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Hot Melt Extrusion: an Emerging Green Technique for the Synthesis of High-Quality Pharmaceutical Cocrystals

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Abstract

Hot melt extrusion (HME) is emerging as a continuous, single-step, scalable, and industrially feasible process for the production of cocrystals. HME has gained momentum as a continuous and solvent-free process in the manufacturing of cocrystals. The incorporation of the matrix and the use of process analytical tool (PAT) for real-time monitoring further facilitate the process. The advantages and disadvantages of various cocrystal production methods including HME process are provided in the manuscript. Besides, an overview of the HME process and equipment, critical process parameters, and PAT for real-time monitoring of process has been reviewed in this article. Finally, recent literature related to the cocrystal synthesis via HME has been presented critically. This review provides useful information for the synthesis of the cocrystals using HME process.

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References

  1. 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(10):6370–87.

    Article  CAS  Google Scholar 

  2. Kavanagh ON, Croker DM, Walker GM, Zaworotko MJ. Pharmaceutical cocrystals: from serendipity to design to application. Drug Discov Today. 2019;24(3):796–4.

    Article  CAS  PubMed  Google Scholar 

  3. Duggirala NK, Lacasse SM, Zaworotko MJ, Krzyzaniak JF, Arora KK. Pharmaceutical cocrystals: formulation approaches to develop robust drug products. Cryst Growth Des. 2020;20:617–26.

    Article  CAS  Google Scholar 

  4. Kumar S, Prakash O, Gupta A, Singh S. Solvent-free methods for co-crystal synthesis: a review. Curr Org Synth. 2019;16:385–97.

    Article  CAS  PubMed  Google Scholar 

  5. Wu X, Wang Y, Xue J, Liu J, Qin J, Hong Z, et al. Solid phase drug-drug pharmaceutical co-crystal formed between pyrazinamide and diflunisal: structural characterization based on terahertz/Raman spectroscopy combining with DFT calculation. Spectrochim Acta A Mol Biomol Spectrosc. 2020;118265.

  6. Allu S, Bolla G, Tothadi S, Nangia AK. Novel pharmaceutical cocrystals and salts of bumetanide. Cryst Growth Des. 2019;20(2):793–803.

    Article  CAS  Google Scholar 

  7. Dai XL, Chen JM, Lu TB. Pharmaceutical cocrystallization: an effective approach to modulate the physicochemical properties of solid-state drugs. CrystEngComm. 2018;20(36):5292–316.

    Article  CAS  Google Scholar 

  8. Almansa C, Frampton CS, Vela JM, Whitelock S, Plata-Salamán CR. Co-crystals as a new approach to multimodal analgesia and the treatment of pain. J Pain Res. 2019;12:2679–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shaikh R, Singh R, Walker GM, Croker DM. Pharmaceutical cocrystal drug products: an outlook on product development. Trends Pharmacol Sci. 2018;39(12):1033–48.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang C, Xiong Y, Jiao F, Wang M, Li H. Redefining the term of “cocrystal” and broadening its intention. Cryst Growth Des. 2019;19(3):1471–8.

    Article  CAS  Google Scholar 

  11. Yousef MA, Vangala VR. Pharmaceutical cocrystals: molecules, crystals, formulations, medicines. Cryst Growth Des. 2019;19(12):7420–38.

    Article  CAS  Google Scholar 

  12. Kumari N, Bhattacharya B, Roy P, Michalchuk AA, Emmerling F, Ghosh A. Enhancing the pharmaceutical properties of pirfenidone by mechanochemical cocrystallization. Cryst Growth Des. 2019;19(11):6482–92.

    Article  CAS  Google Scholar 

  13. Panzade P, Shendarkar G. Superior solubility and dissolution of zaltoprofen via pharmaceutical cocrystals. Turk J Pharm Sci. 2019;16(3):310–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Peltonen L. Practical guidelines for the characterization and quality control of pure drug nanoparticles and nano-cocrystals in the pharmaceutical industry. Adv Drug Deliv Rev. 2018;131:101–15.

