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Mitigating Drug Stability Challenges Through Cocrystallization

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Abstract

Drug stability plays a significant role in the pharmaceutical industry from early-phase drug discovery to product registration as well as the entire life cycle of a product. Various formulation approaches have been employed to overcome drug stability issues. These approaches are sometimes time-consuming which ultimately affect the timeline of the product launch and may further require formulation optimization steps, affecting the overall cost. Pharmaceutical cocrystal is a well-established route to fine tune the biopharmaceutical properties of drugs without covalent modification. This article highlights the role of cocrystallization in mitigating the stability issues of challenging drug molecules. Representative case studies wherein the drug stability issue is addressed through pharmaceutical cocrystals have been discussed briefly and are summarized in tabular form. The emphasis has been made on the structural information of cocrystals and understanding the mechanism that improves the stability of the parent drug through cocrystallization. Besides, a guided strategy has been proposed to modulate the stability of drug molecules through cocrystallization approach. Finally, the stability concern of fixed-dose or drug combinations and the challenges associated with cocrystals are also touched.

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References

  1. Aaltonen J, Allesø M, Mirza S, Koradia V, Gordon KC, Rantanen J. Solid form screening - a review. Eur J Pharm Biopharm. 2009;71:23–37.

    Article  CAS  PubMed  Google Scholar 

  2. Hunter CA, Prohens R. Solid form and solubility. CrystEngComm. 2017;19:23–6.

    Article  CAS  Google Scholar 

  3. Singh S, Bakshi M. Guidance on the Cconduct of stress tests to determine inherent stability of drugs. Pharm Technol Asia. 2000;24:1–14.

    Google Scholar 

  4. Bajaj S, Singla D, Sakhuja N. Stability testing of pharmaceutical products. J Appl Pharm Sci. 2012;2:129–38.

    Google Scholar 

  5. Kommanaboyina B, Rhodes CT. Trends in stability testing, with emphasis on stability during distribution and storage. Drug Dev Ind Pharm. 1999;25:857–68.

    Article  CAS  PubMed  Google Scholar 

  6. Alsante KM, Ando A, Brown R, Ensing J, Hatajik TD, Kong W, et al. The role of degradant profiling in active pharmaceutical ingredients and drug products. Adv Drug Deliv Rev. 2007;59:29–37.

    Article  CAS  PubMed  Google Scholar 

  7. Bharate SS. Critical analysis of drug product recalls due to nitrosamine impurities. J Med Chem. 2021;64:2923–36.

    Article  CAS  PubMed  Google Scholar 

  8. FDA. Recalls, market withdrawals, & safety alerts. [Accessed on 2022 Dec 25]. Available from: https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts.

  9. Liu L, Wang J-R, Mei X. Enhancing the stability of active pharmaceutical ingredients by the cocrystal strategy. CrystEngComm. 2022;24:2002–22.

    Article  CAS  Google Scholar 

  10. Berry DJ, Steed JW. Pharmaceutical cocrystals, salts and multicomponent systems; intermolecular interactions and property based design. Adv Drug Deliv Rev. 2017;117:3–24.

    Article  CAS  PubMed  Google Scholar 

  11. Bombicz P, Gruber T, Fischer C, Weber E, Kálmán A. Fine tuning of crystal architecture by intermolecular interactions: synthon engineering. CrystEngComm. 2014;16:3646–54.

    Article  CAS  Google Scholar 

  12. Mukherjee A. Building upon supramolecular synthons: some aspects of crystal engineering. Cryst Growth Des. 2015;15:3076–85.

    Article  CAS  Google Scholar 

  13. Desiraju GR. Crystal engineering: from molecule to crystal. J Am Chem Soc. 2013;135:9952–67.

    Article  CAS  PubMed  Google Scholar 

  14. Shan N, Zaworotko MJ. The role of cocrystals in pharmaceutical science. Drug Discov Today. 2008;13:440–6.

    Article  CAS  PubMed  Google Scholar 

  15. Mir NA, Dubey R, Desiraju GR. Strategy and methodology in the synthesis of multicomponent molecular solids: the quest for higher cocrystals. Acc Chem Res. 2019;52:2210–20.

