Hydromorphone Hydrochloride Oral Solution
DEFINITION
Hydromorphone Hydrochloride Oral Solution contains NLT 90.0% and NMT 110.0% of the labeled amount of hydromorphone hydrochloride (C17H19NO3·HCl). It may contain suitable preservatives.
IDENTIFICATION
Delete the following:
A. Ultraviolet Absorption 197U 
Blank:  0.01 N hydrochloric acid and water (4:1)
Standard solution:  0.04 mg/mL of USP Hydromorphone Hydrochloride RS in 0.01 N hydrochloric acid and water (4:1)
Sample solution:  Equivalent to 0.2 mg/mL of hydromorphone hydrochloride in water
Analysis:  Pretreat a solid phase extraction column containing L1 packing serially with about 10 mL of methanol, and about 10 mL of 0.01 N hydrochloric acid. Transfer 5.0 mL of the Sample solution to the column, add about 19 mL of 0.01 N hydrochloric acid in at least two portions, and elute into a 25-mL volumetric flask. Dilute with 0.01 N hydrochloric acid to volume, and mix. Using a suitable cell, compare the spectrum of the Sample solution with that of the Standard solution, using the Blank to zero the instrument.
Acceptance criteria:  The absorption spectrum of the Sample solution exhibits maxima and minima at the same wavelength as that of the Standard solution.(RB 1-Jul-2011)
Change to read:
•  A.(RB 1-Jul-2011) The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
•  Procedure
Diluent:  Phosphoric acid and water (1:1000)
Solution A:  1.0 mg/mL of sodium 1-heptanesulfonate monohydrate in methanol and water (1:9). To each liter of this solution add 1.0 mL of triethylamine, and adjust with phosphoric acid to a pH of 2.5 ± 0.1.
Solution B:  1.0 mg/mL of sodium 1-heptanesulfonate monohydrate in methanol and water (1:1). To each liter of this solution add 1.0 mL of triethylamine, and adjust with phosphoric acid to a pH of 2.5 ± 0.1.
Mobile phase:  See Table 1.
Table 1
Time
(min)
Solution A
(%)
Solution B
(%)
0 85 15
24 5 95
25 85 15
30 85 15
[Note—The Standard solution and Sample solution should be kept in a cool place, protected from light. ]
Standard solution:  0.08 mg/mL of USP Hydromorphone Hydrochloride RS in Diluent
Sample solution:  Equivalent to 0.08 mg/mL of hydromorphone hydrochloride by diluting a suitable volume of Oral Solution in Diluent
Chromatographic system 
Mode:  LC
Detector:  UV 220 nm
Column:  4.6-mm × 5-cm; 3.5-µm packing L1
Column temperature:  45
Flow rate:  1 mL/min
Injection size:  20 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Tailing factor:  NMT 1.5 for the hydromorphone peak
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of the labeled amount of hydromorphone hydrochloride (C17H19NO3 ·HCl) in the portion of Oral Solution taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of USP Hydromorphone Hydrochloride RS in the Standard solution (mg/mL)
CU== nominal concentration of hydromorphone hydrochloride in the Sample solution (mg/mL)
Acceptance criteria:  90.0%–110.0%
IMPURITIES
•  Organic Impurities
Diluent, Solution A, and Solution B:  Prepare as directed in the Assay.
Mobile phase:  See Table 2.
