Irinotecan Hydrochloride
C33H38N4O6·HCl·3H2O Anhydrous: 623.14 Trihydrate: 677.18
[1,4¢-Bipiperidine]-1¢-carboxylic acid, 4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinolin-9-yl ester, monohydrochloride, trihydrate, (S)-;
(+)-7-Ethyl-10-hydroxycamptothecine 10-[1,4¢-bipiperidine]-1¢-carboxylate, monohydrochloride, trihydrate
[136572-09-3].
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C33H38N4O6·HCl·3H2O Anhydrous: 623.14 Trihydrate: 677.18
[1,4¢-Bipiperidine]-1¢-carboxylic acid, 4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinolin-9-yl ester, monohydrochloride, trihydrate, (S)-;
(+)-7-Ethyl-10-hydroxycamptothecine 10-[1,4¢-bipiperidine]-1¢-carboxylate, monohydrochloride, trihydrate
[136572-09-3].DEFINITION
Irinotecan Hydrochloride contains NLT 98.0% and NMT 102.0% of C33H38N4O6·HCl, calculated on the anhydrous basis.
IDENTIFICATION
• B.
The retention time of the major peak of the Sample solution corresponds to the irinotecan (S-enantiomer) peak in the Identification solution, as obtained in the test for Limit of Irinotecan Hydrochloride Enantiomer.
• C. Identification Tests—General, Chloride 
191
:
A 2-mg/mL solution meets the requirements of the tests.
191:
A 2-mg/mL solution meets the requirements of the tests.
ASSAY
• Procedure
Solution A:
2.8 g/L of monobasic sodium phosphate monohydrate and 1.8 g/L of 1-octanesulfonic acid sodium salt monohydrate in water
Mobile phase:
Acetonitrile, methanol, and Solution A (17:24:59)
Diluent:
Use Mobile phase adjusted with diluted hydrochloric acid to a pH of 3.65 ± 0.15.
Standard solution:
1 mg/mL of USP Irinotecan Hydrochloride RS in Diluent
Sample solution:
1 mg/mL of Irinotecan Hydrochloride in Diluent
Chromatographic system
Mode:
LC
Detector:
UV 255 nm
Column:
4.6-mm × 25-cm; 5-µm packing L1
Column temperature:
40
Flow rate:
1.5 mL/min
Injection size:
15 µL
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
NMT 1.5
Relative standard deviation:
NMT 2.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of irinotecan hydrochloride (C33H38N4O6·HCl) in the portion of Irinotecan Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak area from the Sample solution |
| rS | = | = peak area from the Standard solution |
| CS | = | = concentration of USP Irinotecan Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Irinotecan Hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria:
98.0%–102.0% on the anhydrous basis
IMPURITIES
• Residue on Ignition 281:
NMT 0.1%
281:
NMT 0.1%
• Heavy Metals, Method II 231:
NMT 10 ppm
231:
NMT 10 ppm
• Limit of Irinotecan Hydrochloride Enantiomer
Mobile phase:
Hexane, dehydrated alcohol, and diethylamine (250:250:1)
Diluent:
Dehydrated alcohol and diethylamine (250:1)
System suitability solution:
0.1 mg/mL each of USP Irinotecan Hydrochloride RS and USP Irinotecan Related Compound D RS in Diluent
Identification solution:
1 mg/mL of USP Irinotecan Hydrochloride RS in Diluent. [Note—This solution is used for Identification test B. ]
Standard solution:
1.5 µg/mL of USP Irinotecan Related Compound D RS in Diluent
Sensitivity solution:
0.5 µg/mL of USP Irinotecan Related Compound D RS in Diluent, from the Standard solution
Sample solution:
1 mg/mL of Irinotecan Hydrochloride in Diluent
Chromatographic system
Mode:
LC
Detector:
UV 370 nm
Column:
4.6-mm × 25-cm; 10-µm packing L40
Flow rate:
1.0 mL/min
Injection size:
20 µL
System suitability
Samples:
System suitability solution, Standard solution, and Sensitivity solution
[Note—The relative retention times for irinotecan related compound D (R-enantiomer) and irinotecan (S-enantiomer) are 0.7 and 1.00, respectively. ]
Suitability requirements
Resolution:
NLT 2.5 between irinotecan related compound D and irinotecan, System suitability solution
Relative standard deviation:
NMT 5.0%, Standard solution
Sensitivity:
The irinotecan related compound D peak should be visible, Sensitivity solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of irinotecan hydrochloride R-enantiomer in the portion of Irinotecan Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak area of irinotecan related compound D from the Sample solution |
| rS | = | = peak area of irinotecan related compound D from the Standard solution |
| CS | = | = concentration of USP Irinotecan Related Compound D RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Irinotecan Hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria
R-enantiomer:
NMT 0.15%
[Note—On the basis of the synthetic route, perform either Organic Impurities Procedure 1 or Organic Impurities Procedure 2. ]
• Organic Impurities Procedure 1 (for Material Labeled as Produced by a Synthetic Process)
Mobile phase, Diluent, Sample solution, and Chromatographic system:
Proceed as directed in the Assay.