    Article  CAS  PubMed  Google Scholar 

  16. Bolla G, Nangia A. Pharmaceutical cocrystals: walking the talk. Chem Commun. 2016;52:8342–60.

    Article  CAS  Google Scholar 

  17. Duggirala NK, Perry ML, Almarsson Ö, Zaworotko MJ. Pharmaceutical cocrystals: along the path to improved medicines. Chem Commun. 2016;52:640–55.

    Article  CAS  Google Scholar 

  18. Kale DP, Zode SS, Bansal AK. Challenges in translational development of pharmaceutical cocrystals. J Pharm Sci. 2017;106:457–70.

    Article  CAS  PubMed  Google Scholar 

  19. Arenas-García JI, Herrera-Ruiz D, Morales-Rojas H, Höpfl H. Interrelation of the dissolution behavior and solid-state features of acetazolamide cocrystals. Eur J Pharm Sci. 2017;96:299–308.

    Article  PubMed  Google Scholar 

  20. Batisai E, Ayamine A, Kilinkissa OEY, Báthori NB. Melting point-solubility-structure correlations in multicomponent crystals containing fumaric or adipic acid. CrystEngComm. 2014;16:9992–8.

    Article  CAS  Google Scholar 

  21. Wang C, Sun CC. The landscape of mechanical properties of molecular crystals. CrystEngComm. 2020;22:1149–53.

    Article  CAS  Google Scholar 

  22. Mishra MK, Ramamurty U, Desiraju GR. Mechanical property design of molecular solids. Curr Opin Solid State Mater Sci. 2016;20:361–70.

    Article  CAS  Google Scholar 

  23. Saha S, Mishra MK, Reddy CM, Desiraju GR. From molecules to interactions to crystal engineering: mechanical properties of organic solids. Acc Chem Res. 2018;51:2957–67.

    Article  CAS  PubMed  Google Scholar 

  24. Chavan RB, Thipparaboina R, Yadav B, Shastri NR. Continuous manufacturing of co-crystals: challenges and prospects. Drug Deliv Transl Res. 2018;8:1726–39.

    Article  CAS  PubMed  Google Scholar 

  25. Kawabata Y, Yamamoto K, Debari K, Onoue S, Yamada S. Novel crystalline solid dispersion of tranilast with high photostability and improved oral bioavailability. Eur J Pharm Sci. 2010;39:256–62.

    Article  CAS  PubMed  Google Scholar 

  26. Naohide Hori, Makiko Fujii, Kazuhiko Ikegami, Denichi Momose, Noriyasu Saito MM. Effect of UV-absorbing agents on photodegradation of tranilast in oily gels. Chem Pharm Bull. 1994;17:1460–2.

  27. Shaikh R, Singh R, Walker GM, Croker DM. Pharmaceutical cocrystal drug products: an outlook on product development. Trends Pharmacol Sci. 2018;39:1033–48.

    Article  CAS  PubMed  Google Scholar 

  28. Bolla G, Sarma B, Nangia AK. Crystal engineering of pharmaceutical cocrystals in the discovery and development of improved drugs. Chem Rev. 2022;122:11514–603.

    Article  CAS  PubMed  Google Scholar 

  29. Kavanagh ON, Croker DM, Walker GM, Zaworotko MJ. Pharmaceutical cocrystals: from serendipity to design to application. Drug Discov Today. 2019;24:796–804.

    Article  CAS  PubMed  Google Scholar 

  30. Guo M, Sun X, Chen J, Cai T. Pharmaceutical cocrystals: a review of preparations, physicochemical properties and applications. Acta Pharm Sin B. 2021;11:2537–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Benzaria S, Pélicano H, Johnson R, Maury G, Imbach J-L, Aubertin A-M, et al. Synthesis, in vitro antiviral evaluation, and stability studies of bis(S-acyl-2-thioethyl) ester derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as potential PMEA prodrugs with improved oral bioavailability. J Med Chem. 1996;39:4958–65.

