Abstract
The last decade has witnessed extensive growth in the field of co-crystallization for mitigating the solubility and dissolution-related issues of poorly soluble drugs. This is largely because co-crystals can modify the physicochemical properties of drugs without any covalent modification in the drug molecules. The US Food and Drug Administration (FDA) now considers drug products that are designed to contain a new co-crystal, analogous to new polymorph of the active pharmaceutical ingredient (API). This positive change in regulatory perspective coupled with successful commercialization of valsartan-sacubitril co-crystal (Entresto, Novartis) has now brought co-crystals into focus, in both industries as well as academia. Co-crystal prediction, screening, and synthesis have been reported in literature; however, co-crystal production at a larger scale needs further investigations. With this aim, the article describes various continuous methods for co-crystal production, along with in-line monitoring during co-crystal production, emphasizing on process analytical technology (PAT). In addition, the scale-up issues of continuous and batch co-crystallization and other suitable techniques for pharmaceutical scale up are detailed. Quality control aspects and regulatory viewpoint crucial for commercial success are elaborated in the future perspective.
Similar content being viewed by others
References
Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins: basic science and product development. J Pharm Pharmacol. 2010;62(11):1607–21. https://doi.org/10.1111/j.2042-7158.2010.01030.x.
Aitipamula S, Banerjee R, Bansal AK, Biradha K, Cheney ML, Choudhury AR, et al. Polymorphs, salts, and cocrystals: what’s in a name? Cryst Growth Des. 2012;12(5):2147–52. https://doi.org/10.1021/cg3002948.
Thipparaboina R, Kumar D, Chavan RB, Shastri NR. Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discov Today. 2016;21(3):481–90. https://doi.org/10.1016/j.drudis.2016.02.001.
Nangia A. Supramolecular chemistry and crystal engineering. J Chem Sci. 2010;122(3):295–310. https://doi.org/10.1007/s12039-010-0035-6.
Thipparaboina R, Kumar D, Mittapalli S, Balasubramanian S, Nangia A, Shastri NR. Ionic, neutral, and hybrid acid–base crystalline adducts of lamotrigine with improved pharmaceutical performance. Cryst Growth Des. 2015;15(12):5816–26. https://doi.org/10.1021/acs.cgd.5b01187.
Chattoraj S, Shi L, Sun CC. Understanding the relationship between crystal structure, plasticity and compaction behaviour of theophylline, methyl gallate, and their 1: 1 co-crystal. CrystEngComm. 2010;12(8):2466–72. https://doi.org/10.1039/c000614a.
US-FDA. Regulatory classification of pharmaceutical co-crystals guidance for industry. 2016.
European Medicines Agency. Reflection paper on the use of cocrystals of active substances in medicinal products 2015.
Kale DP, Zode SS, Bansal AK. Challenges in translational development of pharmaceutical Cocrystals. J Pharm Sci. 2017;106(2):457–70. https://doi.org/10.1016/j.xphs.2016.10.021.
Hasa D, Jones W. Screening for new pharmaceutical solid forms using mechanochemistry: a practical guide. Adv Drug Deliv Rev. 2017;117:147–61. https://doi.org/10.1016/j.addr.2017.05.001.
Shan N, Toda F, Jones W. Mechanochemistry and co-crystal formation: effect of solvent on reaction kinetics. Chem Comm. 2002;20:2372–3.
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(6):3425–34. https://doi.org/10.1021/acs.cgd.6b00402.
Yu L. Continuous manufacturing has a strong impact on drug quality. FDA Voice. 2016;12
Svoboda V, MacFhionnghaile P, McGinty J, Connor LE, Oswald ID, Sefcik J. Continuous cocrystallization of benzoic acid and isonicotinamide by mixing-induced supersaturation: exploring opportunities between reactive and antisolvent crystallization concepts. Cryst Growth Des. 2017;17(4):1902–9. https://doi.org/10.1021/acs.cgd.6b01866.
Current good manufacturing practice for manufacturing, processing, packing, or holding of drugs, US FDA Center for Drug Evaluation and Research. FDA. 2014.
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. 2013;14(1):189–98.
McGlone T, Briggs NE, Clark CA, Brown CJ, Sefcik J, Florence AJ. Oscillatory flow reactors (OFRs) for continuous manufacturing and crystallization. Org Process Res Dev. 2015;19(9):1186–202. https://doi.org/10.1021/acs.oprd.5b00225.
