{"id":6201,"date":"2022-09-18T11:35:58","date_gmt":"2022-09-18T07:05:58","guid":{"rendered":"http:\/\/arasto.com\/product\/bortezomib\/"},"modified":"2023-05-08T13:50:11","modified_gmt":"2023-05-08T10:20:11","slug":"bortezomib","status":"publish","type":"product","link":"https:\/\/arasto.com\/fa\/product\/bortezomib\/","title":{"rendered":"Bortezomib"},"content":{"rendered":"

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

(In-house)<\/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: Bortezomib (Brand Name: Velcade, Millenium Pharmaceuticals (Takeda), USA<\/p>\n

    Compendial name: Bortezomib<\/p>\n

    Chemical name: [(1R<\/em>)-3-methyl-1-({(2S<\/em>)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid<\/p>\n

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

    CAS Registry Number: [179324-69-7]<\/p>\n

     <\/p>\n

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

      1.2\u00a0 Structure (ICH 3.2.S.1.2)<\/strong><\/p>\n

      <\/p>\n

      Empirical formula: C19<\/sub>H25<\/sub>BN4<\/sub>O4<\/sub>
      \nMolecular Weight: 384.237 g\/mol<\/p>\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

        Bortezomib is a white crystalline substance. It is soluble in neutral water and polar organic solvents. It is used in injectable form for the treatment of multiple myeloma and cell lymphoma (http:\/\/www.velcade.com\/<\/a>). Boronic acids have a pKa range of 9-10.\u00a0 It has been suggested that mannitol (used as excipient in lyophilization of bortezomib) affords the boric acid ester with a lower pKa value of about 6 (http:\/\/kuscholarworks.ku.edu\/dspace\/bitstream\/1808\/1143\/ 1\/PS02%2 Marinaro.pdf<\/a>). It has been reported to have a lop P of 1.53 (https:\/\/go.drugbank.com\/drugs\/DB00188) Bortezomib is not stable in acid or base (see Stability Studies).Bortezomib is reported to be highly toxic: <2 mg\/kg IV rats and mice (http:\/\/ncifrederick.cancer.gov\/rtp\/LASP\/intra\/forms\/msds\/msds_bortezomib.pdf<\/a>).<\/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.\u00a0Each SRS has undergone extensive characterization (IR, UV, 1<\/sup>HNMR, 13<\/sup>CNMR. Mass Spec) and determination of its purity and assay (HPLC).\u00a0For 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).\u00a0For specification of those products that do not have a monograph (known as House Primary Standard), we compare their UV \u03b5 or \u05d2 \/max<\/sub>, IR major absorptions, 1HNMR d (ppm) , 13 CNMR d (ppm) or HPLC retention time with values reported in the chemical literature for these compounds.<\/p>\n

        \u00a0<\/strong><\/p>\n

        Bortezomib In-house Related Compounds<\/strong><\/p>\n

        <\/p>\n

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

          5.1.\u00a0Active Pharmaceutical Ingredient<\/strong><\/p>\n

          Primary Reference Standard for bortezomib is not available from United States Pharmacopoeia. We will use a House Primary Standard (previously referred to as Working Standard) for direct control of all batches of bortezomib.<\/p>\n

          As per ICH (Q7, 11.1) and ICH (Q6, 2.11, 3.2, 3.3)House Primary \u00a0Standards, which include the API and its Related Compounds,\u00a0must 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 House Primary Standard of the API bortezomib has undergone extensive characterization (UV, IR,\u00a01<\/sup>\u00a0H NMR,\u00a013<\/sup>C NMR, Mass Spec) to assure its structure, assay and purity (HPLC and\/or titration) and specification .<\/p>\n

          The House Primary Standard for bortezomib was produced from a released batch of bortezomib 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.\u00a0It was crystallized twice more to ensure high level of purity.<\/p>\n

          PECIFICATION OF ANALYSIS<\/h1>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
          Product:<\/strong> Bortezomib<\/td>\nCAS No.:<\/strong> 179324-69-7<\/td>\nSpec. No.: <\/strong>APC-QC-SPEC-373-00<\/td>\n<\/tr>\n
          Issue Date: <\/strong>Apr, 2023<\/td>\nValid up to:<\/strong> Apr, 2024<\/td>\nReference: <\/strong>In-house<\/td>\n<\/tr>\n
          Tests<\/strong><\/td>\n\n

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

          Appearance<\/td>\nWhite to off – white crystalline powder.<\/td>\n<\/tr>\n
          Solubility<\/td>\nSoluble in methanol ,dimethyl sulfoxide. Practically insoluble, or insoluble in water.<\/td>\n<\/tr>\n
          Identification<\/td>\nA:<\/strong> IR, conforms to standard.<\/p>\n

