Efavirenz Tablets
DEFINITION
Efavirenz Tablets contain NLT 92.0% and NMT 108.0% of the labeled amount of efavirenz (C14H9ClF3NO2).
IDENTIFICATION
• A. Infrared Absorption 
197K
197K
Sample solution:
Completely remove the coating film from a Tablet using a mortar and pestle to crack the Tablet, grind the contents into fine powder, and place the powder into a suitable container. Dissolve the contents in about 5 mL of acetonitrile by mixing on a vortex mixer. Allow to settle, remove about 3 mL of the solution, and centrifuge for about 5 min using a suitable container. Transfer 1–2 mL of supernatant to a clean suitable container, and evaporate to dryness under nitrogen. Mix 0.5–1 mg of the powder with 200 mg of potassium bromide.
Acceptance criteria:
Meet the requirements
• B.
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:
Acetonitrile and water (500:500)
Solution A:
Methanol, trifluoroacetic acid, and water (100: 0.5: 900)
Solution B:
Methanol, trifluoroacetic acid, and water (900: 0.5: 100)
Mobile phase:
See Table 1.
Table 1
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 60 | 40 |
| 16 | 50 | 50 |
| 23 | 35 | 65 |
| 28 | 30 | 70 |
| 29 | 20 | 80 |
| 31 | 20 | 80 |
| 32 | 60 | 40 |
| 40 | 60 | 40 |
Standard stock solution 1:
0.2 mg/mL of USP Efavirenz Related Compound B RS in Diluent
Standard stock solution 2:
5 mg/mL of USP Efavirenz RS in Diluent. Sonicate to dissolve before diluting to final volume.
Standard solution:
250 µg/mL of USP Efavirenz RS and 1 µg/mL of USP Efavirenz Related Compound B RS in Diluent prepared from Standard solution stock 2 and Standard stock solution 1, respectively. Store protected from light. For the HPLC analysis, it is recommended to use polypropylene vials, because degradation may occur with glass containers.
Sample stock solution:
Nominally, 12 mg/mL of efavirenz in Diluent prepared as follows. Transfer NLT 10 Tablets to a suitable container, and extract the contents in Diluent by mixing for about 90 min. Store protected from light.
Sample solution:
Nominally, 240 µg/mL of efavirenz in Diluent prepared as follows. Filter a portion of the Sample stock solution, and dilute the filtrate with Diluent. Store protected from light. For the HPLC analysis, it is recommended to use polypropylene vials, because degradation may occur with glass containers.
Chromatographic system
Mode:
LC
Detector:
UV 250 nm
Column:
4.6-mm × 15-cm; 5-µm packing L10
Column temperature:
40
Flow rate:
1.5 mL/min
Injection volume:
35 µL
System suitability
Sample:
Standard solution
[Note—The typical retention times for efavirenz related compound B and efavirenz are 0.9 and 1.0, respectively. ]
Suitability requirements
Resolution:
NLT 1.2 between efavirenz related compound B and efavirenz
Relative standard deviation:
NMT 2.0% for efavirenz
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of the labeled amount of efavirenz (C14H9ClF3NO2) in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of efavirenz from the Sample solution |
| rS | = | = peak response of efavirenz from the Standard solution |
| CS | = | = concentration of USP Efavirenz RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of efavirenz in the Sample solution (mg/mL) |
Acceptance criteria:
92.0%–108.0%
PERFORMANCE TESTS
• Dissolution 711
711
Medium:
2.0% (w/v) sodium lauryl sulfate in water; 1000 mL. Do not deaerate.
Apparatus 2:
50 rpm, with helix sinker. In addition, paddle and shaft must be composed of stainless steel and not coated with Teflon or other material. Also, all sampling devices and dissolution vessels must be washed with methanol or ethanol followed by a water wash.
Time:
30 min
Standard solution:
(L/1000) mg/mL of USP Efavirenz RS in Medium, where L is the Tablet label claim in mg. A small volume of methanol, NMT 1% of the final volume, could be used to solubilize efavirenz. Dilute this solution with Medium to obtain a final concentration of about 0.012 mg/mL.
Sample solution:
Pass a portion of the solution under test through a suitable polyethylene filter, and dilute with Medium to obtain a concentration similar to the Standard solution, assuming complete dissolution of the Tablet label claim.
Instrumental conditions
Analytical wavelength:
UV 247 nm
Cell:
1 cm
Blank:
Medium
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of the labeled amount of efavirenz (C14H9ClF3NO2) dissolved:
Result = (AU/AS) × CS × V × D × (1/L) × 100
| AU | = | = absorbance of the Sample solution |
| AS | = | = absorbance of the Standard solution |
| CS | = | = concentration of the Standard solution (mg/mL) |
| V | = | = volume of Medium, 1000 mL |
| D | = | = dilution for the Sample solution |
| L | = | = label claim (mg/Tablet) |
Tolerances:
NLT 80% (Q) of the labeled amount of efavirenz (C14H9ClF3NO2) is dissolved.
• Uniformity of Dosage Units 905
905
Procedure for content uniformity
Diluent:
Acetonitrile and water (50:50)
Standard solution:
12 µg/mL of USP Efavirenz RS in Diluent
Sample solution:
Transfer NLT 10 Tablets into separate and suitable containers, and dissolve in 250 mL of Diluent. Stir for about 90 min, and centrifuge a portion of each solution for 10 min. Pass about 10 mL through a suitable nylon or PVDF membrane filter. Immediately dilute a portion of the filtrate to an efavirenz concentration of about 12 µg/mL.