    Article  CAS  PubMed  Google Scholar 

  32. Yuan L-C, Dahl TC, Oliyai R. Effect of carbonate salts on the kinetics of acid-catalyzed dimerization of adefovir dipivoxil. Pharm Res. 2000;17:1098–103.

    Article  CAS  PubMed  Google Scholar 

  33. Gao Y, Gao J, Liu Z, Kan H, Zu H, Sun W, et al. Coformer selection based on degradation pathway of drugs: a case study of adefovir dipivoxil-saccharin and adefovir dipivoxil-nicotinamide cocrystals. Int J Pharm. 2012;438:327–35.

    Article  CAS  PubMed  Google Scholar 

  34. Gao Y, Zu H, Zhang J. Enhanced dissolution and stability of adefovir dipivoxil by cocrystal formation. J Pharm Pharmacol. 2011;63:483–90.

    Article  CAS  PubMed  Google Scholar 

  35. Lin RZ, Sun PJ, Tao Q, Yao J, Chen JM, Lu TB. Mechanism study on stability enhancement of adefovir dipivoxil by cocrystallization: degradation kinetics and structure-stability correlation. Eur J Pharm Sci. 2016;85:141–8.

    Article  CAS  PubMed  Google Scholar 

  36. Langtry HD, Grant SM, Goa KL. Famotidine Drugs. 1989;38:551–90.

    Article  CAS  PubMed  Google Scholar 

  37. Islam MS, Narurkar MM. Solubility, stability and ionization behaviour of famotidine. J Pharm Pharmacol. 2011;45:682–6.

    Article  Google Scholar 

  38. Saikia B, Sultana N, Kaushik T, Sarma B. Engineering a remedy to improve phase stability of famotidine under physiological pH environments. Cryst Growth Des. 2019;19:6472–81.

    Article  CAS  Google Scholar 

  39. Jivani SG, Stella VJ. Mechanism of decarboxylation of p-aminosalicylic acid. J Pharm Sci. 1985;74:1274–82.

    Article  CAS  PubMed  Google Scholar 

  40. Drozd KV, Manin AN, Churakov AV, Perlovich GL. Drug-drug cocrystals of antituberculous 4-aminosalicylic acid: screening, crystal structures, thermochemical and solubility studies. Eur J Pharm Sci. 2017;99:228–39.

    Article  CAS  PubMed  Google Scholar 

  41. Vangala VR, Chow PS, Tan RBH. Co-crystals and co-crystal hydrates of the antibiotic nitrofurantoin: structural studies and physicochemical properties. Cryst Growth Des. 2012;12:5925–38.

    Article  CAS  Google Scholar 

  42. Vangala VR, Chow PS, Tan RBH. Characterization, physicochemical and photo-stability of a co-crystal involving an antibiotic drug, nitrofurantoin, and 4-hydroxybenzoic acid. CrystEngComm. 2011;13:759–62.

    Article  CAS  Google Scholar 

  43. Hao X, Li J, Wang C, Zhao X, He X, Sun CC. Profoundly improved photostability of dimetronidazole by cocrystallization. CrystEngComm. 2022;24:6165–71.

    Article  CAS  Google Scholar 

  44. Zeina T, Masaru K, Masami T, Asahi Y. X-ray structures of two photodimers of 2-methyl-1, 4-naphthoquinone (menadione). Chem Pharm Bull (Tokyo). 1993;41:2183–6.

    Article  Google Scholar 

  45. Werbin H, Thomas SE. Photochemistry of electron-transport quinones. I. Model studies with 2-methyl-1,4-naphthoquinone (vitamin K3). J Am Chem Soc. 2002;90:7296–301.

  46. Zhu B, Wang JR, Zhang Q, Mei X. Improving dissolution and photostability of vitamin K3 via cocrystallization with naphthoic acids and sulfamerazine. Cryst Growth Des. 2016;16:483–92.

    Article  CAS  Google Scholar 

  47. Ishida T, In Y, Inoue M, Ueno Y, Tanaka C, Hamanaka N. Structural elucidation of epalrestat(ONO-2235), a potent aldose reductase inhibitor, and isomerization of its double bonds. Tetrahedron Lett. 1989;30:959–62.