          B: <\/strong>Retention time of the principle peak obtained with chromatogram of sample preparation should correspond to the standard preparation under test assay.<\/td>\n<\/tr>\n

          Appearance of solution<\/td>\nClear and colorless (1.0% Solution in methanol)<\/td>\n<\/tr>\n
          pH<\/td>\nBetween 2.0 to 6.5 (1.0% Suspension in water)<\/td>\n<\/tr>\n
          Specific Rotation<\/td>\nBetween -49.5 \u00ba to – 57.0\u00b0<\/td>\n<\/tr>\n
          Water Content<\/td>\nBetween 6.0 to 9.0%<\/td>\n<\/tr>\n
          Heavy metals<\/td>\nNMT 20 ppm<\/td>\n<\/tr>\n
          Chromatographic Purity<\/td>\nBortezomib Related Compound A: NMT 0.1%<\/p>\n

          Bortezomib Related Compound B: NMT 0.1%<\/p>\n

          Bortezomib Related Compound D: NMT 0.1%<\/p>\n

          Bortezomib Related Compound E: NMT 0.1%<\/p>\n

          Bortezomib Related Compound F: NMT 0.1%<\/p>\n

          Bortezomib Related Compound G: NMT 0.1%<\/p>\n

          Bortezomib Related Compound I: NMT 0.1%<\/p>\n

          Any unspecified impurity: NMT 0.1%<\/p>\n

          Total impurities: NMT 0.5%<\/td>\n<\/tr>\n

          Residual Solvents<\/td>\nMethanol: Max. 3000 ppm (Class II)<\/p>\n

          Ethanol: Max. 5000 ppm (Class \u0406\u0406\u0406)<\/p>\n

          Ethyl acetate: Max. 5000 ppm (Class \u0406\u0406\u0406)<\/p>\n

          Isopropanol: Max. 5000 ppm (Class \u0406\u0406\u0406)<\/p>\n

          Dichloromethane: Max. 600 ppm (Class II)<\/p>\n

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

          Toluene: Max. 890 ppm (Class II)<\/p>\n

          methyl tert-butyl ether: Max. 5000 ppm (Class III)<\/p>\n

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

          Assay<\/td>\n98.0% to 102.0%<\/td>\n<\/tr>\n
          Microbial limit test (MLT)<\/p>\n

          Total aerobic Microbial count<\/p>\n

          Total Yeast and Moulds count<\/p>\n

          Test of pathogen<\/p>\n

          1. E. Coli<\/p>\n

          2. Pseudomonas .aeroginosa<\/p>\n

          3. Salmonella Species<\/p>\n

          4. Staphylococcus aureus<\/p>\n

          Endotoxin Limit<\/td>\n

          		NMT 250 CFU\/g<\/p>\n

          NMT 50 CFU\/g<\/p>\n

          Should be Absent<\/p>\n

          Should be Absent<\/p>\n

          Should be Absent<\/p>\n

          Should be Absent<\/p>\n

          Max. 16 EU per mg<\/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> Keep container tightly closed. Keep container in a cool refrigerated (-20\u00b0C\u00b15), well-ventilated area. Moisture sensitive.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n","protected":false},"excerpt":{"rendered":"

          Description (In-house) Drug Substance General Information (ICH 3.2.S.1) 1.1. Nomenclature (ICH 3.2.S.1.1) International non-proprietary name: Bortezomib (Brand Name: Velcade, Millenium Pharmaceuticals (Takeda), USA Compendial name: Bortezomib Chemical name: [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid Arasto\u2019s code: BOR CAS Registry Number: [179324-69-7]   Drug Substance General Information (ICH 3.2.S.1) 1.2\u00a0 Structure (ICH 3.2.S.1.2) Empirical formula: C19H25BN4O4 Molecular Weight: 384.237 g\/mol […]<\/p>\n","protected":false},"featured_media":7940,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"product_cat":[73],"product_tag":[],"class_list":["post-6201","product","type-product","status-publish","has-post-thumbnail","hentry","product_cat-73"],"_links":{"self":[{"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product\/6201","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=6201"}],"version-history":[{"count":1,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product\/6201\/revisions"}],"predecessor-version":[{"id":7942,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product\/6201\/revisions\/7942"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/media\/7940"}],"wp:attachment":[{"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/media?parent=6201"}],"wp:term":[{"taxonomy":"product_cat","embeddable":true,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product_cat?post=6201"},{"taxonomy":"product_tag","embeddable":true,"href":"https:\/\/arasto.com\/fa\/wp-json\/wp\/v2\/product_tag?post=6201"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}