Table 2
Time
(min)
Solution A
(%)
Solution B
(%)
0 94 6
25 94 6
40 20 80
70 20 80
75 94 6
90 94 6
[Note—The System suitability solution, Quantitation limit solution, Standard solution, and Sample solution should be kept in a cool place, protected from light. ]
System suitability solution:  0.8 mg/mL of USP Hydromorphone Hydrochloride RS and 0.8 µg/mL of USP Hydromorphone Related Compound A RS in Diluent
Quantitation limit solution:  0.4 µg/mL of USP Hydromorphone Hydrochloride RS in Diluent
Standard solution:  4 µg/mL of USP Hydromorphone Hydrochloride RS in Diluent
Sample solution:  Equivalent to 0.4 mg/mL of hydromorphone hydrochloride in Diluent
Chromatographic system 
Mode:  LC
Detector:  UV 220 nm
Column:  3.9-mm × 15-cm; 5-µm packing L1
Column temperature:  45
Flow rate:  1 mL/min
Injection size:  20 µL
System suitability 
Samples:  System suitability solution, Quantitation limit solution, and Standard solution
Suitability requirements 
Resolution:  NLT 1.0 between the hydromorphone related compound A and hydromorphone peaks, System suitability solution
Signal-to-noise ratio:  10:1, Quantitation limit solution
Tailing factor:  NMT 1.5 for the hydromorphone peak, Standard solution
Relative standard deviation:  NMT 5.0%, Standard solution
Analysis 
Samples:  Diluent, Standard solution, and Sample solution
Calculate the percentage of any specified or unspecified impurity in the portion of Oral Solution taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
rU== peak response for each degradation product found, including those in Table 3, from the Sample solution
rS== peak response of hydromorphone from the Standard solution
CS== concentration of USP Hydromorphone Hydrochloride RS in the Standard solution (mg/mL)
CU== concentration of hydromorphone hydrochloride in the Sample solution (mg/mL)
F== relative response factor for the corresponding individual specified or unspecified impurity (see Table 3)
Calculate the total degradation products by summing the percentage of all individual specified and unspecified degradation products determined to be at a level of 0.1% or greater, excluding the known process impurities, as indicated in Table 3.
Acceptance criteria:  See Table 3.
[Note—Disregard peaks corresponding to those from the Diluent, peaks that elute before a relative retention time of about 0.50, except for any peak with a relative retention time of about 0.34, and peaks that elute at the relative retention times of the process-related substances designated in Table 3. ]
Table 3
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
Unknown degradation product 0.34 1.0 0.2
8-Hydroxy-hydromorphone**a 0.50
Dihydromorphine (DHM)**b 0.61
Morphine**c 0.65
Hydromorphone
N-oxide*d
0.79 0.87 0.2
Hydromorphone 1.0
2,2'-Bishydromorphone
dihydrochloride*e
2.02 1.7 0.2
Individual unspecified degradation
products
1.0 0.2
Total degradation products 1.0
*  Degradation product.
**  Process impurity.
a  4,5-Epoxy-17-methylmorphinan-3,8-diol-6-one.
b  4,5-Epoxy-17-methylmorphinan-3,6-diol.
c  7,8-Didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol.
d  4,5-Epoxy-3-hydroxy-17-methylmorphinan-6-one N-oxide.
e  2,2¢-Bihydromorphone.
SPECIFIC TESTS
•  Microbial Enumeration Tests 61 and Tests for Specified Microorganisms 62: The total aerobic microbial count does not exceed 102 cfu/mL, and the total yeasts and molds count does not exceed 10 cfu/mL. It meets the requirements of the test for the absence of Escherichia coli.
•  pH 791: 4.5–6.5
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers, protected from light. Store at 25, excursions permitted between 15 and 30.
•  Labeling: Identify in the product labeling any preservative used in the Oral Solution.
•  USP Reference Standards 11
USP Hydromorphone Hydrochloride RS Click to View Structure
USP Hydromorphone Related Compound A RS
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
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Senior Scientific Liaison
1-301-816-8139
(SM22010) Monographs - Small Molecules 2
61 Radhakrishna S Tirumalai, Ph.D.
Principal Scientific Liaison
1-301-816-8339
(GCM2010) General Chapters - Microbiology
62 Radhakrishna S Tirumalai, Ph.D.
Principal Scientific Liaison
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(GCM2010) General Chapters - Microbiology
Reference Standards RS Technical Services
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