Lee T, Chen HR, Lin HY, Lee HL. Continuous co-crystallization as a separation technology: the study of 1: 2 co-crystals of phenazine–vanillin. Cryst Growth Des. 2012;12(12):5897–907. https://doi.org/10.1021/cg300763t.
Westhoff G, Kramer H, Jansens P, Grievink J. Design of a multi-functional crystallizer for research purposes. Chem Eng Res Des. 2004;82(7):865–80. https://doi.org/10.1205/0263876041596670.
Powell KA, Bartolini G, Wittering KE, Saleemi AN, Wilson CC, Rielly CD, et al. Toward continuous crystallization of urea-barbituric acid: a polymorphic co-crystal system. Cryst Growth Des. 2015;15(10):4821–36. https://doi.org/10.1021/acs.cgd.5b00599.
Dijck WJD. Process and apparatus for intimately contacting fluids. Google Patents; 1935.
Baird M, Rama Rao N. Characteristics of a countercurrent reciprocating plate bubble column. II. Axial mixing and mass transfer. Can J Chem Eng. 1988;66(2):222–31.
Nogueira X, Taylor BJ, Gomez H, Colominas I, Mackley MR. Experimental and computational modeling of oscillatory flow within a baffled tube containing periodic-tri-orifice baffle geometries. Comput Chem Eng. 2013;49:1–17. https://doi.org/10.1016/j.compchemeng.2012.09.015.
Gough P, Ni X, Symes KC. Experimental flow visualisation in a modified pulsed baffled reactor. J Chem Technol Biot. 1997;69(3):321–8. https://doi.org/10.1002/(SICI)1097-4660(199707)69:3<321::AID-JCTB717>3.0.CO;2-Q.
Zhao L, Raval V, Briggs NE, Bhardwaj RM, McGlone T, Oswald ID, et al. From discovery to scale-up: α-lipoic acid: nicotinamide co-crystals in a continuous oscillatory baffled crystalliser. CrystEngComm. 2014;16(26):5769–80. https://doi.org/10.1039/C4CE00154K.
Kudo S, Takiyama H. Production method of carbamazepine/saccharin cocrystal particles by using two solution mixing based on the ternary phase diagram. J Cryst Growth. 2014;392:87–91. https://doi.org/10.1016/j.jcrysgro.2014.02.003.
Wang I-C, Lee M-J, Sim S-J, Kim W-S, Chun N-H, Choi GJ. Anti-solvent co-crystallization of carbamazepine and saccharin. Int J Pharm. 2013;450(1):311–22. https://doi.org/10.1016/j.ijpharm.2013.04.012.
Nishimaru M, Kudo S, Takiyama H. Cocrystal production method reducing deposition risk of undesired single component crystals in anti-solvent cocrystallization. J Ind Eng Chem. 2016;36:40–3. https://doi.org/10.1016/j.jiec.2016.01.027.
Nishimaru M, Nakasa M, Kudo S, Takiyama H. Operation condition for continuous anti-solvent crystallization of CBZ-SAC cocrystal considering deposition risk of undesired crystals. J Cryst Growth. 2017;470:89–93. https://doi.org/10.1016/j.jcrysgro.2017.04.017.
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. https://doi.org/10.1021/acs.molpharmaceut.6b00134.
Medina C, Daurio D, Nagapudi K, Alvarez-Nunez F. Manufacture of pharmaceutical co-crystals using twin screw extrusion: a solvent-less and scalable process. J Pharm Sci. 2010;99(4):1693–6. https://doi.org/10.1002/jps.21942.
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. https://doi.org/10.1007/s11095-010-0273-9.
Kelly AL, Gough T, Dhumal R, Halsey S, Paradkar A. Monitoring ibuprofen–nicotinamide cocrystal formation during solvent free continuous cocrystallization (SFCC) using near infrared spectroscopy as a PAT tool. Int J Pharm. 2012;426(1):15–20. https://doi.org/10.1016/j.ijpharm.2011.12.033.
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. https://doi.org/10.3390/pharmaceutics3030582.
Kulkarni C, Wood C, Kelly AL, Gough T, Blagden N, Paradkar A. Stoichiometric control of co-crystal formation by solvent free continuous co-crystallization (SFCC). Cryst Growth Des. 2015;15(12):5648–51. https://doi.org/10.1021/acs.cgd.5b00806.
Boksa K, Otte A, Pinal R. Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion. J Pharm Sci. 2014;103(9):2904–10. https://doi.org/10.1002/jps.23983.