    Article  CAS  PubMed  Google Scholar 

  15. Ren S, Liu M, Hong C, Li G, Sun J, Wang J, et al. The effects of pH, surfactant, ion concentration, coformer, and molecular arrangement on the solubility behavior of myricetin cocrystals. Acta Pharm Sin B. 2019;9(1):59–73.

    Article  PubMed  Google Scholar 

  16. Panzade P, Shendarkar G, Shaikh S, Rathi PB. Pharmaceutical cocrystal of piroxicam: design, formulation and evaluation. Adv Pharm Bull. 2017;7(3):399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Panzade PS, Shendarkar GR. Pharmaceutical cocrystal: an antique and multifaceted approach. Curr Drug Deliv. 2017;14(8):1097–105.

    Article  CAS  PubMed  Google Scholar 

  18. Douroumis D, Ross SA, Nokhodchi A. Advanced methodologies for cocrystal synthesis. Adv Drug Deliv Rev. 2017;117:178–95.

    Article  CAS  PubMed  Google Scholar 

  19. Vemuri VD, Lankalapalli S. Insight into concept and progress on pharmaceutical co-crystals: an overview. Indian J Pharm Educ Res. 2019;53:s522–38.

    Article  CAS  Google Scholar 

  20. Zhou J, Li L, Zhang H, Xu J, Huang D, Gong N, et al. Crystal structures, dissolution and pharmacokinetic study on a novel phosphodiesterase-4 inhibitor chlorbipram cocrystals. Int J Pharm. 2020;576:118984.

    Article  CAS  PubMed  Google Scholar 

  21. Jambhekar SS, Breen PJ. Drug dissolution: significance of physicochemical properties and physiological conditions. Drug Discov Today. 2013;18(23–24):1173–84.

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Kale DP, Zode SS, Bansal AK. Challenges in translational development of pharmaceutical cocrystals. J Pharm Sci. 2017;106(2):457–70.

    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(6):1726–39.

    Article  CAS  PubMed  Google Scholar 

  25. Bolla G, Nangia A. Pharmaceutical cocrystals: walking the talk. Chem Commun. 2016;52(54):8342–60.

    Article  CAS  Google Scholar 

  26. Kuminek G, Cao F, da Rocha AB, Cardoso SG, Rodríguez-Hornedo N. Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5. Adv Drug Deliv Rev. 2016;101:143–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pindelska E, Sokal A, Kolodziejski W. Pharmaceutical cocrystals, salts and polymorphs: advanced characterization techniques. Adv Drug Deliv Rev. 2017;117:111–46.

    Article  CAS  PubMed  Google Scholar 

  28. Gajda M, Nartowski KP, Pluta J, Karolewicz B. Continuous, one-step synthesis of pharmaceutical cocrystals via hot melt extrusion from neat to matrix-assisted processing–state of the art. Int J Pharm. 2019;558:426–40.

    Article  CAS  PubMed  Google Scholar 

  29. Vioglio PC, Chierotti MR, Gobetto R. Pharmaceutical aspects of salt and cocrystal forms of APIs and characterization challenges. Adv Drug Deliv Rev. 2017;117:86–110.

    Article  CAS  Google Scholar 

  30. Patil H, Tiwari RV, Repka MA. Hot-melt extrusion: from theory to application in pharmaceutical formulation. AAPS PharmSciTech. 2016;17(1):20–42.

    Article  CAS  PubMed  Google Scholar 

  31. Hwang I, Kang CY, Park JB. Advances in hot-melt extrusion technology toward pharmaceutical objectives. J Pharm Investig. 2017;47(2):123–32.

