Glycopyrrolate

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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C₁₉H₂₈BrNO₃ 398.34 (USP 1-Dec-2019)

Pyrrolidinium, 3-[(SR)-(cyclopentylhydroxyphen ylacetyl)oxy]-1,1-dimethyl-, [RS-] bromide;

(RS)-[3-(SR)-Hydroxy-1,1-dimethylpyrrolidinium bromide] α-cyclopentylmandelate CAS RN®: 51186-83-5. _{(USP 1-Dec-2019)}

1 DEFINITION

Glycopyrrolate contains NLT 98.0% and NMT 102.0% of glycopyrrolate (C₁₉H₂₈BrNO₃), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020) or 〈197A〉: Meets the requirements (USP 1-Dec-2019)

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 〈191〉, Chemical Identification Tests, Bromide

Sample solution: 25 mg/mL

Acceptance criteria: Meets the requirements

3 ASSAY

Change to read:

Procedure

Buffer solution: Prepare a solution of 1.0 g of anhydrous sodium sulfate and 200 mg of sodium 1-hexanesulfonate monohydrate in 650 mL of water. To this solution add 3.0 mL of 1 N sulfuric acid, and mix.

Mobile phase: Acetonitrile, methanol, and Buffer solution (20:15:65)

Standard solution: 0.1 mg/mL of USP Glycopyrrolate RS in Mobile phase

Sample solution: 0.1 mg/mL of Glycopyrrolate in Mobile phase

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 222 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 40°

Flow rate: 1.2 mL/min

Injection volume: 50 µL

3.2 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73% (USP 1-Dec-2019)

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of glycopyrrolate (C₁₉H₂₈BrNO₃) in the portion of Glycopyrrolate taken:

Result = (r_U /r_S ) × (C_S /C_U) × 100

r_U = peak response of glycopyrrolate from the Sample solution

r_S = peak response of glycopyrrolate from the Standard solution

C_S = concentration of USP Glycopyrrolate RS in the Standard solution (mg/mL)

C_U = concentration of Glycopyrrolate in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.3%

Change to read:

4.1 Organic Impurities, Procedure 1

[Note—On the basis of the synthetic route, perform either Procedure 1 or Procedure 2. Procedure 1 is recommended when glycopyrrolate related compound A (USP 1-Dec-2019) may be present (see Table 2); Procedure 2 is recommended when didehydroglycopyrrolate, glycopyrrolate related compound I, (USP 1-Dec-2019) and glycopyrrolate related compound L (USP 1-Dec-2019) may be present (see Table 4).] Buffer solution: Prepare a solution of 1.0 g of anhydrous sodium sulfate and 200 mg of sodium 1-hexanesulfonate monohydrate in 650 mL of water. To this solution add 3.0 mL of 1 N sulfuric acid, and mix.

Diluent: Prepare a solution of 1.0 g of anhydrous sodium sulfate, 6.8 g of monobasic potassium phosphate, and 200 mg of sodium 1- hexanesulfonate monohydrate in 650 mL of water. To this solution add 3.0 mL of 1 N sulfuric acid, 150 mL of methanol, and 200 mL of acetonitrile, and mix. Adjust with phosphoric acid to a pH of 2.8.

Solution A: Acetonitrile, methanol, and Buffer solution (20:15:65)

Solution B: Acetonitrile, methanol, and Buffer solution (50:15:35)

Mobile phase: See Table 1.

Table 1

Standard solution: 1.5 µg/mL each of USP Glycopyrrolate RS, USP Glycopyrrolate Related Compound A RS, USP Glycopyrrolate Related Compound B RS, and USP Glycopyrrolate Related Compound C RS in Diluent. Sonicate, if necessary, to facilitate dissolution. Sample solution: 1.0 mg/mL of Glycopyrrolate in Diluent

4.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 222 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 40°

Flow rate: 1 mL/min

Injection volume: 50 µL

4.1.2 System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 2.0 between glycopyrrolate and glycopyrrolate related compound B

Tailing factor: NMT 2.0 for the glycopyrrolate peak

Relative standard deviation: NMT 6.0% for each peak

4.1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the glycopyrrolate related compounds A, B, and C in the portion of Glycopyrrolate taken:

Result = (r_U /r_S ) × (C_S /C_U) × 100

r_U = peak response of each related compound from the Sample solution

r_S = peak response of the corresponding related compound from the Standard solution

C_S = concentration of the corresponding Reference Standard in the Standard solution (mg/mL)

C_U = concentration of Glycopyrrolate in the Sample solution (mg/mL)

Calculate the percentage of any other individual impurity in the portion of Glycopyrrolate taken:

Result = (r_U /r_S ) × (C_S /C_U) × 100

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

r_S = peak response of glycopyrrolate from the Standard solution

C_S = concentration of USP Glycopyrrolate RS in the Standard solution (mg/mL)

C_U = concentration of Glycopyrrolate in the Sample solution (mg/mL)

Acceptance criteria: See Table 2.