Daurio D, Nagapudi K, Li L, Quan P, Nunez F-A. Application of twin screw extrusion to the manufacture of cocrystals: scale-up of AMG 517–sorbic acid cocrystal production. Faraday Discuss. 2014;170:235–49. https://doi.org/10.1039/C3FD00153A.
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. https://doi.org/10.1039/C3CE42457J.
Liu X, Lu M, Guo Z, Huang L, Feng X, Wu C. Improving the chemical stability of amorphous solid dispersion with cocrystal technique by hot melt extrusion. Pharm Res. 2012;29(3):806–17. https://doi.org/10.1007/s11095-011-0605-4.
Maniruzzaman M, Nokhodchi A. Continuous manufacturing via hot-melt extrusion and scale up: regulatory matters. Drug Discov Today. 2017;22(2):340–51. https://doi.org/10.1016/j.drudis.2016.11.007.
Tanaka R, Takahashi N, Nakamura Y, Hattori Y, Ashizawa K, Otsuka M. In-line and real-time monitoring of resonant acoustic mixing by near-infrared spectroscopy combined with chemometric technology for process analytical technology applications in pharmaceutical powder blending systems. Analytical Sci. 2017;33(1):41–6. https://doi.org/10.2116/analsci.33.41.
Am Ende DJ, Anderson SR, Salan JS. Development and scale-up of cocrystals using resonant acoustic mixing. Org Process Res Dev. 2014;18(2):331–41. https://doi.org/10.1021/op4003399.
Nagapudi K, Umanzor EY, Masui C. High-throughput screening and scale-up of cocrystals using resonant acoustic mixing. Int J Pharm. 2017;521(1):337–45. https://doi.org/10.1016/j.ijpharm.2017.02.027.
Anderson SR, Am Ende DJ, Salan JS, Samuels P. Preparation of an energetic-energetic cocrystal using resonant acoustic mixing. Propellants Explos Pyrotech. 2014;39(5):637–40. https://doi.org/10.1002/prep.201400092.
Patil S, Kulkarni J, Mahadik K. Exploring the potential of electrospray technology in cocrystal synthesis. Ind Eng Chem Res. 2016;55(30):8409–14. https://doi.org/10.1021/acs.iecr.6b01938.
Radacsi N, Ambrus R, Szunyogh T, Szabó-Révész P, Stankiewicz A, Van Der Heijden A, et al. Electrospray crystallization for nanosized pharmaceuticals with improved properties. Cryst Growth Des. 2012;12(7):3514–20. https://doi.org/10.1021/cg300285w.
Wang M, Rutledge GC, Myerson AS, Trout BL. Production and characterization of carbamazepine nanocrystals by electrospraying for continuous pharmaceutical manufacturing. J Pharm Sci. 2012;101(3):1178–88. https://doi.org/10.1002/jps.23024.
Patil S, Ujalambkar V, Mahadik A. Electrospray technology as a probe for cocrystal synthesis: influence of solvent and coformer structure. J Drug Deliv Sci Technol. 2017;39:217–22. https://doi.org/10.1016/j.jddst.2017.04.001.
Patil S, Chaudhari K, Kamble R. Electrospray technique for cocrystallization of phytomolecules. J King Saud Univ Sci. 2018;30(1):138-41. https://doi.org/10.1016/j.jksus.2017.04.001
Pasquali I, Bettini R, Giordano F. Supercritical fluid technologies: an innovative approach for manipulating the solid-state of pharmaceuticals. Adv Drug Deliv Rev. 2008;60(3):399–410. https://doi.org/10.1016/j.addr.2007.08.030.
Müllers KC, Paisana M, Wahl MA. Simultaneous formation and micronization of pharmaceutical cocrystals by rapid expansion of supercritical solutions (RESS). Pharm Res. 2015;32(2):702–13. https://doi.org/10.1007/s11095-014-1498-9.
Cuadra IA, Cabañas A, Cheda JA, Martínez-Casado FJ, Pando C. Pharmaceutical co-crystals of the anti-inflammatory drug diflunisal and nicotinamide obtained using supercritical CO 2 as an antisolvent. J CO2 Util. 2016;13:29–37.
Padrela L, Rodrigues MA, Velaga SP, Fernandes AC, Matos HA, de Azevedo EG. Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process. J Supercrit Fluids. 2010;53(1):156–64. https://doi.org/10.1016/j.supflu.2010.01.010.
