Investigating the Physicochemical Stability of Highly Purified Darunavir Ethanolate Extracted from PREZISTA® Tablets
- 113 Downloads
Understanding physicochemical stability of darunavir ethanolate is expected to be of critical importance for the development and manufacturing of high-quality darunavir-related pharmaceutical products. However, there are no enabling monographs for darunavir to illustrate its solid-state chemistry, impurity profile, and assay methods. In addition, the US Pharmacopeia reference standard of darunavir is still not commercially available. It has been also challenging to find reliable vendors to obtain highly purified darunavir ethanolate crystals to conduct the physicochemical stability testing. In the present research, we developed a straightforward and cost-effective approach to extract and purify darunavir ethanolate from PREZISTA® tablets using reverse-engineering and crystallization. Using these highly purified crystals, we thoroughly evaluated the potential risks of degradation and form conversions of darunavir ethanolate at stressed conditions to define the manufacturing and packaging specifications for darunavir-related products. Amorphization was observed under thermal storage caused by desolvation of darunavir ethanolate. The ethanolate-to-hydrate conversion of darunavir was observed at high relative humidity conditions. Moreover, acid/base-induced degradations of darunavir have been investigated herein to determine the possible drug-excipient compatibility issues in formulations. Furthermore, it is of particular interests to allow the production of high-quality darunavir-ritonavir fixed dose combinations for marketing in Africa. Thus, a validated HPLC method was developed according to ICH guideline to simultaneously quantify assays of darunavir and ritonavir in a single injection. In summary, the findings of this study provide important information for pharmaceutical scientists to design and develop reliable formulations and processings for darunavir-related products with improved stability.
KEY WORDSdarunavir ethanolate darunavir hydrate desolvation form conversion darunvair ritonavir combination
The authors would like to thank global fellowship program of United States Pharmacopeial Convention (USP) for supporting this research. Shankari Shivaprasad from USP is thanked for helpful scientific discussions. Dr. Ke Fang is acknowledged for helping with the HPLC method development.
This research received funding from global fellowship program of United States Pharmacopeia Convention (USP).
- 1.Mitsuya H, Maeda K, Das D, Ghosh AK. Development of protease inhibitors and the fight with drug-resistant HIV-1 variants. Advances in Pharmacology: Academic Press; 2008. p. 169–97.Google Scholar
- 4.Ghosh AK, Kincaid JF, Cho W, Walters DE, Krishnan K, Hussain KA, et al. Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett. 1998;8(6):687–90. https://doi.org/10.1016/S0960-894X(98)00098-5. CrossRefPubMedGoogle Scholar
- 10.De Meyer S, Azijn H, Surleraux D, Jochmans D, Tahri A, Pauwels R, et al. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother. 2005;49(6):2314–21. https://doi.org/10.1128/aac.49.6.2314-2321.2005.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Van Gyseghem E, Stokbroekx S, de Armas HN, Dickens J, Vanstockem M, Baert L, et al. Solid state characterization of the anti-HIV drug TMC114: interconversion of amorphous TMC114, TMC114 ethanolate and hydrate. Eur J Pharm Sci. 2009;38(5):489–97. https://doi.org/10.1016/j.ejps.2009.09.013. CrossRefPubMedGoogle Scholar
- 14.Vermeersch HWP, Thone DJC, Janssens LDM-L. US7700645 (B2) - Pseudopolymorphic forms of a HIV protease inhibitor. Tibotec Pharmaceuticals Ltd 2010.Google Scholar
- 15.Byrn S, Pfeiffer R, Ganey M, Hoiberg C, Poochikian G. Pharmaceutical solids: a strategic approach to regulatory considerations. Pharm Res 1995;12(7):945–954. doi: https://doi.org/10.1023/a:1016241927429.
- 16.Byrn SR, Zografi G, Chen X. Solvates and hydrates. Solid state properties of pharmaceutical materials: John Wiley & Sons, Inc.; 2017. p. 38–47.Google Scholar
- 22.Morris K. Structural aspects of hydrates and solvates. In: Brittain HG, editor. Polymorphism in pharmaceutical solids, vol. 1999. New York: Marcel Dekker. p. 125–81.Google Scholar
- 25.Byrn S. Loss of solvent of crystallization. In: Byrn S, Pfeiffer R, Joseph S, editors. Solid-state chemistry of drugs. West Laffayette, IN: SSCI, Inc.; 1999. p. 279–303.Google Scholar
- 26.Byrn S. Chemical transformations in solid state. In: Byrn S, Pfeiffer R, Joseph S, editors. Solid-state chemistry of drugs. West Laffayette, IN: SSCI, Inc.. 1999. p. 305–458.Google Scholar
- 29.Madruga JV, Berger D, McMurchie M, Suter F, Banhegyi D, Ruxrungtham K, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. The Lancet. 370(9581):49–58. https://doi.org/10.1016/s0140-6736(07)61049-6.
- 30.ICH Q2 (R1) Validation of Analytical Procedures: Text and Methodology. 2005.Google Scholar
- 32.Vellanki SRP, Sahu A, Katukuri AK, Vanama V, Kothari S, Ponnekanti S, et al. WO2011048604 (A2)-An improved process for the preparation of darunavir. Matrix Laboratories Limited 2011.Google Scholar
- 33.Acton QA. Therapy and treatment. In: Acton QA, editor. Virus diseases: new insights for the healthcare professional: 2013 Edition: ScholarlyEditions; 2013. p. 921–98.Google Scholar
- 34.Marom E. US2012035142 (A1)-Polymorphs of darunavir. MAPI PHARMA Ltd 2012.Google Scholar
- 37.Fulmer GR, Miller AJM, Sherden NH, Gottlieb HE, Nudelman A, Stoltz BM, et al. NMR chemical shifts of trace impurities: common laboratory solvents, organics, and gases in deuterated solvents relevant to the organometallic chemist. Organometallics. 2010;29(9):2176–9. https://doi.org/10.1021/om100106e.CrossRefGoogle Scholar
- 38.Byrn SR, Zografi G, Chen X. X-ray Powder Diffraction. Solid State Properties of Pharmaceutical Materials: John Wiley & Sons, Inc.; 2017. p. 107–23.Google Scholar
- 41.Phull MS, Rao DR, Kankan RN. WO2011083287 (A2)-Darunavir polymorph and process for preparation thereof. Cipla Limited Curtis, Philip Anthony 2011.Google Scholar
- 42.Byrn S. Solid-state oxidation reactions. In: Byrn S, Pfeiffer R, Joseph S, editors. Solid-state chemistry of drugs. West Laffayette: IN: SSCI, Inc.; 1999. p. 279–303.Google Scholar
- 45.Rao RN, Ramachandra B, Sravan B, Khalid S. LC–MS/MS structural characterization of stress degradation products including the development of a stability indicating assay of darunavir: an anti-HIV drug. J Pharm Biomed Anal. 2014;89:28–33. https://doi.org/10.1016/j.jpba.2013.10.007. CrossRefPubMedGoogle Scholar
- 48.Nie H, Su Y, Zhang M, Song Y, Leone A, Taylor LS, et al. Solid-state spectroscopic investigation of molecular interactions between clofazimine and hypromellose phthalate in amorphous solid dispersions. Mol Pharm. 2016;13:3964–75. https://doi.org/10.1021/acs.molpharmaceut.6b00740.CrossRefPubMedGoogle Scholar
- 53.FDA Reviewer Guidance: Validation of Chromatographic Methods. 5600 Fishers Lane, Rockville, MD 20857: FDA Office of Enforcement; 1994.Google Scholar