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Enhanced Physical Stability and Synchronized Release of Febuxostat and Indomethacin in Coamorphous Solids

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Abstract

Coamorphous formulation, a homogeneous monophasic amorphous system composed of multiple components, has been demonstrated as an effective approach for delivering drugs with poor aqueous solubility. In this study, we prepared the coamorphous system composed of two poorly soluble drugs febuxostat (FEB) and indomethacin (IMC) by using cryogenic milling. The combination of these two drugs in the coamorphous form can attain a synergistic effect, especially on gout therapy. Coamorphous solid of FEB and IMC in 1:1 molar ratio exhibited superior physical stability compared with the individual amorphous components, as evidenced by X-ray powder diffractions after 30 days of storage at ambient and elevated temperature. In addition, the FEB–IMC coamorphous system has been demonstrated to show enhanced dissolution performance. The intrinsic dissolution rates of two components in the coamorphous system exhibited the synchronized drug release. Based on the FT-IR spectroscopy, the excellent physical stability and synchronized release of FEB–IMC coamorphous system could be attributed to the heterodimer structure formed by strong hydrogen bonding interactions between these drugs. Furthermore, the supersaturation potential of FEB–IMC coamorphous solids was also investigated through the cosolvent quenching method. The FEB–IMC coamorphous system can effectively inhibit the fast crystallization of FEB in the supersaturated solution. However, the maximum achievable supersaturation of IMC in the coamorphous system decreases to only one fifth of that achieved for the pure amorphous IMC. These results are relevant for understanding the physical stability and complex solution behaviors of the coamorphous formulation.

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References

  1. Di L, Fish PV, Mano T. Bridging solubility between drug discovery and development. Drug Discov Today. 2012;17:486–95.

    CAS  PubMed  Google Scholar 

  2. Murdande SB, Pikal MJ, Shanker RM, Bogner RH. Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis. J Pharm Sci. 2010;99:1254–64.

    CAS  PubMed  Google Scholar 

  3. Taylor LS, Zhang GG. Physical chemistry of supersaturated solutions and implications for oral absorption. Adv Drug Deliv Rev. 2016;101:122–42.

    CAS  PubMed  Google Scholar 

  4. Wyttenbach N, Kuentz M. Glass-forming ability of compounds in marketed amorphous drug products. Eur J Pharm Biopharm. 2017;112:204–8.

    CAS  PubMed  Google Scholar 

  5. Vasconcelos T, Marques S, das Neves J, Sarmento B. Amorphous solid dispersions: rational selection of a manufacturing process. Adv Drug Deliv Rev. 2016;100:85–101.

    CAS  PubMed  Google Scholar 

  6. Shi Q, Moinuddin SM, Cai T. Advances in coamorphous drug delivery systems. Acta Pharm Sin B. 2019;9:19–35.

    PubMed  Google Scholar 

  7. Newman A, Reutzel-Edens SM, Zografi G. Coamorphous active pharmaceutical ingredient-small molecule mixtures: considerations in the choice of coformers for enhancing dissolution and oral bioavailability. J Pharm Sci. 2018;107:5–17.

    CAS  PubMed  Google Scholar 

  8. Dengale SJ, Grohganz H, Rades T, Lobmann K. Recent advances in co-amorphous drug formulations. Adv Drug Deliv Rev. 2016;100:116–25.

    CAS  PubMed  Google Scholar 

  9. Chavan RB, Thipparaboina R, Kumar D, Shastri NR. Coamorphous systems: a product development perspective. Int J Pharm. 2016;515:403–15.

    CAS  PubMed  Google Scholar 

  10. Korhonen O, Pajula K, Laitinen R. Rational excipient selection for co-amorphous formulations. Exp Opin Drug Del. 2017;14:551–69.

    CAS  Google Scholar 

  11. Cottarel G, Wierzbowski J. Combination drugs, an emerging option for antibacterial therapy. Trends Biotechnol. 2007;25:547–55.

