{"id":6192,"date":"2022-09-18T12:17:14","date_gmt":"2022-09-18T07:47:14","guid":{"rendered":"http:\/\/arasto.com\/product\/ketoconazole\/"},"modified":"2023-05-06T12:31:05","modified_gmt":"2023-05-06T09:01:05","slug":"ketoconazole","status":"publish","type":"product","link":"https:\/\/arasto.com\/fa\/product\/ketoconazole\/","title":{"rendered":"Ketoconazole"},"content":{"rendered":"

Description<\/strong><\/p>\n

(USP 38)<\/p>\n

    \n
  1. Drug Substance General Information (ICH 3.2.S.1)<\/strong><\/li>\n<\/ol>\n

    1.1. Nomenclature (ICH 3.2.S.1.1)<\/strong><\/p>\n

    International non-proprietary name:\u00a0 Ketoconazole (Brand Name: Nizoral, Terzolin, Ketoderm)<\/p>\n

    Compendial name:\u00a0 Ketoconazole<\/p>\n

    Chemical name:\u00a0 cis-1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxoan-4-yl]methoxy]phenyl]piperazine<\/p>\n

    Arasto\u2019s code: KET<\/p>\n

    CAS Registry Number:\u00a0 [65277-42-1]<\/p>\n

    \n

      \n
    1. Drug Substance General Information (ICH 3.2.S.1)<\/strong><\/li>\n<\/ol>\n

      1.2. Structure (ICH 3.2.S.1.2)<\/strong><\/p>\n

      <\/p>\n

      Empirical formula: C26<\/sub>H28<\/sub>Cl2<\/sub>N4<\/sub>O4<\/sub><\/p>\n

      Molecular Weight: 531.43 g\/mol<\/p>\n

      \n

        \n
      1. Drug Substance General Information (ICH 3.2.S.1)<\/strong><\/li>\n<\/ol>\n

        1.3. General Properties (ICH 3.2.S.1.3)<\/strong><\/p>\n

        Ketoconazole is an off-white crystalline substance.\u00a0 It is administered orally and dermally for the treatment of candidiasis<\/a>,\u00a0chronic mucocutaneous candidiasis, oral\u00a0thrush<\/a>, candiduria,\u00a0blastomycosis<\/a>,\u00a0coccidioidomycosis<\/a>,\u00a0histoplasmosis<\/a>, chromomycosis, and paracoccidioid mycosis.<\/p>\n

        Ketoconazole is insoluble in water and soluble in very polar organic solvents (slightly soluble in alcohol and soluble in DMSO and to a lesser extent in DMF).\u00a0 \u00a0It is soluble in water at pH 1 due to salt formation with very strong acids (piperazine pKa<\/sub>= 2.9, imidazole pKa<\/sub>= 6.5, D.A. Williams and T.L. Lemeke, Eds. \u201cFoye\u2019s Principles of Medicinal Chemistry\u201d Fifth Edition, New York, Lippincott Williams & Wilkins, 2001, p. 1074).\u00a0 pKa vales for Ketoconazole have been reported to be 2.94 and 5.51 (www.researchgate.net\/\u2026ketoconazole\u2026\/79e4151225540c8b90.pdf<\/a>) and its log P 3.84 (http:\/\/130.88.242.202\/medicine\/Aspergillus\/Dropbox\/Aspergillus_Website\/asper gillus-web\/articlesoverflow\/12603774.pdf<\/a>).\u00a0 Ketoconazole is stable in acid and base (see Stability Studies).\u00a0\u00a0\u00a0 LD50<\/sub>\u00a0of Ketoconazole has been reported (mice oral 44 mg\/kg; rats oral 86 mg\/kg; guinea pigs oral 28 mg\/kg dogs IV 49 mg\/kg and oral 702, mg\/kg see the\u00a0Merck Index, 12th Edition, 1996).<\/p>\n

        The determination of purity and assay of APIs require comparison of the product with their respective Reference Standards (RS) and Related Compounds (RC or known impurities).\u00a0 Accordingly, ICH regulations on the purity and assay of reference standard and related compounds are clearly defined and must be followed by drug substance and drug product manufacturers.<\/p>\n

        According to ICH Q7, 11.1 there are 3 types of standards.\u00a0 This is summarized in the following chart and discussed in detail below.<\/p>\n

        <\/p>\n

        The impurities provided in the following table represent Secondary Reference Standards (SRS) that are prepared in-house by synthesis or by isolation.\u00a0 Each SRS has undergone extensive characterization ( IR, UV, 1HNMR, 13CNMR. Mass Spec) and determination of its purity and assay (HPLC).\u00a0 For specification of the SRS of those products that have a monograph, the SRS is compared with a pharmacopoeia Primary Reference Standard (UV, HPLC retention time).\u00a0 For specification of those products that do not \u00a0have a monograph (known as \u00a0House Primary Standard), we \u00a0compare their UV \u03b5 or \u05d2\/max<\/sub>\u00a0, IR major absorptions, 1HNMR d (ppm) , 13 CNMR \u00a0d (ppm) or HPLC retention time with values reported in the chemical literature for these compounds.<\/p>\n

        <\/p>\n

          \n
        1. Primary and Secondary Reference Standard (ICH 3.2.S.5)<\/strong><\/li>\n<\/ol>\n

