Pharmaceutical Cocrystals: An Emerging Approach to Modulate Physicochemical Properties of Active Pharmaceutical Ingredients
Abstract
Most of the Active Pharmaceutical Ingredients (APIs) are typically formulated and administered to patients in oral solid dosage forms due to ease of administration, patient compliance and cost effectiveness. Poor water solubility, low permeability and low bioavailability of APIs are major hurdles in development of oral solid dosage forms. In recent years, cocrystal development has evolved as a feasible approach for enhancing the solubility and bioavailability of poorly soluble drugs. Crystal engineering strategies have been asserted to enhance the likelihood of discovering new solid forms of an API. A pharmaceutical cocrystal is made up of two basic components, an API and a harmless material known as a coformer in stoichiometric ratio. Cocrystallization of an API with a pharmaceutically acceptable coformer can improve the physical characteristics of the API, such as solubility, hygroscopicity, and compaction behavior, without affecting the API's pharmacological efficacy. This review article offers a comprehensive overview of pharmaceutical cocrystals, their physiochemical characteristics, and methods of preparation, with an emphasis on cocrystal screening and cocrystal characterization. The review also included recent FDA and EMA guidance on pharmaceutical cocrystals as well as an outline of multidrug cocrystals.
Keywords: Pharmaceutical co-crystals, crystal engineering, coformers, supramolecular synthons, Solubility
Keywords:
Pharmaceutical co-crystals, crystal engineering, coformers, supramolecular synthons, SolubilityDOI
https://doi.org/10.22270/jddt.v13i4.6016References
. Buddhadev SS, Garala KC. Pharmaceutical cocrystals—a review. Multidisciplinary Digital Publishing Institute Proceedings. 2021; 62(1):14.
. Garg U, Azim Y. Challenges and opportunities of pharmaceutical cocrystals: a focused review on non-steroidal anti-inflammatory drugs. RSC medicinal chemistry. 2021; 12(5):705-21.
. Fukte SR, Wagh MP, Rawat S. Coformer selection: An important tool in cocrystal formation. Int. J. Pharm. Pharm. Sci. 2014; 6(7):9-14.
. Yadav AV, Shete AS, Dabke AP, Kulkarni PV, Sakhare SS. Co-crystals: a novel approach to modify physicochemical properties of active pharmaceutical ingredients. Indian journal of pharmaceutical sciences. 2009; 71(4):359.
. Pepinsky R. Crystal engineering-new concept in crystallography. InPhysical Review 1955 Jan 1 (Vol. 100, No. 3, pp. 971-971). ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA: AMERICAN PHYSICAL SOC.
. Schmidt GM. Photodimerization in the solid state. Pure and Applied Chemistry. 1971 Jan 1; 27(4):647-78.
. Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical research. 1995 Mar; 12:413-20.
. Thakuria R, Delori A, Jones W, Lipert MP, Roy L, Rodríguez-Hornedo N. Pharmaceutical cocrystals and poorly soluble drugs. International journal of pharmaceutics. 2013 Aug 30; 453(1):101-25.
. Wöhler F. Untersuchungen über das Chinon. 1844.
. Sathisaran I, Dalvi SV. Engineering cocrystals of poorly water-soluble drugs to enhance dissolution in aqueous medium. Pharmaceutics. 2018 Jul 31; 10(3):108.
. Etter MC. Encoding and decoding hydrogen-bond patterns of organic compounds. Accounts of Chemical Research. 1990 Apr 1; 23(4):120-6.
. Etter MC. Hydrogen bonds as design elements in organic chemistry. The Journal of Physical Chemistry. 1991 Jun; 95(12):4601-10.
. Desiraju GR. Supramolecular synthons in crystal engineering—a new organic synthesis. Angewandte Chemie International Edition in English. 1995 Nov 17; 34(21):2311-27.
. Kumar S. Pharmaceutical cocrystals: an overview. Indian Journal of Pharmaceutical Sciences. 2018 Jan 15; 79(6):858-71.
