Hydromorphone Hydrochloride
(hye'' droe mor' fone hye'' droe klor' ide).
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C17H19NO3·HCl 321.80
Morphinan-6-one, 4,5-epoxy-3-hydroxy-17-methyl-, hydrochloride, (5)-;    
4,5-Epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride     [71-68-1].
DEFINITION
Hydromorphone Hydrochloride, dried at 105 for 2 h, contains NLT 98.0% and NMT 101.0% of C17H19NO3·HCl.
IDENTIFICATION
•  B. Ultraviolet Absorption 197U
Sample solution:  100 µg/mL
Analytical wavelength:  280 nm
Acceptance criteria:  Absorptivities, calculated on the dried basis, do not differ by more than 3.0%.
•  C. Identification Tests—General, Chloride 191
Sample solution:  1 in 20
Acceptance criteria:  Meets the requirements
ASSAY
•  Procedure
Sample:  225 mg, previously dried
Analysis:  Transfer the Sample to a 250-mL conical flask. Dissolve in 80 mL of glacial acetic acid, warming, if necessary. Cool, and add 5 mL of acetic anhydride and 10 mL of mercuric acetate TS. Add 1 drop of crystal violet TS, and titrate with 0.1 N perchloric acid VS to a blue endpoint. Perform a blank determination, and make any necessary correction (see Titrimetry 541). Each mL of 0.1 N perchloric acid is equivalent to 32.18 mg of C17H19NO3·HCl.
Acceptance criteria:  98.0%–101.0%, dried at 105 for 2 h
IMPURITIES
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.3%
•  Sulfate
Sample solution:  100 mg in 5 mL of water
Analysis:  To the Sample solution add 0.5 mL of 3 N hydrochloric acid and 1 mL of barium chloride TS.
Acceptance criteria:  No turbidity is produced.
Change to read:
Organic Impurities 
[Note—If (5)-7-[(5)-3,6-dihydroxy-17-methyl-4,5-epoxymorphinan-6-yl]-3-hydroxy-17-methyl-4,5-epoxymorphinan-6-one (hydromorphone aldol dimer) or (5)-3-hydroxy-8-[(5)-3-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-7-yl]-17-methyl-4,5-epoxymorphinan-6-one (7,8'-bishydromorphone) are potential impurities, Procedure 2 is recommended. ]
•  Procedure 1
Diluent:  Phosphoric acid and water (1:1000)
Solution A:  1.0 mg/mL of sodium 1-heptanesulfonate monohydrate in 1000 mL of methanol and water (1:9). 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 1000 mL of methanol and water (1:1). Add 1.0 mL of triethylamine, and adjust with phosphoric acid to a pH of 2.5 ± 0.1.
Mobile phase:  See the gradient table below.
Time
(min)
Solution A
(%)
Solution B
(%)
0 94 6
25 94 6
40 20 80
70 20 80
75 94 6
90 94 6
System suitability solution:  0.8 mg/mL each of USP Hydromorphone Hydrochloride RS and USP Hydromorphone Related Compound A RS in Diluent. [Note—The solution should be kept in a cool place protected from light. ]
Standard solution:  4 µg/mL of USP Hydromorphone Hydrochloride RS in Diluent
Sample solution:  0.8 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:  1.0 mL/min
Injection size:  20 µL
System suitability 
Samples:  System suitability solution and Standard solution
Suitability requirements 
Resolution:  NLT 1.0 between the hydromorphone related compound A and hydromorphone peaks, System suitability 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 Hydromorphone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 1/F × 100
rU== peak response for each degradation found, including those in Impurity Table 1, 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 from Impurity Table 1
Acceptance criteria:  See Impurity Table 1. [Note—Disregard peaks corresponding to those obtained from the Diluent. ]
Impurity Table 1
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
8-Hydroxyhydromorphonea 0.50 1.0 0.15
Dihydromorphine (DHM)b 0.61 1.0 0.5
Morphinec 0.65 1.8 0.15
Hydromorphone
N-oxided
0.79 1.0 0.15
Hydromorphone
related compound Ae
0.93 1.4 0.1
Hydromorphone 1.0
8,14-Dihydrooripavine* 1.66 1.0 0.15
6-Tetrahydrooripavine* 1.71 1.0 0.15
2,2'-Bis hydromorphonef 2.02 1.7 0.15
Individual unspecified impurities 1.0 0.1
Total impurities 1.0
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  7,8-Didehydro-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one.
f  (5)-3-Hydroxy-2-[(5)-3-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-2-yl]-17-methyl-4,5-epoxymorphinan-6-one.