    Article  CAS  Google Scholar 

  32. Sarabu S, Bandari S, Kallakunta VR, Tiwari R, Patil H, Repka MA. An update on the contribution of hot-melt extrusion technology to novel drug delivery in the twenty-first century: part II. Expert Opin Drug Deliv. 2019;16(6):567–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Silva LA, Almeida SL, Alonso EC, Rocha PB, Martins FT, Freitas LA, et al. Preparation of a solid self-microemulsifying drug delivery system by hot-melt extrusion. Int J Pharm. 2018;541(1–2):1–10.

    Article  CAS  PubMed  Google Scholar 

  34. Lenz E, Löbmann K, Rades T, Knop K, Kleinebudde P. Hot melt extrusion and spray drying of co-amorphous indomethacin-arginine with polymers. J Pharm Sci. 2017;106(1):302–12.

    Article  CAS  PubMed  Google Scholar 

  35. Gajda M, Nartowski KP, Pluta J, Karolewicz B. The role of the polymer matrix in solvent-free hot melt extrusion continuous process for mechanochemical synthesis of pharmaceutical cocrystal. Eur J Pharm Biopharm. 2018;131:48–59.

    Article  CAS  PubMed  Google Scholar 

  36. Huang S, O'Donnell KP, de Vaux SM, O'Brien J, Stutzman J, Williams RO III. Processing thermally labile drugs by hot-melt extrusion: the lesson with gliclazide. Eur J Pharm Biopharm. 2017;119:56–67.

    Article  CAS  PubMed  Google Scholar 

  37. Sanjay A, Manohar D, Bhanudas SR. Pharmaceutical cocrystallization: a review. J Adv Pharm Educ Res. 2014;4:388–96.

    CAS  Google Scholar 

  38. Walsh D, Serrano DR, Worku ZA, Madi AM, O'Connell P, Twamley B, et al. Engineering of pharmaceutical cocrystals in an excipient matrix: spray drying versus hot melt extrusion. Int J Pharm. 2018;551(1–2):241–56.

    Article  CAS  PubMed  Google Scholar 

  39. Moradiya HG, Islam MT, Halsey S, Maniruzzaman M, Chowdhry BZ, Snowden MJ, et al. Continuous cocrystallisation of carbamazepine and trans-cinnamic acid via melt extrusion processing. CrystEngComm. 2014;16(17):3573–83.

    Article  CAS  Google Scholar 

  40. Maniruzzaman M, Nokhodchi A. Continuous manufacturing via hot-melt extrusion and scale up: regulatory matters. Drug Discov Today. 2017;22(2):340–51.

    Article  CAS  PubMed  Google Scholar 

  41. Chabalenge B, Korde S, Kelly AL, Neagu D, Paradkar A. Understanding matrix assisted continuous cocrystallisation using data mining approach in quality by design (QbD). Cryst Growth Des. 2020;20:4540–9. https://doi.org/10.1021/acs.cgd.0c00338.

    Article  CAS  Google Scholar 

  42. Lee HL, Vasoya JM, Cirqueira MD, Yeh KL, Lee T, Serajuddin AT. Continuous preparation of 1: 1 haloperidol–maleic acid salt by a novel solvent-free method using a twin screw melt extruder. Mol Pharm. 2017;14(4):1278–91.

    Article  CAS  PubMed  Google Scholar 

  43. Nanjwade VK, Manvi FV, Basavaraj SAMK, Maste MM. New trends in the co-crystallization of active pharmaceutical ingredients. J Appl Pharm Sci. 2011;01:1–5.

    Google Scholar 

  44. Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, Zhang F, et al. Pharmaceutical applications of hot-melt extrusion: part II. Drug Dev Ind Pharm. 2007;33(10):1043–57.

    Article  CAS  PubMed  Google Scholar 

  45. Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Kumar Battu S, et al. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm. 2007;33(9):909–26.

    Article  CAS  PubMed  Google Scholar 

  46. Barmpalexis P, Karagianni A, Nikolakakis I, Kachrimanis K. Preparation of pharmaceutical cocrystal formulations via melt mixing technique: a thermodynamic perspective. Eur J Pharm Biopharm. 2018;131:130–40.

