{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T22:29:49Z","timestamp":1786487389699,"version":"build-2736575974"},"reference-count":28,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2018,2,16]],"date-time":"2018-02-16T00:00:00Z","timestamp":1518739200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Coumadin\u00ae a nd s everal generic products of warfarin s odium (WS) contain the crystalline form (clathrate) in which WS and isopropanol (IPA) are associated in a 2:1 molar ratio. IPA is critical in maintaining the WS crystalline structure. Physicochemical properties of the drug and drug product may change when the crystalline drug transforms to amorphous form. A headspace-gas chromatography (HS-GC) method was developed and validated for IPA determination in the WS drug product. n-propanol (NPA) was used as internal standard and the method was validated for specificity, system suitability, linearity, accuracy, precision, range, limits of detection and quantification, and robustness. The method was specific, with good resolution between IPA and NPA peaks. Chromatographic parameters (retention time, IPA\/NPA area ratio, tailing factor, theoretical plates, USP symmetry, capacity factor, selectivity and resolution) were consistent over three days of validation. The analytical method was linear from 2-200 \u03bcg mL\n                    <jats:sup>-1<\/jats:sup>\n                    (0.1- 10 % IPA present in the drug product). LOD and LOQ were 0.1 and 2 \u03bcg mL\n                    <jats:sup>-1<\/jats:sup>\n                    , respectively. Accuracy at low (2 \u03bcg mL\n                    <jats:sup>-1<\/jats:sup>\n                    ) and high (200 \u03bcg mL\n                    <jats:sup>-1<\/jats:sup>\n                    ) IPA concentrations of the calibration curve was 103.3-113.3 and 98.9-102.2 % of the nominal value, resp. The validated method was precise, as indicated by the RSD value of less than 2 % at three concentration levels of the calibration curve. The method reported here was utilized to determine accurately and precisely the IPA content in in-house formulations and commercial products. In summary, IPA determination by HS-GC provides an indirect measure of WS crystallinity in the drug product. Nevertheless, it should be confirmed by another analytical method since IPA from the drug substance is not distinguishable from IPA that may be present outside the drug crystals in a dosage form when prepared by wet granulation with IPA.\n                  <\/jats:p>","DOI":"10.2478\/acph-2018-0001","type":"journal-article","created":{"date-parts":[[2018,4,12]],"date-time":"2018-04-12T03:38:55Z","timestamp":1523504335000},"page":"31-46","source":"Crossref","is-referenced-by-count":5,"title":["A headspace-gas chromatography method for isopropanol determination in warfarin sodium products as a measure of drug crystallinity"],"prefix":"10.2478","volume":"68","author":[{"given":"Ziyaur","family":"Rahman","sequence":"first","affiliation":[{"name":"Division of Product Quality and Research Center for Drug Evaluation and Research Food and Drug Administration Maryland , USA"},{"name":"Irma Lerma Rangel College of Pharmacy Texas A&M Health Science Center Texas A&M University Reynolds Medical Building Suite 159 College Station Texas 77843-1114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohail","family":"Akhtar","sequence":"additional","affiliation":[{"name":"Division of Product Quality and Research Center for Drug Evaluation and Research Food and Drug Administration Maryland , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akhtar","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Division of Product Quality and Research Center for Drug Evaluation and Research Food and Drug Administration Maryland , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony B.","family":"Ciavarella","sequence":"additional","affiliation":[{"name":"Division of Product Quality and Research Center for Drug Evaluation and Research Food and