Glycopyrrolate
(glye'' koe pir' oh late).
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C19H28BrNO3 398.33
Pyrrolidinium, 3-[(SR)-USP35(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-, [RS-]USP35 bromide;    
(RS)-[3-(SR)-Hydroxy-1,1-dimethylpyrrolidinium bromide] -cyclopentylmandelateUSP35     [596-51-0].
DEFINITION
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Glycopyrrolate USP35 contains NLT 98.0% and NMT 102.0%USP35 of C19H28BrNO3, calculated on the dried basis.USP35
IDENTIFICATION
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•  B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.USP35
•  C. Identification Tests—General, Bromide 191
Sample solution:  25 mg/mL
Acceptance criteria:  Meets the requirements
ASSAY
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•  Procedure
Buffer:  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 (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
Chromatographic system 
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 size:  50 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Tailing factor:  NMT 2.0
Relative standard deviation:  NMT 1.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of glycopyrrolate (C19H28BrNO3) in the portion of Glycopyrrolate taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of Glycopyrrolate from the Sample solution
rS== peak response of glycopyrrolate from the Standard solution
CS== concentration of USP Glycopyrrolate RS in the Standard solution (mg/mL)
CU== concentration of Glycopyrrolate in the Sample solution (mg/mL)
Acceptance criteria:  98.0%–102.0% on the dried basisUSP35
IMPURITIES
•  Residue on Ignition 281: NMT 0.3%
Delete the following:
•  Ordinary Impurities 466
Standard solutions:  0.05, 0.25, 0.5, and 1.0 mg/mL in alcohol
Sample solution:  50 mg/mL in alcohol
Eluant:  A mixture of ethyl acetate, water, and anhydrous formic acid (74:16:10)
Adsorbent:  Chromatographic silica gel
Application volume:  5 µL
Visualization:  Dry the plate at 105 for 15 min, followed by Visualization Technique 3; then air-dry the developed plate at room temperature for 2 h.
Acceptance criteria:  The intensity of any secondary spot of the Sample solution corresponds to NMT 0.5%, and the sum of the intensities of all secondary spots of the Sample solution corresponds to NMT 2.0%.USP35
Add the following:
•  Organic Impurities
Buffer:  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 (20:15:65)
Solution B:  Acetonitrile, methanol, and Buffer (50:15:35)
Mobile phase:  See Table 1.
Table 1
Time
(min)
Solution A
(%)
Solution B
(%)
0 100 0
10 100 0
25 10 90
35 10 90
37 100 0
45 100 0
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
Chromatographic system 
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 size:  50 µL
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
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of glycopyrrolate related compounds A, B, and C in the portion of Glycopyrrolate taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of each related compound from the Sample solution
rS== peak response of the corresponding related compound from the Standard solution
CS== concentration of the corresponding related compound in the Standard solution (mg/mL)
CU== concentration of Glycopyrrolate in the Sample solution (mg/mL)
Calculate the percentage of any other individual impurity in the portion of Glycopyrrolate taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of each impurity from the Sample solution
rS== peak response of glycopyrrolate from the Standard solution
CS== concentration of USP Glycopyrrolate RS in the Standard solution (mg/mL)
CU== concentration of Glycopyrrolate in the Sample solution (mg/mL)
Acceptance criteria:  See Table 2.
Table 2
Name Relative
Retention
Time
Acceptance
Criteria,
NMT (%)
5-Nitroisophthalic acida 0.45 0.15
Glycopyrrolate 1.00
Glycopyrrolate baseb 1.14 0.15
Cyclopentylmandelic acidc 2.68 0.15
Any other individual impurity 0.10
Total impurities 0.50
a  Glycopyrrolate related compound A.
b  Glycopyrrolate related compound B.
c  Glycopyrrolate related compound C.
USP35
Add the following:
•  Limit of Erythro Isomer
Buffer:  2.8 g/L of monobasic sodium phosphate in water. Adjust with a sodium hydroxide solution (1 in 10) to a pH of 6.50 ± 0.05.
Mobile phase:  Methanol, acetonitrile, and Buffer (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:  10 µg/mL of USP Glycopyrrolate RS in Mobile phase
Sample solution:  500 µg/mL of Glycopyrrolate in Mobile phase
Chromatographic system 
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 size:  10 µL
System suitability 
Samples:  System suitability solution and Standard solution
Suitability requirements 
Resolution:  NLT 1.2 between the erythro isomer and glycopyrrolate, System suitability solution
Tailing factor:  NMT 2.0, Standard solution
Relative standard deviation:  NMT 6.0%, Standard solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of erythro isomer in the portion of Glycopyrrolate taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of the erythro isomer from the Sample solution
rS== peak response of glycopyrrolate from the Standard solution
CS== concentration of USP Glycopyrrolate RS in the Standard solution (mg/mL)
CU== concentration of Glycopyrrolate in the Sample solution (mg/mL)
Acceptance criteria:  See Table 3.
Table 3
Name Relative
Retention
Time
Acceptance
Criteria,
NMT (%)
Erythro isomer (R,R/S,S-glycopyrrolate)a 0.89 0.4
Glycopyrrolate 1.00
a  USP Glycopyrrolate Erythro Isomer RS.
USP35
SPECIFIC TESTS
Delete the following:
•  Melting Range or Temperature, Class I 741: 193–198, but the range between beginning and end of melting does not exceed 2.USP35
•  Loss on Drying 731: Dry at 105 for 3 h: it loses NMT 0.5% of its weight.
ADDITIONAL REQUIREMENTS
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•  Packaging and Storage: Preserve in tight containers. Store at room temperature.USP35
Change to read:
•  USP Reference Standards 11
USP Glycopyrrolate RS Click to View Structure
USP Glycopyrrolate Related Compound A RS
5-Nitrobenzene-1,3-dicarboxylic acid.
    C8H5NO6        211.13
USP Glycopyrrolate Related Compound B RS
1-Methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate.
    C18H25NO3        303.40
USP Glycopyrrolate Related Compound C RS
2-Cyclopentyl-2-hydroxy-2-phenylacetic acid.
    C13H16O3        220.26
USP Glycopyrrolate Erythro Isomer RS
(RS)-3-[(RS)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy]-1,1-dimethylpyrrolidinium bromide.
    C19H28BrNO3        398.33
USP35
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Topic/Question Contact Expert Committee
Monograph Elena Gonikberg, Ph.D.
Principal Scientific Liaison
1-301-816-8251
(SM32010) Monographs - Small Molecules 3
Reference Standards RS Technical Services
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USP35–NF30 Page 3356
Pharmacopeial Forum: Volume No. 37(1)