    Article  CAS  PubMed  Google Scholar 

  47. Lang B, McGinity JW, Williams RO III. Hot-melt extrusion–basic principles and pharmaceutical applications. Drug Dev Ind Pharm. 2014;40(9):1133–55.

    Article  CAS  PubMed  Google Scholar 

  48. Shaikh R, Walker GM, Croker DM. Continuous, simultaneous cocrystallization and formulation of theophylline and 4-aminobenzoic acid pharmaceutical cocrystals using twin screw melt granulation. Eur J Pharm Biopharm. 2019;137:104981.

    CAS  Google Scholar 

  49. Soliman II, Kandil SM, Abdou EM. Gabapentin–saccharin co-crystals with enhanced physicochemical properties and in vivo absorption formulated as oro-dispersible tablets. Pharm Dev Technol. 2020;25(2):227–36.

    Article  CAS  PubMed  Google Scholar 

  50. Daurio D, Medina C, Saw R, Nagapudi K, Alvarez-Núñez F. Application of twin screw extrusion in the manufacture of cocrystals, part I: four case studies. Pharmaceutics. 2011;3(3):582–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dhumal RS, Kelly AL, York P, Coates PD, Paradkar A. Cocrystalization and simultaneous agglomeration using hot melt extrusion. Pharm Res. 2010;27(12):2725–33.

    Article  CAS  PubMed  Google Scholar 

  52. Fernandes RP, do Nascimento AL, Carvalho AC, Teixeira JA, Ionashiro M, Caires FJ. Mechanochemical synthesis, characterization, and thermal behavior of meloxicam cocrystals with salicylic acid, fumaric acid, and malic acid. J Therm Anal Calorim. 2019;138(1):765–77.

    Article  CAS  Google Scholar 

  53. Ren Y, Mei L, Zhou L, Guo G. Recent perspectives in hot melt extrusion-based polymeric formulations for drug delivery: applications and innovations. AAPS PharmSciTech. 2019;20(3):92.

    Article  CAS  PubMed  Google Scholar 

  54. Lin SY. Mechanochemical approaches to pharmaceutical cocrystal formation and stability analysis. Curr Pharm Des. 2016;22(32):5001–18.

    Article  CAS  PubMed  Google Scholar 

  55. Suryawanshi D, Shinde U, Jha DK, Amin P. Application of quality by design approach for hot-melt extrusion process optimization. In: Pharmaceutical Quality by Design: Academic Press; 2019. p. 209–28.

  56. Repka MA, Bandari S, Kallakunta VR, Vo AQ, McFall H, Pimparade MB, et al. Melt extrusion with poorly soluble drugs–an integrated review. Int J Pharm. 2018;535(1–2):68–85.

    Article  CAS  PubMed  Google Scholar 

  57. Rodrigues M, Baptista B, Lopes JA, Sarraguça MC. Pharmaceutical cocrystallization techniques. Advances and challenges. Int J Pharm. 2018;547(1–2):404–20.

    Article  CAS  PubMed  Google Scholar 

  58. Thakkar R, Thakkar R, Pillai A, Ashour EA, Repka MA. Systematic screening of pharmaceutical polymers for hot melt extrusion processing: a comprehensive review. Int J Pharm. 2020;576:118989.

    Article  CAS  PubMed  Google Scholar 

  59. Butreddy A, Sarabu S, Bandari S, Dumpa N, Zhang F, Repka MA. Polymer-assisted aripiprazole–adipic acid cocrystals produced by hot melt extrusion techniques. Cryst Growth Des. 2020. https://doi.org/10.1021/acs.cgd.0c00020.

  60. Karimi-Jafari M, Ziaee A, Iqbal J, O'Reilly E, Croker D, Walker G. Impact of polymeric excipient on cocrystal formation via hot-melt extrusion and subsequent downstream processing. Int J Pharm. 2019;566:745–55.