Instrumental conditions
Mode:
UV
Analytical wavelength:
UV 246 nm
Cell:
1 cm
Blank:
Diluent
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of the labeled amount of efavirenz (C14H9ClF3NO2) in each Tablet taken:
Result = (AU/AS) × (CS/L) × V × D × 100
| AU | = | = absorbance of efavirenz from the Sample solution |
| AS | = | = absorbance of efavirenz from the Standard solution |
| CS | = | = concentration of USP Efavirenz RS in the Standard solution (mg/mL) |
| L | = | = label claim (mg/Tablet) |
| V | = | = volume of the Sample solution (mL) |
| D | = | = dilution factor of the Sample solution |
Acceptance criteria:
Meet the requirements
IMPURITIES
• Organic Impurities
Diluent, Solution A, Solution B, Sample solution, and Chromatographic system:
Prepare as directed in the Assay.
System suitability solution:
Use the Standard solution prepared as directed in the Assay.
Standard solution:
1.25 µg/mL of USP Efavirenz RS and 0.005 µg/mL of USP Efavirenz Related Compound B RS in Diluent from the System suitability solution
System suitability
Samples:
System suitability solution and Standard solution
Suitability requirements
Resolution:
NLT 1.2 between efavirenz related compound B and efavirenz, System suitability solution
Relative standard deviation:
NMT 5.0% for efavirenz, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of any individual degradation product in the Tablet taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
| rU | = | = peak response of any individual impurity (degradation product) from the Sample solution |
| rS | = | = peak response of efavirenz from the Standard solution |
| CS | = | = concentration of USP Efavirenz RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of efavirenz in the Sample solution (mg/mL) |
| F | = | = relative response factor (see Table 2) |
Acceptance criteria:
See Table 2.
Table 2
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| Efavirenz aminoalcohol (degradation product)a | 0.48 | 0.26 | 0.25 |
| Efavirenz ethene analog (efavirenz related compound B)b,c | 0.93 | — | — |
| Efavirenz | 1.0 | — | — |
| Efavirenz pent-3-ene-1-yne (cis)c,d | 1.16 | — | — |
| Efavirenz pent-3-ene-1-yne (trans)c,e | |||
| Efavirenz penteneynec,f | |||
| Efavirenz pentyne analogc,g | 1.2 | — | — |
| Methylefavirenzc,h | 1.28 | — | — |
| Efavirenz aminoalcohol methyl carbamatec,i | 1.33 | — | — |
| Quinoline analog (degradation product)j | 1.45 | 2.0 | 0.20 |
| Efavirenz aminoalcohol ethyl carbamatec,k | 1.53 | — | — |
| Unidentified impurityc | 1.60 | — | — |
| Efavirenz aminoalcohol bis(ethoxycarbonyl)c,l | 1.63 | — | — |
| N-Benzylefavirenzc,m | 1.8 | — | — |
| Efavirenz benzoylaminoalcoholc,n | 1.9 | — | — |
| Unidentified impurityc | 2.1 | — | — |
| Cyclobutenylindole analogc,o | 2.18 | — | — |
| Any other individual degradation product | — | 1.0 | 0.20 |
| Totalc,p | — | — | 0.50 |
|
a
(S)-2-(2-Amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol.
b
(S,E)-6-Chloro-4-(2-cyclopropylvinyl)-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
c
For information purposes only. These are process impurities monitored in the drug substance and are not included in the total impurities. Include only the degradation products in the calculation of the total impurities.
d
(S,E)-6-Chloro-4-(pent-3-en-1-ynyl)-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
e
(S,Z)-6-Chloro-4-(pent-3-en-1-ynyl)-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
f
(S)-6-Chloro-4-(3-methylbut-3-en-1-ynyl)-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
g
(S)-6-Chloro-4-(pent-1-ynyl)-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
h
(S)-6-Chloro-4-{[(2RS,2RS)-2-methylcyclopropyl]ethynyl}-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
i
(S)-Methyl 4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenylcarbamate.
j
6-Chloro-2-cyclopropyl-4-(trifluoromethyl)quinoline.
k
(S)-Ethyl 4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenylcarbamate.
l
(S)-Ethyl 4-chloro-2-[4-cyclopropyl-2-(ethoxycarbonyloxy)-1,1,1-trifluorobut-3-yn-2-yl]phenylcarbamate.
m
(S)-6-Chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
n
(S)-N-[4-Chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl]-4-methoxybenzamide.
o
Ethyl 5-chloro-2-cyclobutenyl-3-(trifluoromethyl)-1H-indole-1-carboxylate.
p
Disregard any peak less than 0.05%.
|
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ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Store in well-closed containers at controlled room temperature.
• USP Reference Standards 11
11
USP Efavirenz RS 
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USP Efavirenz Related Compound B RS
(S,E)-6-Chloro-4-(2-cyclopropylvinyl)-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
C14H11ClF3NO2 317.69
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(S,E)-6-Chloro-4-(2-cyclopropylvinyl)-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
C14H11ClF3NO2 317.69
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Shankari Shivaprasad, Ph.D.
Scientific Liaison (301) 230-7426 |
(SM12010) Monographs - Small Molecules 1 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison (301) 816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP38–NF33 Page 3270
Pharmacopeial Forum: Volume No. 39(2)