          \u00a0\u00a05.1. Active Pharmaceutical Ingredient<\/strong><\/p>\n

          Primary Reference Standard for Ketoconazole\u00a0\u00a0 is available from United States Pharmacopoeia. We will use a Secondary Reference Standard (previously referred to as Working Standard) for direct control of all batches of Ketoconazole.<\/p>\n

          As per ICH (Q7, 11.1) and ICH (Q6, 2.11, 3.2, 3.3) the Secondary Reference Standards, which include the API and its Related Compounds, must be examined for their proof of structure (characterization), assay and purity and specification (identification by comparison). Furthermore, ICH Guideline on the Preparation of Common Technical Document (Q4M) requires that the data obtained from characterization, assay and purity and specification must be included in section 3.2.S.3.2 for Related Compounds (already discussed in that section) and section 3.2.S.5 of the DMF for the API.\u00a0To this end, the Secondary Reference Standards of the API Ketoconazole\u00a0\u00a0 has undergone extensive characterization (UV, IR,\u00a01<\/sup>\u00a0H NMR,\u00a013<\/sup>C NMR, and Mass Spec) to assure its structure, assay and purity (HPLC and\/or titration) and specification (comparison of its HPLC retention time and UV \u05d2\/max<\/sub>\u00a0with USP Primary Reference Standard.<\/p>\n

          The Secondary Reference Standard for Ketoconazole was produced from a released batch of Ketoconazole\u00a0\u00a0 by subjecting it to an additional crystallization from the final solvent system used in the production of the API to avoid the possibility of other polymorph formation.<\/p>\n

          SPECIFICATION OF ANALYSIS<\/h1>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
          Product:<\/strong> Ketoconazole<\/td>\nCAS No: <\/strong>65277-42-1<\/td>\nSpec. No.: <\/strong>APC-QC-SPEC-397-00<\/td>\n<\/tr>\n
          Issue Date: <\/strong>Apr, 2023<\/td>\nValid up to:<\/strong> Apr, 2024<\/td>\nReference: <\/strong>USP38<\/td>\n<\/tr>\n
          Tests<\/strong><\/td>\n\n

          Specifications<\/h2>\n<\/td>\n<\/tr>\n

          Description<\/td>\nWhite to off-white powder.<\/td>\n<\/tr>\n
          Identification<\/td>\nInfrared Absorption.<\/td>\n<\/tr>\n
          Melting Range<\/td>\nBetween 148\u00b0C and 152\u00b0C<\/td>\n<\/tr>\n
          Specific Rotation<\/td>\nBetween -1\u00b0 and +1\u00b0 (at 20\u00b0C)<\/td>\n<\/tr>\n
          Loss on drying<\/td>\nNMT 0.5%<\/td>\n<\/tr>\n
          Residue on ignition<\/td>\nNMT 0.1%<\/td>\n<\/tr>\n
          Heavy Metals<\/td>\nNMT 0.002%<\/td>\n<\/tr>\n
          Residual Solvents<\/td>\nMethanol: Max. 3000 ppm (Class II)<\/p>\n

          Acetone: Max. 5000 ppm (Class III)<\/p>\n

          Isopropanol: Max. 5000 ppm (Class III)<\/td>\n<\/tr>\n

          Chromatographic Purity (TLC)<\/td>\nTotal impurities: NMT 2.0%<\/td>\n<\/tr>\n
          Assay<\/td>\n98.0% to 102.0% (on the dried basis)<\/td>\n<\/tr>\n
          Prepared by:<\/strong> M. Shahbazi, B.Sc.Chem.<\/td>\nChecked by:<\/strong> A. Forghani, B.Sc.Chem.<\/td>\n<\/tr>\n
          Approved by:<\/strong> F. Javadizadeh, M.Sc.Chem.<\/td>\n<\/tr>\n
          Storage:<\/strong> Preserve in well-closed containers.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n","protected":false},"excerpt":{"rendered":"

          Description (USP 38) Drug Substance General Information (ICH 3.2.S.1) 1.1. Nomenclature (ICH 3.2.S.1.1) International non-proprietary name:\u00a0 Ketoconazole (Brand Name: Nizoral, Terzolin, Ketoderm) Compendial name:\u00a0 Ketoconazole Chemical name:\u00a0 cis-1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxoan-4-yl]methoxy]phenyl]piperazine Arasto\u2019s code: KET CAS Registry Number:\u00a0 [65277-42-1] Drug Substance General Information (ICH 3.2.S.1) 1.2. Structure (ICH 3.2.S.1.2) Empirical formula: C26H28Cl2N4O4 Molecular Weight: 531.43 g\/mol Drug Substance General […]<\/p>\n","protected":false},"featured_media":7117,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"product_cat":[72],"product_tag":[],"class_list":["post-6192","product","type-product","status-publish","has-post-thumbnail","hentry","product_cat-72"],"_links":{"self":[{"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product\/6192","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product"}],"about":[{"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/types\/product"}],"replies":[{"embeddable":true,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/comments?post=6192"}],"version-history":[{"count":1,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product\/6192\/revisions"}],"predecessor-version":[{"id":7119,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product\/6192\/revisions\/7119"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/media\/7117"}],"wp:attachment":[{"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/media?parent=6192"}],"wp:term":[{"taxonomy":"product_cat","embeddable":true,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product_cat?post=6192"},{"taxonomy":"product_tag","embeddable":true,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product_tag?post=6192"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}