Amitriptyline Hydrochloride
(am'' i trip' ti leen hye'' droe klor' ide).
+'&img=../../images/v35300/cas-549-18-8.gif&casNumber=549-18-8&usp=35&nf=30&chemicalStructureImage=true&ID='+parent.myID,600,500);)
313.861-Propanamine, 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-, hydrochloride.
10,11-Dihydro-N,N-dimethyl-5H-dibenzo[a,d]cycloheptene-D5,
-propylamine hydrochloride
[549-18-8].» Amitriptyline Hydrochloride contains not less than 98.0 percent and not more than 102.0 percent of C20H23N·HCl, calculated on the dried basis.
Packaging and storage—
Preserve in well-closed containers.
USP Reference standards 
11
—
11—
USP Amitriptyline Hydrochloride RS 
') + '&img=../../images/v35300/cas-549-18-8.gif',600,500);)
USP Amitriptyline Related Compound A RS
(also known as Dibenzosuberone) 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-one.
C15H12O 208.26
') + '&img=../../images/v35300/c11rs2065.gif',600,500);)
(also known as Dibenzosuberone) 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-one.
C15H12O 208.26
USP Amitriptyline Related Compound B RS
(also known as Amitriptynol) 5-[3-(Dimethylamino)propyl]-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ol.
C20H25NO 295.42
') + '&img=../../images/v35300/c11rs2066.gif',600,500);)
(also known as Amitriptynol) 5-[3-(Dimethylamino)propyl]-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ol.
C20H25NO 295.42
USP Cyclobenzaprine Hydrochloride RS
') + '&img=../../images/v35300/cas-6202-23-9.gif',600,500);)
USP Nortriptyline Hydrochloride RS
') + '&img=../../images/v35300/cas-894-71-3.gif',600,500);)
Identification—
B:
The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
C:
It meets the requirements of the tests for Chloride 191.
191.
Melting range 741:
between 195
and 199.
741:
between 195 and 199.
pH 791:
between 5.0 and 6.0, in a solution (1 in 100).
791:
between 5.0 and 6.0, in a solution (1 in 100).
Loss on drying 731—
Dry it at a pressure not exceeding 5 mm of mercury at 60 to constant weight: it loses not more than 0.5% of its weight.
731—
Dry it at a pressure not exceeding 5 mm of mercury at 60 to constant weight: it loses not more than 0.5% of its weight.
Residue on ignition 281:
not more than 0.1%.
281:
not more than 0.1%.
Heavy metals, Method II 231:
0.001%.
231:
0.001%.
Related compounds—
Diluted phosphoric acid, Buffer, Mobile phase, and Chromatographic system—
Proceed as directed in the Assay.
Standard solution—
Use the System suitability preparation, prepared as directed in the Assay.
Test solution—
Use the Assay stock preparation.
Procedure—
Inject a volume (about 20 µL) of the Test solution into the chromatograph, record the chromatogram, and measure the peak responses. Calculate the percentages of individual amitriptyline related compounds in the portion of Amitriptyline Hydrochloride taken by the formula:
[note—Discard any peak with a relative retention time of less than 0.22. Use the response of the amitriptyline hydrochloride peak obtained from the Standard solution and the concentration of amitriptyline hydrochloride in the Standard solution to calculate the percentage of unknown individual impurities. ]
100(rU / rS)(CS / CT)
in which rU is the individual peak response for each amitriptyline related compound obtained from the Test solution; rS is the response of the corresponding peak in the Standard solution; CS is the concentration, in mg per mL, of each of the amitriptyline related compounds in the Standard solution; and CT is the concentration, in mg per mL, of amitriptyline hydrochloride in the Test solution. The related compound requirements are listed in Table 1.
Table 1
| Related Compound | Relative Retention Time |
Limit (%) |
|---|---|---|
| Amitriptyline related compound A |
0.35 | 0.05 |
| Amitriptyline related compound B |
0.52 | 0.15 |
| Nortriptyline hydrochloride | 0.60 | 0.15 |
| Cyclobenzaprine hydrochloride | 0.76 | 0.15 |
| Amitriptyline hydrochloride | 1.0 | — |
| Unknown | — | 0.10 each |
| Total known and unknown | — | 1.0 |
Assay—
Diluted phosphoric acid—
Prepare a mixture of phosphoric acid and water (1:10), and mix well.
Buffer—
Dissolve 1.42 g of dibasic sodium phosphate (Na2HPO4) in 1 L of water, and adjust with Diluted phosphoric acid to a pH of 7.7.
Mobile phase—
Prepare a mixture of filtered and degassed methanol and Buffer (7:3).
Standard preparation—
Dissolve an accurately weighed amount of USP Amitriptyline Hydrochloride RS in Mobile phase to obtain a solution having a known concentration of 0.2 mg per mL of amitriptyline hydrochloride.
Assay stock preparation—
Dissolve an accurately weighed amount of Amitriptyline Hydrochloride in Mobile phase to obtain a solution having a known concentration of about 1 mg per mL of amitriptyline hydrochloride.
Assay preparation—
Dilute the Assay stock preparation with Mobile phase (1:5).
Stock solution A—
Dissolve an accurately weighed amount of USP Amitriptyline Related Compound A RS in methanol to obtain a solution having a known concentration of about 1 mg per mL of amitriptyline related compound A.
Stock solution B—
Dissolve accurately weighed amounts of USP Amitriptyline Hydrochloride RS, USP Amitriptyline Related Compound B RS, USP Cyclobenzaprine Hydrochloride RS, and USP Nortriptyline Hydrochloride RS in Mobile phase to obtain a solution having a known concentration of about 0.4 mg per mL of amitriptyline hydrochloride and about 0.6 mg per mL each of amitriptyline related compound B, cyclobenzaprine hydrochloride, and nortriptyline hydrochloride.
System suitability preparation—
Dilute suitable volumes of Stock solution A and Stock solution B with Mobile phase to obtain a solution having 1 µg per mL of amitriptyline hydrochloride, 0.5 µg per mL of amitriptyline related compound A, and 1.5 µg per mL each of amitriptyline related compound B, cyclobenzaprine hydrochloride, and nortriptyline hydrochloride.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 215-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L7. The flow rate is about 1.5 mL per minute. The column temperature is maintained at 45. Chromatograph the System suitability preparation, and record the peak areas as directed for Procedure: the approximate relative retention times for related compounds are given in Table 1; and the resolution, R, between amitriptyline related compound B and nortriptyline is not less than 1.5. Chromatograph the Standard preparation, and record the peak areas as directed for Procedure: the relative standard deviation for amitriptyline replicate injections is not more than 2.0%.
621)—
The liquid chromatograph is equipped with a 215-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L7. The flow rate is about 1.5 mL per minute. The column temperature is maintained at 45. Chromatograph the System suitability preparation, and record the peak areas as directed for Procedure: the approximate relative retention times for related compounds are given in Table 1; and the resolution, R, between amitriptyline related compound B and nortriptyline is not less than 1.5. Chromatograph the Standard preparation, and record the peak areas as directed for Procedure: the relative standard deviation for amitriptyline replicate injections is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms for about 40 minutes, and measure the responses for the major peaks. Calculate the percentage of C20H23N·HCl in the portion of Amitriptyline Hydrochloride taken by the formula:
100(CS /CU)(rU / rS)
in which CS and CU are the concentrations, in mg per mL, of the Standard preparation and the Assay preparation; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Ravi Ravichandran, Ph.D.
Principal Scientific Liaison 1-301-816-8330 |
(SM42010) Monographs - Small Molecules 4 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 2183
Pharmacopeial Forum: Volume No. 31(6) Page 1606