Drug Administration Maryland , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Nguyenpho","sequence":"additional","affiliation":[{"name":"Division of Product Quality and Research Center for Drug Evaluation and Research Food and Drug Administration Maryland , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Faustino","sequence":"additional","affiliation":[{"name":"Division of Product Quality and Research Center for Drug Evaluation and Research Food and Drug Administration Maryland , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansoor A.","family":"Khan","sequence":"additional","affiliation":[{"name":"Division of Product Quality and Research Center for Drug Evaluation and Research Food and Drug Administration Maryland , USA"},{"name":"Irma Lerma Rangel College of Pharmacy Texas A&M Health Science Center Texas A&M University Reynolds Medical Building Suite 159 College Station Texas 77843-1114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2018,2,16]]},"reference":[{"key":"2026081121581551766_j_acph-2018-0001_ref_001_w2aab2b8c20b1b7b1ab1ab1Aa","doi-asserted-by":"crossref","unstructured":"1. G. Levy, What are narrow therapeutic index drugs? Clin. Pharmacol. Ther. 63 (1998) 501-505; https:\/\/doi.org\/10.1016\/S0009-9236(98)90100-X10.1016\/S0009-9236(98)90100-X","DOI":"10.1016\/S0009-9236(98)90100-X"},{"key":"2026081121581551766_j_acph-2018-0001_ref_002_w2aab2b8c20b1b7b1ab1ab2Aa","unstructured":"2. L. X. Yu, Quality and bioequivalence standards for narrow therapeutic index drugs, GPhA 2011 Fall Technical Workshop, Bethesda, Maryland, USA, Oct 1-2, 2012; http:\/\/www.fda.gov\/downloads\/Drugs\/DevelopmentApprovalProcess\/HowDrugsareDevelopedandApproved\/ApprovalApplications\/AbbreviatedNewDrugApplicationANDAGenerics\/UCM292676.pdf; last access date March 19, 2017."},{"key":"2026081121581551766_j_acph-2018-0001_ref_003_w2aab2b8c20b1b7b1ab1ab3Aa","unstructured":"3. US Food&Drug Administration, CFR - Code of Federal Regulations, Title 21 - Food and Drugs, Chapter I - Food and Drug Administration, Subchapter D - Drugs for Human Use, Part 320 - Bioavailability and Bioequivalence Requirements, Subpart B - Procedures for Determining the Bioavailability or Bioequivalence of Drug Products, Sec. 320.33 - Criteria and Evidence to Assess Actual or Potential Problems, Department of Health and Human Services, Silver Spring (MD) 2017, Vol. 5; https:\/\/www.accessdata.fda.gov\/scripts\/cdrh\/cfdocs\/cfcfr\/CFRSearch.cfm?fr=320.33; last acces date March 19, 2017."},{"key":"2026081121581551766_j_acph-2018-0001_ref_004_w2aab2b8c20b1b7b1ab1ab4Aa","doi-asserted-by":"crossref","unstructured":"4. J. Tamargo, J. L. Heuzey and P. Mabo, Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide, Eur. J. Clin. Pharmacol. 71 (2015) 549-567; https:\/\/doi.org\/10.1007\/s00228-015-1832-010.1007\/s00228-015-1832-0441268825870032","DOI":"10.1007\/s00228-015-1832-0"},{"key":"2026081121581551766_j_acph-2018-0001_ref_005_w2aab2b8c20b1b7b1ab1ab5Aa","doi-asserted-by":"crossref","unstructured":"5. G. M. Currie, J. M. Wheat and H. Kiat, Pharmacokinetic considerations for digoxin in older people, Open Cardiovasc. Med. J. 5 (2011) 130-135; https:\/\/doi.org\/10.2174\/187419240110501013010.2174\/1874192401105010130313494621769303","DOI":"10.2174\/1874192401105010130"},{"key":"2026081121581551766_j_acph-2018-0001_ref_006_w2aab2b8c20b1b7b1ab1ab6Aa","doi-asserted-by":"crossref","unstructured":"6. A. Yacobi, E. Masson, D. Moros, D. Ganes, C. Lapointe, Z. Abolfathi, M. LeBel, Y. Golander, D. Doepner, T. Blumberg, Y. Cohen and B. Levitt, Who needs individual bioequivalence studies for narrow therapeutic index drugs? A case for warfarin, J. Clin. Pharmacol. 40 (2000) 826-835; https:\/\/doi.org\/10.1177\/0091270002200955810.1177\/0091270002200955810934666","DOI":"10.1177\/00912700022009558"},{"key":"2026081121581551766_j_acph-2018-0001_ref_007_w2aab2b8c20b1b7b1ab1ab7Aa","doi-asserted-by":"crossref","unstructured":"7. M. Bialer, R. H. Levy and E. Perucca, Does carbamazepine have a narrow therapeutic plasma concentration range? Ther. Drug Monit. 