. Panzade P, Shendarkar G, Shaikh S, Rathi PB. Pharmaceutical cocrystal of piroxicam: design, formulation and evaluation. Advanced pharmaceutical bulletin. 2017 Sep; 7(3):399.
. Karimi-Jafari M, Padrela L, Walker GM, Croker DM. Creating cocrystals: A review of pharmaceutical cocrystal preparation routes and applications. Crystal Growth & Design. 2018 Aug 10; 18(10):6370-87.
. Seddon KR, Zaworotko M, editors. Crystal engineering: the design and application of functional solids. Springer Science & Business Media; 1999 Sep 30.
. Ancheria RK, Jain S, Kumar D, Soni SL, Sharma M. An overview of pharmaceutical co-crystal. Asian Journal of Pharmaceutical Research and Development. 2019 Apr 14; 7(2):39-46.
. Kumar S, Nanda A. Approaches to design of pharmaceutical cocrystals: A review. Molecular Crystals and Liquid Crystals. 2018 May 24; 667(1):54-77.
. Morissette SL, Almarsson Ö, Peterson ML, Remenar JF, Read MJ, Lemmo AV, Ellis S, Cima MJ, Gardner CR. High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Advanced drug delivery reviews. 2004 Feb 23; 56(3):275-300.
. Kavanagh ON, Croker DM, Walker GM, Zaworotko MJ. Pharmaceutical cocrystals: from serendipity to design to application. Drug Discovery Today. 2019 Mar 1; 24(3):796-804.
. Babu NJ, Reddy LS, Aitipamula S, Nangia A. Polymorphs and polymorphic cocrystals of temozolomide. Chemistry–An Asian Journal. 2008 Jul 7; 3(7):1122-33.
. Sarma B, Reddy LS, Nangia A. The role of π-stacking in the composition of phloroglucinol and phenazine cocrystals. Crystal Growth and Design. 2008 Dec 3; 8(12):4546-52.
. Patole T, Deshpande A. Co-crystallization-a technique for solubility enhancement. International journal of pharmaceutical sciences and research. 2014 Sep 1; 5(9):3566.
. Garg U, Azim Y. Challenges and opportunities of pharmaceutical cocrystals: a focused review on non-steroidal anti-inflammatory drugs. RSC medicinal chemistry. 2021; 12(5):705-21.
. Childs SL, Rodríguez-Hornedo N, Reddy LS, Jayasankar A, Maheshwari C, McCausland L, Shipplett R, Stahly BC. Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine. CrystEngComm. 2008; 10(7):856-64.
. Bhogala BR, Basavoju S, Nangia A. Tape and layer structures in cocrystals of some di-and tricarboxylic acids with 4, 4′-bipyridines and isonicotinamide. From binary to ternary cocrystals. CrystEngComm. 2005 Aug 17; 7(90):551-62.
. Karagianni A, Malamatari M, Kachrimanis K. Pharmaceutical cocrystals: New solid phase modification approaches for the formulation of APIs. Pharmaceutics. 2018 Jan 25; 10(1):18.
. Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: an overview. International journal of pharmaceutics. 2011 Oct 31; 419(1-2):1-1.
. Guo M, Sun X, Chen J, Cai T. Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications. Acta Pharmaceutica Sinica B. 2021 Aug 1; 11(8):2537-64.
. Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Crystal growth and design. 2009 Jun 3; 9(6):2950-67.
. Vemuri VD, Lankalapalli S. Insight into concept and progress on pharmaceutical co-crystals: an overview. Indian J. Pharm. Educ. Res. 2019 Oct 1; 53(4):s522-38.
. Guzmán HR, Tawa M, Zhang Z, Ratanabanangkoon P, Shaw P, Gardner CR, Chen H, Moreau JP, Almarsson Ö, Remenar JF. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. Journal of pharmaceutical sciences. 2007 Oct 1; 96(10):2686-702.