Neurohr C, Erriguible A, Laugier S, Subra-Paternault P. Challenge of the supercritical antisolvent technique SAS to prepare cocrystal-pure powders of naproxen-nicotinamide. Chem Eng J. 2016;303:238–51. https://doi.org/10.1016/j.cej.2016.05.129.
Kotbantao G, Charoenchaitrakool M. Processing of ketoconazole–4-aminobenzoic acid cocrystals using dense CO 2 as an antisolvent. J CO2 Util. 2017;17:213–9. https://doi.org/10.1016/j.jcou.2016.12.007.
Hiendrawan S, Veriansyah B, Widjojokusumo E, Soewandhi S, Wikarsa S, Tjandrawinata RR. Simultaneous cocrystallization and micronization of paracetamol-dipicolinic acid cocrystal by supercritical antisolvent (SAS). Int J Pharm Pharm Sci. 2016;8:89–98.
Padrela L, Rodrigues MA, Tiago J, Velaga SP, Matos HA, de Azevedo EG. Tuning physicochemical properties of theophylline by cocrystallization using the supercritical fluid enhanced atomization technique. J Supercrit Fluids. 2014;86:129–36. https://doi.org/10.1016/j.supflu.2013.12.011.
Ginty PJ, Whitaker MJ, Shakesheff KM, Howdle SM. Drug delivery goes supercritical. Mater Today. 2005;8(8):42–8. https://doi.org/10.1016/S1369-7021(05)71036-1.
Constable DJ, Jimenez-Gonzalez C, Henderson RK. Perspective on solvent use in the pharmaceutical industry. Org Process Res Dev. 2007;11(1):133–7. https://doi.org/10.1021/op060170h.
Pasquali I, Bettini R, Giordano F. Solid-state chemistry and particle engineering with supercritical fluids in pharmaceutics. Eur J Pharm Sci. 2006;27(4):299–310. https://doi.org/10.1016/j.ejps.2005.11.007.
Pasquali I, Bettini R. Are pharmaceutics really going supercritical? Int J Pharm. 2008;364(2):176–87. https://doi.org/10.1016/j.ijpharm.2008.05.014.
Poole RM, Dungo RT. Ipragliflozin: first global approval. Drugs. 2014;74(5):611–7. https://doi.org/10.1007/s40265-014-0204-x.
Bernhardson D, Brandt TA, Hulford CA, Lehner RS, Preston BR, Price K, et al. Development of an early-phase bulk enabling route to sodium-dependent glucose cotransporter 2 inhibitor ertugliflozin. Org Process Res Dev. 2014;18(1):57–65. https://doi.org/10.1021/op400289z.
Almansa C, Mercè R, Tesson N, Farran J, Tomàs J, Plata-Salamán CR. Co-crystal of tramadol hydrochloride–celecoxib (ctc): a novel API–API co-crystal for the treatment of pain. Cryst Growth Des. 2017;17(4):1884–92. https://doi.org/10.1021/acs.cgd.6b01848.
Harrison WT, Yathirajan H, Bindya S, Anilkumar H. Escitalopram oxalate: co-existence of oxalate dianions and oxalic acid molecules in the same crystal. Acta Crystallogr C: crystal structure. Communications. 2007;63(2):o129–o31.
US FDA Draft Guidance. PAT—a framework for innovative pharmaceutical manufacturing and Quality Assurance. August; 2003.
Sarraguça MC, Ribeiro PR, Santos AO, Silva MC, Lopes JAAPAT. Approach for the on-line monitoring of pharmaceutical co-crystals formation with near infrared spectroscopy. Int J Pharm. 2014;471(1):478–84. https://doi.org/10.1016/j.ijpharm.2014.06.003.
Lee K-S, Kim K-J, Ulrich J. In situ monitoring of cocrystallization of salicylic acid–4, 4′-dipyridyl in solution using Raman spectroscopy. Cryst Growth Des. 2014;14(6):2893–9. https://doi.org/10.1021/cg5001864.
Funding
The authors acknowledge the financial support from the Department of Pharmaceuticals (DoP), Ministry of Chemicals and Fertilizers, Govt. of India.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interest.
Rights and permissions
About this article
Cite this article
Chavan, R.B., Thipparaboina, R., Yadav, B. et al. Continuous manufacturing of co-crystals: challenges and prospects. Drug Deliv. and Transl. Res. 8, 1726–1739 (2018). https://doi.org/10.1007/s13346-018-0479-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13346-018-0479-7