    Article  CAS  Google Scholar 

  48. Putra OD, Umeda D, Nugraha YP, Nango K, Yonemochi E, Uekusa H. Simultaneous improvement of epalrestat photostability and solubility via cocrystallization: a case study. Cryst Growth Des. 2018;18:373–9.

    Article  CAS  Google Scholar 

  49. Sun J, Jia L, Wang M, Liu Y, Li M, Han D, et al. Novel drug–drug multicomponent crystals of epalrestat–metformin: improved solubility and photostability of epalrestat and reduced hygroscopicity of metformin. Cryst Growth Des. 2022;22:1005–16.

    Article  CAS  Google Scholar 

  50. Shinozaki T, Ono M, Higashi K, Moribe K. A novel drug-drug cocrystal of levofloxacin and metacetamol: reduced hygroscopicity and improved photostability of levofloxacin. J Pharm Sci. 2019;108:2383–90.

    Article  CAS  PubMed  Google Scholar 

  51. Geng N, Chen J-M, Li Z-J, Jiang L, Lu T-B. Approach of cocrystallization to improve the solubility and photostability of tranilast. Cryst Growth & Des. 2013;13:3546–53.

    Article  CAS  Google Scholar 

  52. Nagai H, Kikuchi M, Nagano H, Shiba M. The stability of nicorandil in aqueous solution. I. Kinetics and mechanism of decomposition of N-(2-hydroxyethyl)nicotinamide nitrate (ester) in aqueous solution. Chem Pharm Bull. 1984;32:1063–70.

  53. Guo C, Zhang Q, Zhu B, Zhang Z, Bao J, Ding Q, et al. Pharmaceutical cocrystals of nicorandil with enhanced chemical stability and sustained release. Cryst Growth Des. 2020;20:6995–7005.

    Article  CAS  Google Scholar 

  54. Kim H, Likhari P, Parker D, Statkevich P, Marco A, Lin CC, et al. High-performance liquid chromatographic analysis and stability of anti-tumor agent temozolomide in human plasma. J Pharm Biomed Anal. 2001;24:461–8.

    Article  CAS  PubMed  Google Scholar 

  55. Babu NJ, Sanphui P, Nangia A. Crystal engineering of stable temozolomide cocrystals. Chem - An Asian J. 2012;7:2274–85.

    Article  CAS  Google Scholar 

  56. Jacobs HJC. Photochemistry of conjugated trienes: vitamin D revisited. Pure Appl Chem. 1995;67:63–70.

    Article  CAS  Google Scholar 

  57. Tan ES, Tham FS, Okamura WH. Vitamin D1. Chem Commun. 2000;2345–6.

  58. Wang JR, Zhou C, Yu X, Mei X. Stabilizing vitamin D3 by conformationally selective co-crystallization. Chem Commun. 2014;50:855–8.

    Article  CAS  Google Scholar 

  59. Yu Q, Yan Z, Bao J, Wang JR, Mei X. Taming photo-induced oxidation degradation of dihydropyridine drugs through cocrystallization. Chem Commun. 2017;53:12266–9.

    Article  CAS  Google Scholar 

  60. Suresh K, Goud NR, Nangia A. Andrographolide: solving chemical instability and poor solubility by means of cocrystals. Chem - An Asian J. 2013;8:3032–41.

    Article  CAS  Google Scholar 

  61. Narayanam M, Handa T, Sharma P, Jhajra S, Muthe PK, Dappili PK, et al. Critical practical aspects in the application of liquid chromatography–mass spectrometric studies for the characterization of impurities and degradation products. J Pharm Biomed Anal. 2014;87:191–217.

    Article  CAS  PubMed  Google Scholar 

  62. Narayanam M, Sahu A, Singh S. Use of LC–MS/TOF, LC–MSn, NMR and LC–NMR in characterization of stress degradation products: application to cilazapril. J Pharm Biomed Anal. 2015;111:190–203.

    Article  CAS  PubMed  Google Scholar 

  63. Torres S, Brown R, Szucs R, Hawkins JM, Zelesky T, Scrivens G, et al. The application of electrochemistry to pharmaceutical stability testing - comparison with in silico prediction and chemical forced degradation approaches. J Pharm Biomed Anal. 2015;115:487–501.

