Midodrine Hydrochloride
(mye' doe dreen hye'' droe klor' ide).
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C12H18N2O4·HCl 290.74
Acetamide, 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-, monohydrochloride, (±)-;    
(±)-2-Amino-N-(-hydroxy-2,5-dimethoxyphenethyl)acetamide monohydrochloride     [3092-17-9].
DEFINITION
Midodrine Hydrochloride contains NLT 98.0% and NMT 102.0% of midodrine hydrochloride (C12H18N2O4·HCl), calculated on the anhydrous basis.
IDENTIFICATION
•  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: A 10 mg/mL solution of Midodrine Hydrochloride in water meets the requirements.
ASSAY
•  Procedure
Buffer:  13.6 g/L of monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 4.00 ± 0.05.
Mobile phase:  Acetonitrile and Buffer (3:22)
Standard solution:  0.05 mg/mL of USP Midodrine Hydrochloride RS in Mobile phase
Sample solution:  0.05 mg/mL of Midodrine Hydrochloride in Mobile phase
Chromatographic system 
Mode:  LC
Detector:  UV 290 nm
Column:  4.6-mm × 15-cm; 5-µm packing L1
Flow rate:  1 mL/min
Injection size:  20 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Column efficiency:  NLT 3000 theoretical plates
Tailing factor:  NMT 2.0
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of C12H18N2O4·HCl in the portion of Midodrine Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of midodrine from the Sample solution
rS== peak response of midodrine from the Standard solution
CS== concentration of USP Midodrine Hydrochloride RS in the Standard solution (mg/mL)
CU== concentration of Midodrine Hydrochloride in the Sample solution (mg/mL)
Acceptance criteria:  98.0%–102.0% on the anhydrous basis
IMPURITIES
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.2%. A 1-g sample is used.
•  Heavy Metals, Method II 231: NMT 10 ppm
Organic Impurities 
•  Procedure
Buffer and Mobile phase:  Proceed as directed in the Assay.
Standard solution:  1.0 µg/mL of USP Midodrine Hydrochloride RS and 2.0 µg/mL of USP Midodrine Related Compound A RS in Mobile phase
Sample solution:  1.0 mg/mL of Midodrine Hydrochloride in Mobile phase
Chromatographic system:  Proceed as directed in the Assay except for the following:
Injection size:  50 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Resolution:  NLT 2.0 between midodrine hydrochloride and midodrine hydrochloride related compound A
Tailing factor:  NMT 2.0 for midodrine hydrochloride
Relative standard deviation:  NMT 2.0% for both midodrine hydrochloride and midodrine related compound A
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of midodrine related compound A in the portion of Midodrine Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of midodrine related compound A from the Sample solution
rS== peak response of midodrine related compound A from the Standard solution
CS== concentration of USP Midodrine Related Compound A RS in the Standard solution (mg/mL)
CU== concentration of Midodrine Hydrochloride in the Sample solution (mg/mL)
Calculate the percentage of any individual impurity in the portion of Midodrine Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of each impurity from the Sample solution
rS== peak response of midodrine from the Standard solution
CS== concentration of USP Midodrine Hydrochloride RS in the Standard solution (mg/mL)
CU== concentration of Midodrine Hydrochloride in the Sample solution (mg/mL)
Acceptance criteria:  See Impurity Table 1.
Impurity Table 1
Name Relative
Retention
Time
Acceptance
Criteria,
NMT (%)
Midodrine related compound Aa 0.8 0.2%
Midodrine hydrochloride 1
Individual unspecified impurity 0.1%
Total impurities 0.5%
a  1-(2,5 Dimethoxyphenyl)-2-aminoethanol.
SPECIFIC TESTS
•  pH 791: 4.0–5.0. Use 50 mg/mL of the midodrine hydrochloride sample.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers and store at room temperature.
•  USP Reference Standards 11
USP Midodrine Hydrochloride RS
USP Midodrine Related Compound A RS
1-(2,5 Dimethoxyphenyl)-2-aminoethanol.
    C10H15NO3        197.23
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Sujatha Ramakrishna, Ph.D.
Senior Scientific Liaison
1-301-816-8349
(SM22010) Monographs - Small Molecules 2
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
USP35–NF30 Page 3922
Pharmacopeial Forum: Volume No. 36(2) Page 414