USPUSP-NF
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Captopril
C9H15NO3S 217.29217.28
l-Proline, 1-[(2S)-3-mercapto-2-methyl-1-oxopropyl]-;
1-[(2S)-3-Mercapto-2-methylpropionyl]-l-proline;
[(S)-3-Mercapto-2-methylpropanoyl]-l-proline [62571-86-2]

BRIEFING

Captopril. This proposal is based on the version of the monograph official as of December 1, 2021. It is proposed to revise the monograph with the following changes:

  1. Add an additional chemical name and update the molecular weight in the Chemical Information section to be consistent with the current chemical information.

  2. Revise Identification A to allow the flexibility of using either 〈197A〉 or 〈197K〉.

  3. Add Identification B based on retention time agreement, as obtained in the proposed Assay.

  4. Replace the titration procedure in the Assay with a liquid chromatographic procedure similar to the Organic Impurities test, based on the validation performed using a Microbondapak C18 brand of column with L1 packing. The typical retention time for captopril is about 6 min.

  5. In the test for Organic Impurities:

    • Update the Mobile phase preparation to provide additional clarification.

    • Update the preparation of the System suitability solution to provide flexibility.

    • Update the HPLC column particle size.

    • Add an Autosampler temperature and Run time in the Chromatographic system section based on available data.

    • Add a table and Note in the System suitability section to present relative retention times as an aid in peak assignment.

    • Update the quantitation to calculating the content against USP Captopril Disulfide RS.

    • Update the acceptance criteria for any unspecified impurity in Table 2 to 0.10% based on the International Council for Harmonisation (ICH) Q3A guideline for drug substances with a maximum daily dose of <2 g/day. Manufacturers are encouraged to submit their FDA-approved specifications, if different. The Standard solution is updated to the same concentration as per the expectations of the Expert Committee.

    • Clarify that Total impurities excludes captopril disulfide.

    • Add Relative standard deviation and Signal-to-noise ratio requirements to the System suitability section to strengthen the method. A Sensitivity solution is also added to support the additional requirement.

    • Add a reporting threshold to the Acceptance criteria. The proposed reporting threshold corresponds to that of the ICH guideline for drug substances with a maximum daily dose of <2 g/day. Manufacturers are encouraged to submit their FDA-approved level(s), if different.

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

 (SM2: S. Shane)

 Case ID—SUB-842

USP REFERENCE STANDARDS FOR PURCHASE

USP Captopril Disulfide RS
USP Captopril RS
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