    Article  CAS  PubMed  Google Scholar 

  64. Kleinman MH, Baertschi SW, Alsante KM, Reid DL, Mowery MD, Shimanovich R, et al. In silico prediction of pharmaceutical degradation pathways: a benchmarking study. Mol Pharm. 2014;11:4179–88.

    Article  CAS  PubMed  Google Scholar 

  65. Parenty ADC, Button WG, Ott MA. An expert system to predict the forced degradation of organic molecules. Mol Pharm. 2013;10:2962–74.

    Article  CAS  PubMed  Google Scholar 

  66. Socorro IM, Taylor K, Goodman JM. ROBIA: a reaction prediction program. Org Lett. 2005;7:3541–4.

    Article  CAS  PubMed  Google Scholar 

  67. Pole DL, Ando HY, Murphy ST. Prediction of drug degradants using DELPHI: an expert system for focusing knowledge. Mol Pharm. 2007;4:539–49.

    Article  CAS  PubMed  Google Scholar 

  68. Karimi-Jafari M, Padrela L, Walker GM, Croker DM. Creating cocrystals: a review of pharmaceutical cocrystal preparation routes and applications. Cryst Growth Des. 2018;18:6370–87.

    Article  CAS  Google Scholar 

  69. Moradiya HG, Islam MT, Scoutaris N, Halsey SA, Chowdhry BZ, Douroumis D. Continuous manufacturing of high quality pharmaceutical cocrystals integrated with process analytical tools for in-line process control. Cryst Growth Des. 2016;16:3425–34.

    Article  CAS  Google Scholar 

  70. Thakral NK, Zanon RL, Kelly RC, Thakral S. Applications of powder X-ray diffraction in small molecule pharmaceuticals: achievements and aspirations. J Pharm Sci. 2018;107:2969–82.

    Article  CAS  PubMed  Google Scholar 

  71. Vogt FG, Clawson JS, Strohmeier M, Edwards AJ, Pham TN, Watson SA. Solid-state NMR analysis of organic cocrystals and complexes. Cryst Growth Des. 2009;9:921–37.

    Article  CAS  Google Scholar 

  72. Yamashita H, Hirakura Y, Yuda M, Terada K. Coformer screening using thermal analysis based on binary phase diagrams. Pharm Res. 2014;31:1946–57.

    Article  CAS  PubMed  Google Scholar 

  73. Aaltonen J, Gordon KC, Strachan CJ, Rades T. Perspectives in the use of spectroscopy to characterise pharmaceutical solids. Int J Pharm. 2008;364:159–69.

    Article  CAS  PubMed  Google Scholar 

  74. ICH Q1A(R2):Stability testing of new drug substances and products. Q1A(R2). 2003 [Accessed on 2022 Jan 10]. Available from: https://database.ich.org/sites/default/files/Q1A%28R2%29 Guideline.pdf.

  75. Battini S, Mannava MKC, Nangia A. Improved stability of tuberculosis drug fixed-dose combination using isoniazid-caffeic acid and vanillic acid cocrystal. J Pharm Sci. 2018;107:1667–79.

    Article  CAS  PubMed  Google Scholar 

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Funding

Dr. Jamshed Haneef gratefully acknowledges the University Grant Commission (UGC), New Delhi, India, for providing financial support in the form of a Start-up research grant [BSR: 30–520/2020].

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110 062, India

    Jamshed Haneef, Mohd Amir & Nadeem Ahmed Sheikh

  2. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160 014, India

    Renu Chadha

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  1. Jamshed Haneef
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JH has conceptualized and written the original draft; NAS performed the data curation; MA and RC have reviewed and edited the final draft. All authors have approved the final version of the manuscript.

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Correspondence to Jamshed Haneef.

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Haneef, J., Amir, M., Sheikh, N.A. et al. Mitigating Drug Stability Challenges Through Cocrystallization. AAPS PharmSciTech 24, 62 (2023). https://doi.org/10.1208/s12249-023-02522-x

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