BRIEFING

 Dextromethorphan. This proposal is based on the version of the monograph official as of May 1, 2020. On the basis of comments received, the previous proposal that appeared in PF 43(5) [Sept.–Oct. 2017] has been canceled and is being replaced with the following proposal. It is proposed to revise the monograph with the following changes:

1. Increase the specification upper limit in the Definition and Assay from NMT 101.0% to NMT 102.0% to align with the precision of the proposed Assay procedure.

2. Add 197A to Identification A to allow the flexibility of using either 197A or 197K.

3. Relocate the test for Identification B to the Impurities section as the test for Limit of Levomethorphan.

4. Replace the test for Identification B with the retention time agreement of dextromethorphan in the Sample solution and System suitability solution, as obtained in the Limit of Levomethorphan test.

5. Replace the titration-based Assay with a validated liquid chromatographic procedure. The chromatographic procedure was validated using the Symmetry C18 brand of column with L1 packing. The typical retention time for dextromethorphan is about 25 min.

6. Add an Organic Impurities test to strengthen the quality standard for this drug substance. The proposed liquid chromatographic procedure is similar to the proposed Assay procedure. The proposed limits for specified and unspecified impurities are consistent with those published in the PF 49(5) [Sept.–Oct. 2023] proposed revision for Dextromethorphan Hydrobromide, a closely related drug substance.

7. Update the Chromatographic system in the Limit of Levomethorphan test to add the Run time based on supporting data.

8. Delete the test for Limit of Phenolic Compounds because all the other tests in this proposal can adequately monitor the quality of this drug substance.

9. Replace the wet chemistry-based procedure in the Limit of N,N-Dimethylaniline test with a specific gas chromatographic procedure. The proposed GC procedure is based on the analysis performed with the DB-35 brand of column with G42 phase. The typical retention time for N,N-dimethylaniline is about 4.5 min.

10. Add the storage temperature in the Packaging and Storage section.

11. Add USP Dextromethorphan Related Compound A RS to the USP Reference Standards section to support the proposed test for Organic Impurities.

 Manufacturers are encouraged to submit their FDA-approved specifications to USP if they are different from those proposed in this revision.

 Additionally, minor editorial changes have been made to update the monograph to current USP style.

 (SM2: R. Ivaturi)

 Case ID: SUB-481