    Article  CAS  PubMed  Google Scholar 

  61. Gajda M, Nartowski KP, Pluta J, Karolewicz B. Tuning the cocrystal yield in matrix-assisted cocrystallisation via hot melt extrusion: a case of theophylline-nicotinamide cocrystal. Int J Pharm. 2019;569:118579.

    Article  CAS  PubMed  Google Scholar 

  62. Fernandes GJ, Rathnanand M, Kulkarni V. Mechanochemical synthesis of carvedilol cocrystals utilizing hot melt extrusion technology. J Pharm Innov. 2019;14(4):373–81.

    Article  Google Scholar 

  63. Ross SA, Ward A, Basford P, McAllister M, Douroumis D. Coprocessing of pharmaceutical cocrystals for high quality and enhanced physicochemical stability. Cryst Growth Des. 2018;19(2):876–88.

    Article  CAS  Google Scholar 

  64. Li S, Yu T, Tian Y, McCoy CP, Jones DS, Andrews GP. Mechanochemical synthesis of pharmaceutical cocrystal suspensions via hot melt extrusion: feasibility studies and physicochemical characterization. Mol Pharm. 2016;13(9):3054–68.

    Article  CAS  PubMed  Google Scholar 

  65. Li S, Yu T, Tian Y, Lagan C, Jones DS, Andrews GP. Mechanochemical synthesis of pharmaceutical cocrystal suspensions via hot melt extrusion: enhancing cocrystal yield. Mol Pharm. 2017;15(9):3741–54.

    Article  CAS  Google Scholar 

  66. Wesholowski J, Prill S, Berghaus A, Thommes M. Inline UV/Vis spectroscopy as PAT tool for hot-melt extrusion. Drug Deliv Transl Res. 2018;8(6):1595–603.

    Article  CAS  PubMed  Google Scholar 

  67. Hitzer P, Bäuerle T, Drieschner T, Ostertag E, Paulsen K, van Lishaut H, et al. Process analytical techniques for hot-melt extrusion and their application to amorphous solid dispersions. Anal Bioanal Chem. 2017;409(18):4321–33.

    Article  CAS  PubMed  Google Scholar 

  68. Ishihara S, Hattori Y, Otsuka M. MCR-ALS analysis of IR spectroscopy and XRD for the investigation of ibuprofen-nicotinamide cocrystal formation. Spectrochim Acta A. 2019;221:117142.

    Article  CAS  Google Scholar 

  69. Vo AQ, He H, Zhang J, Martin S, Chen R, Repka MA. Application of FT-NIR analysis for in-line and real-time monitoring of pharmaceutical hot melt extrusion: a technical note. AAPS PharmSciTech. 2018;19(8):3425–9.

    Article  CAS  PubMed  Google Scholar 

  70. Dadou SM, Senta-Loys Z, Almajaan A, Li S, Jones DS, Healy AM, et al. The development and validation of a quality by design based process analytical tool for the inline quantification of ramipril during hot-melt extrusion. Int J Pharm. 2020;119382.

  71. Moradiya H, Islam MT, Woollam GR, Slipper IJ, Halsey S, Snowden MJ, et al. Continuous cocrystallization for dissolution rate optimization of a poorly water-soluble drug. Cryst Growth Des. 2014;14:189–98.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Center for Research in Pharmaceutical Sciences, Nanded Pharmacy College, Sham Nagar, Nanded, India

    Prabhakar S. Panzade & Giridhar R. Shendarkar

  2. Department of Pharmaceutics, Srinath College of Pharmacy, Waluj, Aurangabad, India

    Prabhakar S. Panzade & Deepak A. Kulkarni

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  1. Prabhakar S. Panzade
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Panzade, P.S., Shendarkar, G.R. & Kulkarni, D.A. Hot Melt Extrusion: an Emerging Green Technique for the Synthesis of High-Quality Pharmaceutical Cocrystals. J Pharm Innov 17, 283–293 (2022). https://doi.org/10.1007/s12247-020-09512-7

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