    CAS  PubMed  Google Scholar 

  12. Keith CT, Borisy AA, Stockwell BR. Innovation: multicomponent therapeutics for networked systems. Nat Rev Drug Discov. 2005;4:71–8.

    CAS  PubMed  Google Scholar 

  13. Lakshman JP, Cao Y, Kowalski J, SeraJuddin AT. Application of melt extrusion in the development of a physically and chemically stable high-energy amorphous solid dispersion of a poorly water-soluble drug. Mol Pharm. 2008;5:994–1002.

    CAS  PubMed  Google Scholar 

  14. Descamps M, Willart JF. Perspectives on the amorphization/milling relationship in pharmaceutical materials. Adv Drug Deliv Rev. 2016;100:51–66.

    CAS  PubMed  Google Scholar 

  15. Trasi NS, Byrn SR. Mechanically induced amorphization of drugs: a study of the thermal behavior of cryomilled compounds. AAPS PharmSciTech. 2012;13:772–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Moinuddin SM, Ruan S, Huang Y, Gao Q, Shi Q, et al. Facile formation of co-amorphous atenolol and hydrochlorothiazide mixtures via cryogenic-milling: enhanced physical stability, dissolution and pharmacokinetic profile. Int J Pharm. 2017;532:393–400.

    CAS  PubMed  Google Scholar 

  17. Willart JF, Descamps M. Solid state amorphization of pharmaceuticals. Mol Pharm. 2008;5:905–20.

    CAS  PubMed  Google Scholar 

  18. Khosravan R, Wu JT, Joseph-Ridge N, Vernillet L. Pharmacokinetic interactions of concomitant administration of febuxostat and NSAIDs. J Clin Pharmacol. 2006;46:855–66.

    CAS  PubMed  Google Scholar 

  19. Maddileti D, Jayabun SK, Nangia A. Soluble cocrystals of the xanthine oxidase inhibitor febuxostat. Cryst Growth Des. 2013;13:3188–96.

    CAS  Google Scholar 

  20. Sharma OP, Patel V, Mehta T. Design of experiment approach in development of febuxostat nanocrystal: application of Soluplus® as stabilizer. Powder Technol. 2016;302:396–405.

    CAS  Google Scholar 

  21. Conaghan PG, Day RO. Risks and benefits of drugs used in the management and prevention of gout. Drug Saf. 1994;11:252–8.

    CAS  PubMed  Google Scholar 

  22. Löbmann K, Strachan C, Grohganz H, Rades T, Korhonen O, et al. Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions. Eur J Pharm Biopharm. 2012;81:159–69.

    PubMed  Google Scholar 

  23. Jensen KT, Larsen FH, Cornett C, Lobmann K, Grohganz H, et al. Formation mechanism of coamorphous drug–amino acid mixtures. Mol Pharm. 2015;12:2484–92.

    CAS  PubMed  Google Scholar 

  24. Qiu JB, Li G, Sheng Y, Zhu MR. Quantification of febuxostat polymorphs using powder X-ray diffraction technique. J Pharm Biomed Anal. 2015;107:298–303.

    CAS  PubMed  Google Scholar 

  25. Wu T, Yu L. Surface crystallization of indomethacin below Tg. Pharm Res. 2006;23:2350–5.

    CAS  PubMed  Google Scholar 

  26. Zhu L, Brian CW, Swallen SF, Straus PT, Ediger MD, et al. Surface self-diffusion of an organic glass. Phys Rev Lett. 2011;106:256103.

    CAS  PubMed  Google Scholar 

  27. Chieng N, Aaltonen J, Saville D, Rades T. Physical characterization and stability of amorphous indomethacin and ranitidine hydrochloride binary systems prepared by mechanical activation. Eur J Pharm Biopharm. 2009;71:47–54.

    CAS  PubMed  Google Scholar 

  28. Löbmann K, Grohganz H, Laitinen R, Strachan C, Rades T. Amino acids as co-amorphous stabilizers for poorly water soluble drugs—part 1: preparation, stability and dissolution enhancement. Eur J Pharm Biopharm. 2013;85:873–81.