. Jayram P, Sudheer P. Pharmaceutical Co-crystals: A Systematic Review. International Journal of Pharmaceutical Investigation. 2020 Jul 1; 10(3).
. Sugandha K, Kaity S, Mukherjee S, Isaac J, Ghosh A. Solubility enhancement of ezetimibe by a cocrystal engineering technique. Crystal Growth & Design. 2014 Sep 3; 14(9):4475-86.
. Wang JR, Yu X, Zhou C, Lin Y, Chen C, Pan G, Mei X. Improving the dissolution and bioavailability of 6-mercaptopurine via co-crystallization with isonicotinamide. Bioorganic & medicinal chemistry letters. 2015 Mar 1; 25(5):1036-9.
. Chaudhari S, Nikam SA, Khatri N, Wakde S, Co-crystals: a review, Journal of Drug Delivery and Therapeutics 2018; 8(6-s):350-358
. Jung MS, Kim JS, Kim MS, Alhalaweh A, Cho W, Hwang SJ, Velaga SP. Bioavailability of indomethacin-saccharin cocrystals. Journal of pharmacy and pharmacology. 2010 Nov; 62(11):1560-8.
. Chaudhari S, Nikam SA, Khatri N, Wakde S. Co-crystals: a review. Journal of Drug Delivery and Therapeutics. 2018 Dec 15;8(6-s):350-8.
. Zhou Z, Li W, Sun WJ, Lu T, Tong HH, Sun CC, Zheng Y. Resveratrol cocrystals with enhanced solubility and tabletability. International journal of pharmaceutics. 2016 Jul 25; 509(1-2):391-9.
. Shaikh R, Singh R, Walker GM, Croker DM. Pharmaceutical cocrystal drug products: an outlook on product development. Trends in pharmacological sciences. 2018 Dec 1; 39(12):1033-48.
. Remenar JF, Peterson ML, Stephens PW, Zhang Z, Zimenkov Y, Hickey MB. Celecoxib: nicotinamide dissociation: using excipients to capture the cocrystal's potential. Molecular pharmaceutics. 2007 Jun 4; 4(3):386-400.
. Emami S, Siahi-Shadbad M, Adibkia K, Barzegar-Jalali M. Recent advances in improving oral drug bioavailability by cocrystals. BioImpacts: BI. 2018; 8(4):305.
. Sanphui P, Devi VK, Clara D, Malviya N, Ganguly S, Desiraju GR. Cocrystals of hydrochlorothiazide: solubility and diffusion/permeability enhancements through drug–coformer interactions. Molecular pharmaceutics. 2015 May 4; 12(5):1615-22.
. Arigo A, Jawahar N, Nikhitha K, Jubie S. Effect of Hygroscopicity on pharmaceutical ingredients, methods to determine and overcome: An Overview. Journal of Pharmaceutical Sciences and Research. 2019; 11(1):6-10.
. Qi MH, Li H, Zhu B, Hong M, Ren GB. Cocrystals of Oxymatrine: Reducing Hygroscopicity and Affecting the Dissolution Rate. Crystal Growth & Design. 2021 May 27; 21(7):3874-88.
. Patel DJ, Puranik PK. Pharmaceutical Co-crystal: An Emerging Technique to enhance Physicochemical properties of drugs. Int. J. ChemTech Res. 2020; 13:283-90.
. Corey EJ. General methods for the construction of complex molecules. Pure and Applied chemistry. 1967 Jan 1;14(1):19-38.
. Desiraju GR. Supramolecular synthons in crystal engineering—a new organic synthesis. Angewandte Chemie International Edition in English. 1995 Nov 17; 34(21):2311-27.
. Sopyan IY, Alvin B, Insan Sunan KS, Megantara SA. Systematic review: co-crystal as efforts to improve physicochemical and bioavailability properties of oral solid dosage form. Int. J. Appl. Pharm. 2021 Jan 7; 13(1):43-52.