Table 2

(USP 1-Dec-2019)

Change to read:

4.2 Organic Impurities, Procedure 2

Buffer solution: 3.4 g/L of monobasic potassium phosphate in water (25 mM monobasic potassium phosphate buffer). Adjust with phosphoric acid to a pH of 2.5 ± 0.2.

Diluent: Acetonitrile and Buffer solution (1:1)

Solution A: Buffer solution

Solution B: Methanol

Mobile phase: See Table 3. Return to original conditions, and equilibrate the system.

Table 3

System suitability solution: 0.5 mg/mL of USP Glycopyrrolate RS and 1.0 µg/mL each of benzoic acid, USP Glycopyrrolate Related Compound B RS, USP Glycopyrrolate Related Compound C RS, USP Glycopyrrolate Related Compound I RS, and USP Glycopyrrolate Related Compound L RS in Diluent

Standard solution: 1.0 µg/mL of USP Glycopyrrolate RS in Diluent

Sample solution: 0.5 mg/mL of Glycopyrrolate in Diluent

4.2.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 215 nm

Column: 2.1-mm × 10-cm; 1.7-µm packing L1

Column temperature: 45°

Flow rate: 0.42 mL/min

Injection volume: 2.5 µL

4.2.2 System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 2.0 between glycopyrrolate and glycopyrrolate related compound B

Tailing factor: NMT 2.0 for the glycopyrrolate peak

4.2.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual impurity in the portion of Glycopyrrolate taken:

Result = (r_U /r_S ) × (C_S /C_U) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of glycopyrrolate from the Standard solution

C_S = concentration of USP Glycopyrrolate RS in the Standard solution (mg/mL)

C_U = concentration of Glycopyrrolate in the Sample solution (mg/mL)

F = relative response factor (see Table 4)

Acceptance criteria: See Table 4.

Table 4

(USP 1-Dec-2019)

^a 3-[2-(Cyclopent-1-en-1-yl)-2-hydroxy-2-phenylacetoxy]-1,1-dimethylpyrrolidin-1-ium bromide.

Change to read:

4.3 Limit of Erythro Isomer

Buffer solution: 2.8 g/L of monobasic sodium phosphate in water. Adjust with 2.5 M sodium hydroxide (USP 1-Dec-2019) to a pH of 6.50 ± 0.05.

Mobile phase: Methanol, acetonitrile, and Buffer solution (50:10:40)

System suitability solution: 40 µg/mL each of USP Glycopyrrolate Erythro Isomer RS and USP Glycopyrrolate RS in Mobile phase Standard solution: 0.01 mg/mL of USP Glycopyrrolate RS in Mobile phase

Sample solution: 0.5 mg/mL of Glycopyrrolate in Mobile phase

4.3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 222 nm

Column: 4.0-mm × 25-cm; 5-µm packing L45

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 10 µL

4.3.2 System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.2 between the glycopyrrolate (USP 1-Dec-2019) erythro isomer and glycopyrrolate, System suitability solution Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 6.0%, Standard solution

4.3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of glycopyrrolate (USP 1-Dec-2019) erythro isomer in the portion of Glycopyrrolate taken:

Result = (r_U /r_S ) × (C_S /C_U) × 100

r_U = peak response of the glycopyrrolate (USP 1-Dec-2019) erythro isomer from the Sample solution

r_S = peak response of glycopyrrolate from the Standard solution

C_S = concentration of USP Glycopyrrolate RS in the Standard solution (mg/mL)

C_U = concentration of Glycopyrrolate in the Sample solution (mg/mL)

Acceptance criteria: See Table 5.

Table 5

(USP 1-Dec-2019)

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° for 3 h

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Store at room temperature.

Labeling: If a test for Organic Impurities other than Procedure 1 is used, the labeling states the test with which the article complies.

Change to read:

USP Reference Standards 〈11〉

USP Glycopyrrolate RS

USP Glycopyrrolate Erythro Isomer RS

(RS)-3-[(RS)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1,1-dimethylpyrrolidinium bromide.

C₁₉H₂₈BrNO₃     398.33

USP Glycopyrrolate Related Compound A RS

5-Nitrobenzene-1,3-dicarboxylic acid.

C₈H₅NO₆           211.13

USP Glycopyrrolate Related Compound B RS

[Note—May be available as a free base or a hydrochloride salt.] (USP 1-Dec-2019)

1-Methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate.

C₁₈H₂₅NO₃         303.40

18 25 3

1-Methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate hydrochloride.

C₁₈H₂₅NO₃ ·  HCl     339.86 _{(USP 1-Dec-2019)}

USP Glycopyrrolate Related Compound C RS

2-Cyclopentyl-2-hydroxy-2-phenylacetic acid.

C₁₃H₁₆O₃           220.26

USP Glycopyrrolate Related Compound I RS

(RS)-3-[(SR)-2-(4-Chlorophenyl)-2-cyclopentyl-2-hydroxyacetoxy]-1,1-dimethylpyrrolidin-1-ium bromide.

C₁₉H₂₇BrClNO₃    432.78

USP Glycopyrrolate Related Compound L RS

Methyl 2-cyclopentyl-2-hydroxy-2-phenylacetate.

C₁₄H₁₈O₃           234.29