20 (1998) 56-59; https:\/\/doi.org\/10.1097\/00007691-199802000-0001010.1097\/00007691-199802000-000109485555","DOI":"10.1097\/00007691-199802000-00010"},{"key":"2026081121581551766_j_acph-2018-0001_ref_008_w2aab2b8c20b1b7b1ab1ab8Aa","unstructured":"8. J. Pesce, M. Rashkin and U. Kotagal, Standards of laboratory practice: theophylline and caffeine monitoring, Clin. Chem. 44 (1998) 1124-1128."},{"key":"2026081121581551766_j_acph-2018-0001_ref_009_w2aab2b8c20b1b7b1ab1ab9Aa","doi-asserted-by":"crossref","unstructured":"9. J. W. Shin, K. Chu, K. H. Jung, S. T. Lee, J. Moon and S. K. Lee, Switching between phenytoin generics in patients with epilepsy may lead to increased risk of breakthrough seizure: chart analysis and practice recommendations, Int. J. Clin. Pharmacol. Ther. 52 (2014) 1017-1022; https:\/\/doi.org\/10.5414\/CP20215310.5414\/CP20215325295717","DOI":"10.5414\/CP202153"},{"key":"2026081121581551766_j_acph-2018-0001_ref_010_w2aab2b8c20b1b7b1ab1ac10Aa","unstructured":"10. M. S. Paveliu, S. Bengea and F. S. Paveliu, Generic substitution issues: brand-generic substitution, generic-generic substitution, and generic substitution of narrow therapeutic index (NTI)\/critical dose drugs, Maedica (Bucharest) 6 (2011) 52-58."},{"key":"2026081121581551766_j_acph-2018-0001_ref_011_w2aab2b8c20b1b7b1ab1ac11Aa","unstructured":"11. Commonwealth of Pennsylvania, Generic Drug Equivalency\/Substitution Laws and Regulations, Philadelphia (PA) April 1, 2017; https:\/\/apps.health.pa.gov\/pdf\/ddc\/generic34.pdf; last access date June 21, 2017."},{"key":"2026081121581551766_j_acph-2018-0001_ref_012_w2aab2b8c20b1b7b1ab1ac12Aa","unstructured":"12. W. C. Tom and K. Dotson, State regulations on generic substitution, Pharm. Lett. 22 (2006) Document# 220901."},{"key":"2026081121581551766_j_acph-2018-0001_ref_013_w2aab2b8c20b1b7b1ab1ac13Aa","doi-asserted-by":"crossref","unstructured":"13. M. L. Chen, V. P. Shah, D. J. Crommelin, L. Shargel, D. Bashaw, M. Bhatti, H. Blume, J. Dressman, M. Ducharme, P. Fackler, T. Hyslop, L. Lutter, J. Morais, E. Ormsby, S. Thomas, Y. C. Tsang, R. Velagapudi and L. X. Yu, Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report, AAPS J. 13 (2011) 556-564; https:\/\/doi.org\/10.1208\/s12248-011-9294-510.1208\/s12248-011-9294-5323185521845486","DOI":"10.1208\/s12248-011-9294-5"},{"key":"2026081121581551766_j_acph-2018-0001_ref_014_w2aab2b8c20b1b7b1ab1ac14Aa","unstructured":"14. FDA@Drugs, Coumadin Label (2016); http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2011\/009218s107lbl.pdf; last access date March 19, 2017."},{"key":"2026081121581551766_j_acph-2018-0001_ref_015_w2aab2b8c20b1b7b1ab1ac15Aa","doi-asserted-by":"crossref","unstructured":"15. A. R. Sheth, W. W. Brennessel, V. G. Young, F. X. Muller and D. J. Grant, Solid-state properties of warfarin sodium 2-propanol solvate, J. Pharm. Sci. 93 (2004) 2669-2680; https:\/\/doi.org\/10.1002\/jps.2016410.1002\/jps.2016415389677","DOI":"10.1002\/jps.20164"},{"key":"2026081121581551766_j_acph-2018-0001_ref_016_w2aab2b8c20b1b7b1ab1ac16Aa","unstructured":"16. United States Pharmacopeia 39 - National Formulary 34, USP Convention, Rockville (MD) 2016."},{"key":"2026081121581551766_j_acph-2018-0001_ref_017_w2aab2b8c20b1b7b1ab1ac17Aa","doi-asserted-by":"crossref","unstructured":"17. Z. Rahman, M. Korang-Yeboah, A. Siddiqui, A. Mohammad and M. A. Khan, Understanding effect of formulation and manufacturing variables on the critical quality attributes of warfarin sodium product, Int. J. Pharm. 