*  8,14-Dihydrooripavine and 6-tetrahydrooripavine are process impurities from another process and are controlled only if present.
•  Procedure 2
Diluent:  Phosphoric acid and water (1:100)
Solution A:  Mix 3520 mL of water, 18.40 g of monobasic ammonium phosphate, and 4.32 g of sodium 1-octanesulfonate. Add 4.0 mL of triethylamine, adjust with phosphoric acid to a pH of 2.90, and add 480 mL of acetonitrile.
Solution B:  Acetonitrile and water (1600:400)
Mobile phase:  See the gradient table below.
Time
(min)
Solution A
(%)
Solution B
(%)
0 100 0
20 80 20
21 100 0
30 100 0
System suitability solution:  0.15 mg/mL of USP Hydromorphone Hydrochloride RS and 0.1 mg/mL of USP Morphine RS in Diluent. [Note—The solution should be kept in a cool place protected from light. ]
Standard solution:  15 µg/mL of USP Hydromorphone Hydrochloride RS in Diluent
Sample solution:  3 mg/mL of Hydromorphone Hydrochloride in Diluent
Chromatographic system 
Mode:  LC
Detector:  UV 280 nm
Column:  3.9-mm × 15-cm; 5-µm packing L7
Column temperature:  40
Flow rate:  1.5 mL/min
Injection size:  10 µL
Run time:  30 min
System suitability 
Samples:  System suitability solution and Standard solution
Suitability requirements 
Resolution:  NLT 4.0 between the morphine and hydromorphone peaks, System suitability solution
Tailing factor:  NMT 1.5 for the hydromorphone peak, System suitability 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 Hydromorphone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 1/F × 100
rU== peak response for each peak found, including those in Impurity Table 2, 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== concentration of Hydromorphone Hydrochloride in the Sample solution (mg/mL)
F== relative response factor for the corresponding individual specified or unspecified impurity from Impurity Table 2
Acceptance criteria:  See Impurity Table 2. [Note—Disregard peaks corresponding to those obtained from the Diluent. ]
Impurity Table 2
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
Dihydromorphine (DHM)a 0.63 1.0 0.5
Morphineb 0.70 1.0 0.5
Hydromorphone 1.0
2,2'-Bishydromorphonec 1.82 2.0 0.5
Hydromorphone Hydrochloride Aldol Dimerd 2.12 1.0 0.5
7,8-Bishydromorphonee 2.32 1.0 0.5
Individual unspecified impurities 1.0 0.10
Total impurities 2.0
a  4,5-Epoxy-17-methylmorphinan-3,6-diol.
b  7,8-Didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol.
c  (5)-3-Hydroxy-2-[(5)-3-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-2-yl]-17-methyl-4,5-epoxymorphinan-6-one.
d  (5)-7-[(5)-3,6-Dihydroxy-17-methyl-4,5-epoxymorphinan-6-yl]-3-hydroxy-17-methyl-4,5-epoxymorphinan-6-one.
e  (5)-3-Hydroxy-8-[(5)-3-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-7-yl]-17-methyl-4,5-epoxymorphinan-6-one.
USP35
SPECIFIC TESTS
•  Optical Rotation, Specific Rotation 781S
Sample solution:  50 mg/mL
Acceptance criteria:  Between 136 and 139
•  Acidity
Sample:  300 mg
Analysis:  Dissolve the Sample in 10 mL of water, add 1 drop of methyl red TS, and titrate with 0.020 N sodium hydroxide VS.
Acceptance criteria:  NMT 0.30 mL is required to produce a yellow color.
•  Loss on Drying 731: Dry a sample at 105 for 2 h: it loses NMT 1.5% of its weight.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight, light-resistant containers. Store at 25, excursions permitted between 15 and 30.
Change to read:
•  USP Reference Standards 11
USP Hydromorphone Hydrochloride RS Click to View Structure
USP Hydromorphone Related Compound A RS
USP35
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USP35–NF30 Page 3446
Pharmacopeial Forum: Volume No. 35(5) Page 1156