    PubMed  Google Scholar 

  29. Lenz E, Jensen KT, Blaabjerg LI, Knop K, Grohganz H, et al. Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin–arginine. Eur J Pharm Biopharm. 2015;96:44–52.

    CAS  PubMed  Google Scholar 

  30. Qian S, Heng WL, Wei YF, Zhang JJ, Gao Y. Coamorphous lurasidone hydrochloride–saccharin with charge-assisted hydrogen bonding interaction shows improved physical stability and enhanced dissolution with pH-independent solubility behavior. Cryst Growth Des. 2015;15:2920–8.

    CAS  Google Scholar 

  31. Gao Y, Liao J, Qi X, Zhang J. Coamorphous repaglinide–saccharin with enhanced dissolution. Int J Pharm. 2013;450:290–5.

    CAS  PubMed  Google Scholar 

  32. Kini A, Patel SB. Phase behavior, intermolecular interaction, and solid state characterization of amorphous solid dispersion of Febuxostat. Pharm Dev Technol. 2017;22:45–57.

    CAS  PubMed  Google Scholar 

  33. Taylor LS, Zografi G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res. 1997;14:1691–8.

    CAS  PubMed  Google Scholar 

  34. Löbmann K, Laitinen R, Grohganz H, Gordon KC, Strachan C, Rades T. Coamorphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen. Mol Pharm. 2011;8:1919–28.

    PubMed  Google Scholar 

  35. Löbmann K, Laitinen R, Grohganz H, Strachan C, Rades T, Gordon KC. A theoretical and spectroscopic study of co-amorphous naproxen and indomethacin. Int J Pharm. 2013;453:80–7.

    PubMed  Google Scholar 

  36. Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48:27–42.

    CAS  PubMed  Google Scholar 

  37. Jung MS, Kim JS, Kim MS, Alhalaweh A, Cho W, et al. Bioavailability of indomethacin–saccharin cocrystals. J Pharm Pharmacol. 2010;62:1560–8.

    CAS  PubMed  Google Scholar 

  38. Skieneh JM, Sathisaran I, Dalvi SV, Rohani S. Co-amorphous form of curcumin–folic acid dihydrate with increased dissolution rate. Cryst Growth Des. 2017;17:6273–80.

    CAS  Google Scholar 

  39. Alleso M, Chieng N, Rehder S, Rantanen J, Rades T, et al. Enhanced dissolution rate and synchronized release of drugs in binary systems through formulation: amorphous naproxen–cimetidine mixtures prepared by mechanical activation. J Control Release. 2009;136:45–53.

    PubMed  Google Scholar 

  40. Saboo S, Mugheirbi NA, Zemlyanov DY, Kestur US, Taylor LS. Congruent release of drug and polymer: a “sweet spot” in the dissolution of amorphous solid dispersions. J Control Release. 2019;298:68–82.

    CAS  PubMed  Google Scholar 

  41. Laitinen R, Lobmann K, Grohganz H, Priemel P, Strachan CJ, et al. Supersaturating drug delivery systems: the potential of co-amorphous drug formulations. Int J Pharm. 2017;532:1–12.

    CAS  PubMed  Google Scholar 

  42. Jackson MJ, Kestur US, Hussain MA, Taylor LS. Dissolution of danazol amorphous solid dispersions: supersaturation and phase behavior as a function of drug loading and polymer type. Mol Pharm. 2016;13:223–31.

    CAS  PubMed  Google Scholar 

  43. Raina SA, Zhang GG, Alonzo DE, Wu J, Zhu D, et al. Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs. J Pharm Sci. 2014;103:2736–48.

    CAS  PubMed  Google Scholar 

  44. Alhalaweh A, Bergstrom CAS, Taylor LS. Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations. J Control Release. 2016;229:172–82.

