USP Pending Monograph
Draft 1—For Public Comment
BRIEFING
Latanoprost. A new USP Pending Monograph, based on
validated methods of analysis and using the flexible
monograph approach, is being proposed. Two different
Organic Impurities procedures, each one suitable for a
different synthetic route, are included.
1. The liquid chromatographic procedures in the test for
Organic Impurities, Procedure 1 are based on analyses
performed with the LiChrospher Si60 brand of L3
column. The typical retention time for latanoprost is
about 25 min. This procedure is based on the test for
Organic Impurities in the new USP monograph
Latanoprost published in PF 38(2), with the following
changes:
(a) USP Latanoprost Related Compound B RS and USP
Orlistat Related Compound C RS are included in
the System suitability solution for peak identification.
(b) The specified impurity orlistat related compound C
is added to the impurity table, Table 1.
2. The liquid chromatographic procedures in the test for
Organic Impurities, Procedure 2 and in the Assay are
based on analyses performed with the Chiracel OD-R
brand of L## column. The typical retention time for
latanoprost is about 38 min.
3. The thin-layer chromatographic procedure in the test for
Limit of Latanoprost Related Compound D is based on
analyses performed with a chromatographic silica gel
mixture. The typical RF value for latanoprost related
compound D is about 0.7.
(SM3: F. Mao, C. Anthony.)
Correspondence Number—C88452;
C104215
Latanoprost / 1
ASSAY
• PROCEDURE
Solution A: Fill a 1-L volumetric flask approximately twothirds full of water. Add 17 mL of phosphoric acid, and
dilute with water to volume.
Mobile phase: Acetonitrile, Solution A, and water
(75:1:125)
System suitability solution: 0.25 mg/mL of USP Latanoprost RS and 7.5 µg/mL of USP Latanoprost Related
Compound A RS in Mobile phase
Standard solution: 0.25 mg/mL of USP Latanoprost RS in
Mobile phase
Sample solution: 0.25 mg/mL of Latanoprost in Mobile
phase
Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 200 nm
Column: 4.6-mm × 25-cm; 10-µm packing L##
Flow rate: 1 mL/min
Injection volume: 20 µL
System suitability
Samples: Standard solution and System suitability solution
[NOTE—The relative retention times of latanoprost and
latanoprost related compound A are 1.0 and 1.12,
respectively.]
Suitability requirements
Resolution: NLT 1.5 between latanoprost and latanoprost related compound A, System suitability solution
Relative standard deviation: NMT 1.0%, Standard
solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of latanoprost (C26H40O5) in the
portion of Latanoprost taken:
Result = (rU/rS) × (CS/CU) × 100
rU
rS
CS
Add the following:
.
Latanoprost
c
Draft 1
C26H40O5
432.59
5-Heptenoic acid, 7-[3,5-dihydroxy-2-(3-hydroxy-5phenylpentyl)cyclopentyl]-1-methylethyl ester, [1R[1α(Z),2β(R*),3α,5α]]-;
Isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.
[130209-82-4].
DEFINITION
Latanoprost contains NLT 95.0% and NMT 105.0% of latanoprost (C26H40O5), calculated on the anhydrous basis.
IDENTIFICATION
• A. INFRARED ABSORPTION 〈197F〉
• B. The retention time of the major peak in the chromatogram of the Sample solution corresponds to that of the
Standard solution, as obtained in the Assay.
= peak area from the Sample solution
= peak area from the Standard solution
= concentration of USP Latanoprost RS in the
Standard solution (mg/mL)
CU
= concentration of Latanoprost in the Sample
solution (mg/mL)
Acceptance criteria: 95.0%–105.0% on the anhydrous
basis
IMPURITIES
• RESIDUE ON IGNITION 〈281〉: NMT 0.50%
• HEAVY METALS, Method II 〈231〉: NMT 20 ppm
[NOTE—On the basis of the synthetic route, perform either
Organic Impurities, Procedure 1 or Organic Impurities,
Procedure 2. Procedure 1 is recommended if
triphenylphosphine oxide may be present. Procedure 2 is
recommended if (3S,E)-latanoprost isomer may be
present.]
