stream of nitrogen. Dissolve the residue in 3 mL of acetonitrile, add 3 drops of (S)-(-)-a-methylbenzyl isocyanate (discard the reagent if it is colored), and allow to react for 5 min on a water bath maintained at 50°. Evaporate the mixture to dryness on a water bath maintained at 50° under a stream of nitrogen. Dissolve the residue in 10 mL of a mixture of tert-butyl methyl ether, glacial acetic acid, and acetonitrile (87:10:3).

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 25-cm; packing L3

Flow rate: 2 mL/min

Injection volume: 10 µL

System suitability

Sample: System suitability solution

[Note—The relative retention times for dorzolamide and dorzolamide hydrochloride related compound A are about 1.0 and 1.5, respectively.]

Suitability requirements

Resolution: NLT 4.0 between dorzolamide and dorzolamide hydrochloride related compound A

Column eciency: NLT 4000 theoretical plates for the dorzolamide hydrochloride peak

Tailing factor: NMT 1.4

Analysis

Samples: System suitability solution and Sample solution

Calculate the percentage of dorzolamide hydrochloride related compound A in the portion of Dorzolamide Hydrochloride taken:

Result = [r_i /(r_i + r_s )] × 100

r_i = peak area of dorzolamide hydrochloride related compound A from the Sample solution

r_s = peak area of dorzolamide hydrochloride from the Sample solution

Acceptance criteria: NMT 0.5%

5 SPECIFIC TESTS

WATER DETERMINATION, Method (921)

Sample: 0.4 g

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers, protected from light, and store at 15°-30°.

Change to read:

USP REFERENCE STANDARDS (11)

USP Dorzolamide Hydrochloride RS

USP Dorzolamide Hydrochloride Related Compound A RS

(4R,6R)-4-(Ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7- dioxide, monohydrochloride.

C₁₀H₁₆N₂O₄S₃ · HCl        360.89 _{(ERR 1-Aug-2021)}