    CAS  PubMed  Google Scholar 

  45. Li N, Taylor LS. Tailoring supersaturation from amorphous solid dispersions. J Control Release. 2018;279:114–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Almeida e Sousa L, Reutzel-Edens SM, Stephenson GA, Taylor LS. Assessment of the amorphous “solubility” of a group of diverse drugs using new experimental and theoretical approaches. Mol Pharm. 2015;12:484–95.

    CAS  PubMed  Google Scholar 

  47. Mosquera-Giraldo LI, Taylor LS. Glass-liquid phase separation in highly supersaturated aqueous solutions of telaprevir. Mol Pharm. 2015;12:496–503.

    CAS  PubMed  Google Scholar 

  48. Wallace AF, Hedges LO, Fernandez-Martinez A, Raiteri P, Gale JD, et al. Microscopic evidence for liquid–liquid separation in supersaturated CaCO3 solutions. Science. 2013;341:885–9.

    CAS  PubMed  Google Scholar 

  49. Lafferrère L, Hoff C, Veesler S. Study of liquid–liquid demixing from drug solution. J Cryst Growth. 2004;269:550–7.

    Google Scholar 

  50. Ilevbare GA, Taylor LS. Liquid–liquid phase separation in highly supersaturated aqueous solutions of poorly water-soluble drugs: implications for solubility enhancing formulations. Cryst Growth Des. 2013;13:1497–509.

    CAS  Google Scholar 

  51. Indulkar AS, Box KJ, Taylor R, Ruiz R, Taylor LS. pH-dependent liquid–liquid phase separation of highly supersaturated solutions of weakly basic drugs. Mol Pharm. 2015;12:2365–77.

    CAS  PubMed  Google Scholar 

  52. Trasi NS, Taylor LS. Thermodynamics of highly supersaturated aqueous solutions of poorly water-soluble drugs—impact of a second drug on the solution phase behavior and implications for combination products. J Pharm Sci. 2015;104:2583–93.

    CAS  PubMed  Google Scholar 

  53. Trasi NS, Taylor LS. Dissolution performance of binary amorphous drug combinations—impact of a second drug on the maximum achievable supersaturation. Int J Pharm. 2015;496:282–90.

    CAS  PubMed  Google Scholar 

  54. Arca HC, Mosquera-Giraldo LI, Dahal D, Taylor LS, Edgar KJ. Anti-HIV amorphous solid dispersions: nature and mechanisms of impacts of drugs on each other's solution concentrations. Mol Pharm. 2017;14:3617–27.

    CAS  PubMed  Google Scholar 

  55. Ilevbare GA, Liu HY, Edgar KJ, Taylor LS. Maintaining supersaturation in aqueous drug solutions: impact of different polymers on induction times. Cryst Growth Des. 2013;13:740–51.

    CAS  Google Scholar 

  56. Curatolo W, Nightingale JA, Herbig SM. Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu. Pharm Res. 2009;26:1419–31.

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful for financial support of this work by the National Science Foundation of China (Nos. 81872813 and 81803452), the State Project for Essential Drug Research and Development (No. 2017ZX09301075), the Program of State Key Laboratory of Natural Medicines–China Pharmaceutical University (No. SKLNMZZCX201826), and the 111 project (B16046).

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Author notes

  1. Sakib M. Moinuddin and Qin Shi contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Sakib M. Moinuddin, Qin Shi, Jun Tao, Minshan Guo, Jie Zhang, Qian Xue, Sida Ruan & Ting Cai

  2. R&D Department, Guilin Pharmaceutical Company Limited, Guilin, 541994, China

    Sakib M. Moinuddin

  3. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China

    Ting Cai

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  1. Sakib M. Moinuddin
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Moinuddin, S.M., Shi, Q., Tao, J. et al. Enhanced Physical Stability and Synchronized Release of Febuxostat and Indomethacin in Coamorphous Solids. AAPS PharmSciTech 21, 41 (2020). https://doi.org/10.1208/s12249-019-1578-6

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