• ORGANIC IMPURITIES, PROCEDURE 1
Mobile phase: Hexane and dehydrated alcohol (94:6)
System suitability solution: 2.0 mg/mL of USP
Latanoprost RS, 20 µg/mL each of USP Latanoprost
Related Compound A RS and USP Latanoprost Related
Compound B RS, and 5 µg/mL of USP Orlistat Related
Compound C RS prepared as follows. Transfer the
Reference Standards into a suitable volumetric flask,
dissolve in an amount of dehydrated alcohol equivalent to
20% of the final flask volume, and dilute with hexane to
volume.
Standard solution: 0.04 mg/mL of USP Latanoprost RS
prepared as follows. Transfer a quantity of USP Latanoprost
RS into a suitable volumetric flask, dissolve in an amount
of dehydrated alcohol equivalent to 20% of the final flask
volume, and dilute with hexane to volume.
Sample solution: 2.0 mg/mL of Latanoprost prepared as
follows. Transfer a quantity of Latanoprost into a suitable
volumetric flask, dissolve in an amount of dehydrated
alcohol equivalent to 20% of the final flask volume, and
dilute with hexane to volume.
This monograph has been developed under USP‘s Pending Monographs Guideline and is not a USP–NF monograph.
http://www.usp.org
2012 The United States Pharmacopeia. All Rights Reserved.
USP Pending Monograph
Draft 1—For Public Comment
2 / Latanoprost
Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 210 nm
Column: 4.0-mm × 25-cm; 5-µm packing L3
Column temperature: 30°
Flow rate: 1 mL/min
Injection volume: 10 µL
System suitability
Samples: Standard solution and System suitability solution
Suitability requirements
Resolution: NLT 2.0 between latanoprost and
latanoprost related compound A, System suitability
solution
Relative standard deviation: NMT 5.0%, Standard
solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of each impurity in the portion
of Latanoprost taken:
System suitability
Samples: System suitability solution
Suitability requirements:
Resolution: NLT 1.5 between latanoprost and
latanoprost related compound A
Relative standard deviation: NMT 5.0% for
latanoprost related compound A and latanoprost
related compound B
Analysis
Sample: Sample solution
Calculate the percentage of each impurity in the portion
of Latanoprost taken:
Result = (rU/rT) × 100
rU
= peak area of each impurity
rT
= sum of the peak areas of all the peaks
Acceptance criteria: See Table 2.
Table 2
Result = (rU/rS) × (CS/CU) × (1/F) × 100
rU
= peak area of each impurity from the Sample
solution
rS
= peak area of USP Latanoprost RS from the
Standard solution
CS
= concentration of latanoprost in the Standard
solution (mg/mL)
CU
= concentration of Latanoprost in the Sample
solution (mg/mL)
F
= relative response factor for each individual
impurity (see Table 1)
Acceptance criteria: See Table 1. Disregard any impurity
peak less than 0.05%.
Table 1
Name
Orlistat related
compound Ca
Isopropyl
diphenylphosphorylpentanoateb
Latanoprost related
compound Bc
Latanoprost
Latanoprost related
compound Ad
Any unspecified
impurity
Sum of isopropyl
diphenylphosphorylpentanoate
and all unspecified
impurities
Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
0.76
7.2
0.15
0.79
2.4
0.10
0.89
1.00
1.0
—
0.5
—
1.10
1.0
3.5
1.0
0.10
—
—
—
0.35
Triphenylphosphine oxide.
b Isopropyl 5-(diphenylphosphoryl)pentanoate.
c Isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3S)-3-hydroxy-5phenylpentyl]cyclopentyl]-5-heptenoate.
d Isopropyl (E)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5phenylpentyl]cyclopentyl]-5-heptenoate.
a
• ORGANIC IMPURITIES, PROCEDURE 2
Mobile phase: Proceed as directed in the Assay.
