BRIEFING

 Clorazepate Dipotassium. This proposal is based on the version of the monograph official as of May 1, 2020. It is proposed to revise the monograph with the following changes:

1. Update the Definition to reflect the widened Acceptance criteria per the proposed Assay by liquid chromatography.

2. Replace Identification B by Ultraviolet-Visible Spectroscopy 〈197U〉 with the retention time agreement as determined in the proposed Assay by liquid chromatography per current USP practice.

3. Replace the titrimetric procedure for the Assay with a more specific liquid chromatographic procedure. This procedure was validated using the Cortecs C18 brand of column with L1 packing. The typical retention time of clorazepate is about 4 min. Widen the Acceptance criteria for the Assay to reflect the typical expectation of the new procedure.

4. Update the tests for Organic Impurities as follows:

   • Replace the existing Test 1, which uses the internal standard for determination of Nordazepam, and Test 2 for determination of 2-Amino-5-chlorobenzophenone and individual impurities with a more specific liquid chromatographic procedure that determines all impurities other than clorazepate related compound C (ethyl clorazepate) and is also used for the Assay.

   • Add a new liquid chromatographic procedure for the determination of clorazepate related compound C. This procedure was validated using the Cortecs C18 brand of column with L1 packing. The typical retention time for clorazepate related compound C is about 8 min.

5. Replace the numerical reporting threshold in the Acceptance criteria section of Organic Impurities, Procedure 1 with a reference to User-Determined Reporting Thresholds 〈477〉 for user flexibility.

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

7. Add USP Benzophenone RS and USP Clorazepate Related Compound C RS in the USP Reference Standards section to align with the Reference Standards used in the Organic Impurities procedures. Update the chemical information for USP Nordazepam RS and USP 2-Amino-5-chlorobenzophenone RS.

 Manufacturers are encouraged to submit their FDA-approved organic impurities specifications to USP if they are different from those proposed.

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

 (SM4: S. Dragan)

 Case ID—SUB-1330