. Thayyil AR, Juturu T, Nayak S, Kamath S. Pharmaceutical co-crystallization: Regulatory aspects, design, characterization, and applications. Advanced Pharmaceutical Bulletin. 2020 Jun; 10(2):203.
. Kumar A, Nanda A. In-silico methods of cocrystal screening: A review on tools for rational design of pharmaceutical cocrystals. Journal of Drug Delivery Science and Technology. 2021 Jun 1; 63:102527.
. Cruz-Cabeza AJ. Acid–base crystalline complexes and the p K a rule. CrystEngComm. 2012; 14(20):6362-5.
. Mohammad MA, Alhalaweh A, Velaga SP. Hansen solubility parameter as a tool to predict cocrystal formation. International journal of pharmaceutics. 2011 Apr 4; 407(1-2):63-71.
. Wood PA, Feeder N, Furlow M, Galek PT, Groom CR, Pidcock E. Knowledge-based approaches to co-crystal design. CrystEngComm. 2014; 16(26):5839-48.
. Fábián L. Cambridge structural database analysis of molecular complementarity in cocrystals. Crystal Growth and Design. 2009 Mar 4; 9(3):1436-43.
. Karki S, Friščić T, Fábián L, Jones W. New solid forms of artemisinin obtained through cocrystallisation. CrystEngComm. 2010; 12(12):4038-41.
. Chiarella RA, Davey RJ, Peterson ML. Making co-crystals the utility of ternary phase diagrams. Crystal growth & design. 2007 Jul 3; 7(7):1223-6.
. Sun X, Yin Q, Ding S, Shen Z, Bao Y, Gong J, Hou B, Hao H, Wang Y, Wang J, Xie C. Solid–liquid phase equilibrium and ternary phase diagrams of ibuprofen–nicotinamide cocrystals in ethanol and ethanol/water mixtures at (298.15 and 313.15) K. Journal of Chemical & Engineering Data. 2015 Apr 9; 60(4):1166-72.
. Ngilirabanga JB, Samsodien H. Pharmaceutical co‐crystal: An alternative strategy for enhanced physicochemical properties and drug synergy. Nano Select. 2021 Mar; 2(3):512-26.
. Panzade PS, Shendarkar GR. Pharmaceutical cocrystal: a game changing approach for the administration of old drugs in new crystalline form. Drug development and industrial pharmacy. 2020 Oct 2; 46(10):1559-68.
. MacFhionnghaile P, Crowley CM, McArdle P, Erxleben A. Spontaneous solid-state cocrystallization of caffeine and urea. Crystal Growth & Design. 2020 Jan 9; 20(2):736-45.
. Jones W, Motherwell WS, Trask AV. Pharmaceutical cocrystals: An emerging approach to physical property enhancement. MRS bulletin. 2006 Nov; 31(11):875-9.
. Thenge RR, Patond VB, Ajmire PV, Barde LN, Mahajan NM, Tekade NP. Preparation and characterization of co-crystals of diacerein. Indonesian journal of Pharmacy. 2017 Mar 7; 28(1):34.
. 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 Aug 31; 3(3):582-600.
. Yadav BK, Khursheed AT, Singh RD. Cocrystals: A complete review on conventional and novel methods of its formation and its evaluation. Asian J. Pharm. Clin. Res. 2019; 12(7):68-74.
. Boksa K, Otte A, Pinal R. Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion. Journal of pharmaceutical sciences. 2014 Sep 1; 103(9):2904-10.
. Basavoju S, Boström D, Velaga SP. Pharmaceutical cocrystal and salts of norfloxacin. Crystal growth & design. 2006 Dec 6; 6(12):2699-708.
. Sheikh AY, Abd Rahim S, Hammond RB, Roberts KJ. Scalable solution cocrystallization: case of carbamazepine-nicotinamide I. CrystEngComm. 2009; 11(3):501-9.
. Rodríguez-Hornedo N, Nehm SJ, Seefeldt KF, Pagan-Torres Y, Falkiewicz CJ. Reaction crystallization of pharmaceutical molecular complexes. Molecular pharmaceutics. 2006 Jun 5; 3(3):362-7.