System suitability stock solution:
0.01 mg/mL each of USP Irinotecan Related Compound B RS and USP Irinotecan Related Compound C RS in methanol
System suitability solution:
1.0 µg/mL each of USP Irinotecan Related Compound B RS and USP Irinotecan Related Compound C RS in Diluent, from System suitability stock solution
Standard solution:
2.0 µg/mL of USP Irinotecan Hydrochloride RS in Diluent
Sensitivity solution:
0.5 µg/mL of USP Irinotecan Hydrochloride RS in Diluent
System suitability
Samples:
System suitability solution, Standard solution, and Sensitivity solution
Suitability requirements
Resolution:
NLT 1.1 between irinotecan related compound B and irinotecan related compound C, System suitability solution
Relative standard deviation:
NMT 2.0%, Standard solution
Signal-to-noise ratio:
NLT 10, Sensitivity solution
Analysis
Samples:
Sample solution and Standard solution
Calculate the percentage of each impurity in the portion of Irinotecan Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak area of each impurity from the Sample solution |
| rS | = | = peak area of irinotecan from the Standard solution |
| CS | = | = concentration of irinotecan hydrochloride in the Standard solution (mg/mL) |
| CU | = | = concentration of Irinotecan Hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria
Individual impurities:
See Table 1. [Note—Disregard any impurity peaks less than 0.05%. ]
Table 1
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|---|---|---|
| Irinotecan related compound B | 0.55 | 0.15 |
| Irinotecan related compound C | 0.60 | 0.10 |
| Irinotecan hydrochloride | 1.0 | — |
| Any unspecified impurity | — | 0.10 |
| Total impurities | — | 0.5 |
• Organic Impurities Procedure 2 (for Material Labeled as Produced by a Semi-synthetic Process)
Solution A:
2.72 g/L of monobasic potassium phosphate in water. Adjust with dilute phosphoric acid (1 in 20) to a pH of 3.5 ± 0.05.
Solution B:
Acetonitrile and methanol (3:2)
Mobile phase:
See Table 2.