System suitability solution: 1.0 mg/mL of USP
Latanoprost RS, 0.03 mg/mL of USP Latanoprost Related
Compound A RS, and 2 µg/mL of USP Latanoprost Related
Compound B RS in Mobile phase
Sample solution: 1.0 mg/mL of Latanoprost in Mobile
phase
Chromatographic system
Proceed as directed in the Assay.
Name
Latanoprost
Latanoprost related
compound Aa
Latanoprost related
compound Bb
(3S,E)-Latanoprost isomerc
Any unspecified impurity
Total impurities
Relative
Retention
Time
1.0
Acceptance
Criteria,
NMT (%)
—
1.12
3.0
1.36
1.47
—
—
0.2
0.2
0.1
4
Isopropyl (E)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5phenylpentyl]cyclopentyl]-5-heptenoate.
b Isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3S)-3-hydroxy-5phenylpentyl]cyclopentyl]-5-heptenoate.
c Isopropyl (E)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3S)-3-hydroxy-5phenylpentyl]cyclopentyl]-5-heptenoate.
a
• LIMIT OF LATANOPROST RELATED COMPOUND D (performed if
Organic Impurities, Procedure 2 is used)
Standard solution: 0.1 mg/mL of USP Latanoprost Related
Compound D RS in dehydrated alcohol
Sample solution: 100 mg/mL of Latanoprost in
dehydrated alcohol
Chromatographic system
(See Chromatography 〈621〉, Thin-Layer Chromatography.)
Mode: TLC
Adsorbent: 0.25-mm layer of chromatographic silica gel
mixture
Application volume 10 µL
Developing solvent system: Hexane and ethyl acetate
(4:1)
Analysis
Samples: Standard solution and Sample solution
Develop with the Developing solvent system over a path of
15 cm, and then air-dry. Dip in phosphomolybdic acid
TS, allow to drain, and visualize by heating the plate at
100° for 3 min.
Acceptance criteria: NMT 0.1%; the spot for latanoprost
related compound D from the Sample solution is not more
intense than the spot for latanoprost related compound D
from the Standard solution.
SPECIFIC TESTS
• OPTICAL ROTATION, Specific Rotation 〈781S〉
Sample solution: 9 mg/mL in acetonitrile
Acceptance criteria: +32.4° to +35.9° at 20°
• WATER DETERMINATION, Method Ic 〈921〉: NMT 0.5%
ADDITIONAL REQUIREMENTS
• PACKAGING AND STORAGE: Preserve in well-closed, lightresistant containers, and store in a refrigerator.
• LABELING: If a test for Organic Impurities other than
Procedure 1 is used, the labeling states the test with which
the article complies.
This monograph has been developed under USP‘s Pending Monographs Guideline and is not a USP–NF monograph.
http://www.usp.org
2012 The United States Pharmacopeia. All Rights Reserved.
USP Pending Monograph
Draft 1—For Public Comment
• USP REFERENCE STANDARDS 〈11〉
USP Latanoprost RS
USP Latanoprost Related Compound A RS
Isopropyl (E)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.
C26H40O5
432.59
USP Latanoprost Related Compound B RS
Isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3S)-3hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.
C26H40NO5
432.59
USP Latanoprost Related Compound D RS
Isopropyl (Z)-7-{(1R,2R,3R,5S)-2-[(R)-5-phenyl-3(triethylsilyloxy)pentyl]-3,5bis(triethylsilyloxy)cyclopentyl}hept-5-enoate.
Latanoprost / 3
C44H82O5Si3
775.38
USP Orlistat Related Compound C RS
Triphenylphosphine oxide.
C18H15OP 278.29b(1-Sep-2012)
This monograph has been developed under USP‘s Pending Monographs Guideline and is not a USP–NF monograph.
http://www.usp.org
2012 The United States Pharmacopeia. All Rights Reserved.