495 (2015) 19-30; https:\/\/doi.org\/10.1016\/j.ijpharm.2015.08.06510.1016\/j.ijpharm.2015.08.06526319638","DOI":"10.1016\/j.ijpharm.2015.08.065"},{"key":"2026081121581551766_j_acph-2018-0001_ref_018_w2aab2b8c20b1b7b1ab1ac18Aa","doi-asserted-by":"crossref","unstructured":"18. A. Nguyenpho, A. B. Ciavarella, A. Siddiqui, Z. Rahman, S. Akhtar, R. Hunt, M. Korang-Yeboah and M. A. Khan, Evaluation of in-use stability of anticoagulant drug products: warfarin sodium, J. Pharm. Sci. 104 (2015) 4232-4240; https:\/\/doi.org\/10.1002\/jps.2465710.1002\/jps.2465726501849","DOI":"10.1002\/jps.24657"},{"key":"2026081121581551766_j_acph-2018-0001_ref_019_w2aab2b8c20b1b7b1ab1ac19Aa","unstructured":"19. M. Korang-Yeboah, S. Akhtar, A. Siddiqui, Z. Rahman and M. A. Khan, Application of NIR chemometric methods for quantification of the crystalline fraction of warfarin sodium in drug products, Drug Dev. Ind. Pharm. 13 (2015) 1-11; https:\/\/doi.org\/10.3109\/03639045.2015.105881710.3109\/03639045.2015.1058817"},{"key":"2026081121581551766_j_acph-2018-0001_ref_020_w2aab2b8c20b1b7b1ab1ac20Aa","doi-asserted-by":"crossref","unstructured":"20. A. Siddiqui, Z. Rahman, M. Korang-Yeboah and M. A. Khan, Development and validation of X-ray diffraction method for quantitative determination of crystallinity in warfarin sodium products, Int. J. Pharm. 493 (2015) 1-6; https:\/\/doi.org\/10.1016\/j.ijpharm.2015.07.05110.1016\/j.ijpharm.2015.07.051","DOI":"10.1016\/j.ijpharm.2015.07.051"},{"key":"2026081121581551766_j_acph-2018-0001_ref_021_w2aab2b8c20b1b7b1ab1ac21Aa","doi-asserted-by":"crossref","unstructured":"21. Z. Rahman, A. A. Mohammad, S. Akhtar, A. Siddiqui, M. Korang-Yeboah and M. A. Khan, Chemometric model development and comparison of Raman and (13)C solid-state nuclear magnetic resonance-chemometric methods for quantification of crystalline\/amorphous warfarin sodium fraction in the formulations, J. Pharm. Sci. 104 (2015) 2550-2558; https:\/\/doi.org\/10.1002\/jps.2452410.1002\/jps.24524","DOI":"10.1002\/jps.24524"},{"key":"2026081121581551766_j_acph-2018-0001_ref_022_w2aab2b8c20b1b7b1ab1ac22Aa","unstructured":"22. C. F. Poole and S. K. Poole, Chromatography Today, Elsevier Science, Amsterdam 1991, pp. 133."},{"key":"2026081121581551766_j_acph-2018-0001_ref_023_w2aab2b8c20b1b7b1ab1ac23Aa","doi-asserted-by":"crossref","unstructured":"23. C. A. Cramers, J. A. Rijiks and P. Bocek, Packed versus capillary columns in gas chromatography, Clin. Chim. Acta 34 (1971) 159-167; https:\/\/doi.org\/10.1016\/0009-8981(71)90169-010.1016\/0009-8981(71)90169-0","DOI":"10.1016\/0009-8981(71)90169-0"},{"key":"2026081121581551766_j_acph-2018-0001_ref_024_w2aab2b8c20b1b7b1ab1ac24Aa","unstructured":"24. E. Sarban, S. Socaci, M. Tofana, M. Simona and M. Bojita, Advantages of \u201eheadspace\u201d technique for GC\/MS analysis of essential oils, Farmacia 60 (2012) 249-256."},{"key":"2026081121581551766_j_acph-2018-0001_ref_025_w2aab2b8c20b1b7b1ab1ac25Aa","unstructured":"25. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Validation of Analytical Procedures: Text and Methodology Q2(R1), Current Step 4 version, ICH, Geneva, November 2005; https:\/\/www.ich.org\/fileadmin\/Public_Web_Site\/ICH_Products\/Guidelines\/Quality\/Q2_R1\/Step4\/Q2_R1__Guideline.pdf; last access March 19, 2017."},{"key":"2026081121581551766_j_acph-2018-0001_ref_026_w2aab2b8c20b1b7b1ab1ac26Aa","doi-asserted-by":"crossref","unstructured":"26. A. Gupta, A. B. Ciavarella, V. A. Sayeed, M. A. Khan and P. J. Faustino, Development and application of validated HPLC method for the analysis of dissolution samples of gabapentin drug products, J. Pharm. Biomed. Anal. 46 (2008) 181-186; https:\/\/doi.org\/org\/10.1016\/j.jpba.2007.08.02310.1016\/j.jpba.2007.08.02317935923","DOI":"10.1016\/j.jpba.2007.08.023"},{"key":"2026081121581551766_j_acph-2018-0001_ref_027_w2aab2b8c20b1b7b1ab1ac27Aa","doi-asserted-by":"crossref","unstructured":"27. D. Awotwe-Otoo, C. Agarabi, P. J. Faustino, M. J. Habib, S. Lee, M. A. Khan, and R. B. Shah, Application of quality by design elements for the development and optimization of an analytical method for protamine sulfate, J. Pharm. Biomed. Anal. 62 (2012) 61-67; https:\/\/doi.org\/10.1016\/j.jpba.2012.01.00210.1016\/j.jpba.2012.01.00222316620","DOI":"10.1016\/j.jpba.2012.01.002"},{"key":"2026081121581551766_j_acph-2018-0001_ref_028_w2aab2b8c20b1b7b1ab1ac28Aa","unstructured":"28. 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