Table 2
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 80 | 20 |
| 40 | 30 | 70 |
| 45 | 30 | 70 |
| 50 | 80 | 20 |
| 55 | 80 | 20 |
Diluent:
Acetonitrile, methanol, and Solution A (1:1:2)
System suitability solution:
0.1 mg/mL each of USP Irinotecan Hydrochloride RS and USP Irinotecan Related Compound A RS in Diluent
Standard solution:
1 µg/mL of USP Irinotecan Hydrochloride RS in Diluent
Sample solution:
1 mg/mL of Irinotecan Hydrochloride in Diluent
Chromatographic system
Mode:
LC
Detector:
UV 220 nm
Column:
4.6-mm × 25-cm; 5-µm packing L1
Flow rate:
1 mL/min
Injection size:
10 µL
System suitability
Samples:
System suitability solution and Standard solution
Suitability requirements
Resolution:
NLT 3.0 between irinotecan and irinotecan related compound A, System suitability solution
Relative standard deviation:
NMT 2.0%, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Irinotecan Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
| rU | = | = peak area of each individual impurity from the Sample solution |
| rS | = | = peak area of irinotecan from the Standard solution |
| CS | = | = concentration of USP Irinotecan Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Irinotecan Hydrochloride in the Sample solution (mg/mL) |
| F | = | = relative response factor for each individual impurity (see Table 3) |
Acceptance criteria
Individual impurities:
See Table 3. [Note—Disregard any unspecified impurity peaks less than 0.05%. ]
Table 3
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| 7-Desethyl irinotecana | 0.82 | 0.77 | 0.15 |
| Irinotecan | 1.00 | — | — |
| Irinotecan related compound Ab | 1.15 | 1.4 | 0.15 |
| 11-Ethyl irinotecanc | 1.27 | 0.63 | 0.15 |
| Camptothecind | 1.35 | 1.4 | 0.15 |
| Irinotecan related compound Be | 1.50 | 1.3 | 0.15 |
| 7-Ethylcamptothecinf | 1.76 | 1.2 | 0.15 |
| 7,11-Diethyl-10-hydroxycamptothecing | 2.05 | 0.65 | 0.15 |
| Any unspecified impurity | — | 1.0 | 0.10 |
| Total impurities | — | — | 0.50 |
|
a
(S)-4-Ethyl-4-hydroxy-1H-pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione-9-yl (1,4¢-bipiperidine)-1¢-carboxylate.
b
(S)-4-Ethyl-4,9-dihydroxy-1H-pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.
c
(S)-4,8,11-Triethyl-4-hydroxy-1H-pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione-9-yl (1,4¢-bipiperidine)-1¢-carboxylate.
d
(S)-4-Ethyl-4-hydroxy-1H-pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.
e
(S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.
f
(S)-4,11-Diethyl-4-hydroxy-1H-pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.
g
(S)-4,8,11-Triethyl-4,9-dihydroxy-1H-pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.
|
|||
SPECIFIC TESTS
• Microbial Enumeration Tests 61 and Tests for Specified Microorganisms 62:
The total aerobic microbial count does not exceed 1000 cfu/g, and the total combined molds and yeasts count does not exceed 100 cfu/g.
61 and Tests for Specified Microorganisms 62:
The total aerobic microbial count does not exceed 1000 cfu/g, and the total combined molds and yeasts count does not exceed 100 cfu/g.
• Water Determination, Method I 921:
Between 7.0% and 9.0%
921:
Between 7.0% and 9.0%
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight, light-resistant containers, and store at controlled room temperature.
• Labeling:
If a test for Organic Impurities other than Procedure 1 is used, the labeling states the test with which the article complies.
• USP Reference Standards 11
11
USP Irinotecan Hydrochloride RS 
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USP Irinotecan Related Compound A RS
(S)-4-Ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.
C20H16N2O5 364.35
(S)-4-Ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.
C20H16N2O5 364.35
USP Irinotecan Related Compound B RS
(S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.
C22H20N2O5 392.40
(S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.
C22H20N2O5 392.40
USP Irinotecan Related Compound C RS
(S)-9-[(1,4'-Bipiperidine)-1'-carbonyloxy]-4-methyl-11-ethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline hydrochloride.
C32H36N4O6·HCl 609.11
(S)-9-[(1,4'-Bipiperidine)-1'-carbonyloxy]-4-methyl-11-ethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline hydrochloride.
C32H36N4O6·HCl 609.11
USP Irinotecan Related Compound D RS
(R)-9-[(1,4'-Bipiperidine)-1'-carbonyloxy]-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline hydrochloride, trihydrate.
C33H38N4O6·HCl·3 H2O 677.18
(R)-9-[(1,4'-Bipiperidine)-1'-carbonyloxy]-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline hydrochloride, trihydrate.
C33H38N4O6·HCl·3 H2O 677.18
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Feiwen Mao, M.S.
Senior Scientific Liaison 1-301-816-8320 |
(SM32010) Monographs - Small Molecules 3 |
| 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 1-301-816-8339 |
(GCM2010) General Chapters - Microbiology |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 3560