. Pawar N, Saha A, Nandan N, Parambil JV. Solution cocrystallization: A scalable approach for cocrystal production. Crystals. 2021 Mar 18; 11(3):303.
. Thakor P, Yadav B, Modani S, Shastri NR. Preparation and optimization of nano-sized cocrystals using a quality by design approach. CrystEngComm. 2020; 22(13):2304-14.
. Douroumis D, Ross SA, Nokhodchi A. Advanced methodologies for cocrystal synthesis. Advanced drug delivery reviews. 2017 Aug 1; 117:178-95.
. Rodrigues M, Lopes J, Guedes A, Sarraguça J, Sarraguça M. Considerations on high-throughput cocrystals screening by ultrasound assisted cocrystallization and vibrational spectroscopy. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2020 Mar 15; 229:117876.
. Alhalaweh A, Kaialy W, Buckton G, Gill H, Nokhodchi A, Velaga SP. Theophylline cocrystals prepared by spray drying: physicochemical properties and aerosolization performance. Aaps Pharmscitech. 2013 Mar; 14:265-76.
. Eddleston MD, Patel B, Day GM, Jones W. Cocrystallization by freeze-drying: preparation of novel multicomponent crystal forms. Crystal growth & design. 2013 Oct 2; 13(10):4599-606.
. Padrela L, de Azevedo EG, Velaga SP. Powder X-ray diffraction method for the quantification of cocrystals in the crystallization mixture. Drug development and industrial pharmacy. 2012 Aug 1; 38(8):923-9.
. Aakeröy CB, Salmon DJ, Smith MM, Desper J. Cyanophenyloximes: reliable and versatile tools for hydrogen-bond directed supramolecular synthesis of cocrystals. Crystal growth & design. 2006 Apr 5; 6(4):1033-42.
. Parrott EP, Zeitler JA, Friscic T, Pepper M, Jones W, Day GM, Gladden LF. Testing the sensitivity of terahertz spectroscopy to changes in molecular and supramolecular structure: a study of structurally similar cocrystals. Crystal Growth and Design. 2009 Mar 4; 9(3):1452-60.
. Steed JW. The role of co-crystals in pharmaceutical design. Trends in pharmacological sciences. 2013 Mar 1; 34(3):185-93.
. Jiang L, Huang Y, Zhang Q, He H, Xu Y, Mei X. Preparation and solid-state characterization of dapsone drug–drug co-crystals. Crystal Growth & Design. 2014 Sep 3; 14(9):4562-73.
. Shaikh R, Singh R, Walker GM, Croker DM. Pharmaceutical cocrystal drug products: an outlook on product development. Trends in pharmacological sciences. 2018 Dec 1; 39(12):1033-48.
. Thipparaboina R, Kumar D, Chavan RB, Shastri NR. Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discovery Today. 2016 Mar 1; 21(3):481-90.
. Grobelny P, Mukherjee A, Desiraju GR. Drug-drug co-crystals: Temperature-dependent proton mobility in the molecular complex of isoniazid with 4-aminosalicylic acid. CrystEngComm. 2011; 13(13):4358-64.
. Cheney ML, Weyna DR, Shan N, Hanna M, Wojtas L, Zaworotko MJ. Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics. Journal of pharmaceutical sciences. 2011 Jun 1; 100(6):2172-81.
. Sopyan IY, Alvin B, Insan Sunan KS, Megantara SA. Systematic review: co-crystal as efforts to improve physicochemical and bioavailability properties of oral solid dosage form. Int. J. Appl. Pharm. 2021 Jan 7; 13(1):43-52.
. European Medicines Agency. Reflection paper on the use of cocrystals of active substances in medicinal products
Published
Abstract Display: 1972 
PDF Downloads: 1599 PDF Downloads: 686 How to Cite
Issue
Section
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
How to Cite
.