Polymer Composite-Assisted Crystal Engineering for Drug Synthesis and Property Control through Solid Solutions and Co-Crystals

Year : 2026 | Volume : 14 | Issue : 03 | Page : 172 189
    By

    Sandeep P. Shewale,

  • Dipti Y. Sakhare,

  1. Associate Professor, Department of Chemical Engineering, MIT Academy of Engineering Alandi (D), Pune, Maharashtra, India
  2. Professor, Department of Electronics and Telecommunication, MIT Academy of Engineering Alandi (D), Pune, Maharashtra, India

Abstract

The long-standing problem of low aqueous solubility, which affects about 90% of all new drug molecules under development, requires an immediate need for alternative approaches apart from the usual practice of crystallization. Polymer-composite-assisted crystal engineering is a novel technique for overcoming the aforementioned problem. This involves the addition of accepted pharmaceutical polymers, such as HPMC, PVP, PEG, and Eudragit copolymers in a single process, which can promote nucleation, stabilize the metastable crystals, and maintain drug supersaturation in the gastrointestinal tract. A pharmaceutical co-crystal is a multicomponent system where one of the components is an active pharmaceutical ingredient (API) while other components are pharmaceutically acceptable co-formers held by weak intermolecular interactions, including hydrogen bonding, van der Waals forces, and π-π stacking. The co-crystallization strategy proves to be a promising way for enhancing solubility, dissolution, bioavailability, stability, hygroscopicity, and tableting properties of API regardless of the ionization range. With the addition of a polymer into this binary API co-former system, a ternary architecture is created, which demonstrates performance that outperforms both that of the polymer-free co-crystal as well as an amorphous solid dispersion. An increase in solubility by factors of 2-8 over the parent API has been reported in the case of polymer-composite co-crystals, compared to that of the polymer-free co-crystal with an increase by factors of 1.5-5. This review provides a comprehensive overview of the preparation approaches, changes to physicochemical properties, and biomedical applications of the newly emerging class of polymers incorporated within co-crystals and solid solutions. Various solid-state approaches include polymer-assisted liquid-assisted grinding, hot-melt extrusion, and melt crystallization, while liquid state approaches include polymer-directed slurry conversion, reaction co-crystallisation, spray drying, and antisolvent co-precipitation. Changes to the physicochemical properties including physical and chemical stability, hygroscopicity, solubility, dissolution rate, and optical behavior due to incorporation of polymers are reviewed.

Keywords: Polymer composites; pharmaceutical co-crystals; crystal engineering; physicochemical properties; solid solutions; solid dosage forms; HPMC; PVP; PEG; Eudragit; co-crystallisation; bioavailability; BCS Class II/IV drugs

[This article belongs to Journal of Polymer & Composites ]

66238e53 fi
How to cite this article:
Sandeep P. Shewale, Dipti Y. Sakhare. Polymer Composite-Assisted Crystal Engineering for Drug Synthesis and Property Control through Solid Solutions and Co-Crystals. Journal of Polymer & Composites. 2026; 14(03):172-189.
How to cite this URL:
Sandeep P. Shewale, Dipti Y. Sakhare. Polymer Composite-Assisted Crystal Engineering for Drug Synthesis and Property Control through Solid Solutions and Co-Crystals. Journal of Polymer & Composites. 2026; 14(03):172-189. Available from: https://journals.stmjournals.com/jopc/article=2026/view=243532


References

  1. Trask AV. An overview of pharmaceutical cocrystals as intellectual property. Mol Pharm. 2007;4(3):301–309.
  2. Kale DP, Zode SS, Bansal AK. Challenges in translational development of pharmaceutical cocrystals. J Pharm Sci. 2016;2:1–14.
  3. Childs SL, Hardcastle KI. Cocrystals of piroxicam with carboxylic acids. Cryst Growth Des. 2007;7(7):1291–1204.
  4. Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. Pharmaceutical co-crystals. J Pharm Sci. 2006;95(3):499–516.
  5. Newman AW, Byrn SR. Solid-state analysis of the active pharmaceutical ingredient in drug development. Drug Discov Today. 2003;8(19):898–905.
  6. Duggirala NK, Perry ML, Almarsson Ö, Zaworotko MJ. Pharmaceutical cocrystals: along the path to improved medicines. Chem Commun. 2016;52(4):640–655.
  7. Bolla G, Nangia A. Pharmaceutical cocrystals: walking the talk. Chem Commun. 2016;52(54):8342–8360.
  8. McNamara DP, Childs SL, Giordano J, Iarriccio A, Cassidy J, Shet MS, et al. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm Res. 2006;23(8):1888–1897.
  9. Padrela L, Rodrigues MA, Tiago J, Velaga SP, Matos HA, de Azevedo EG. Tuning physicochemical properties of theophylline via supercritical fluid technologies. J Supercrit Fluids. 2014;86:129–136.
  10. Haeria A, Ismail NI. Pharmaceutical co-crystals: preparation and characterisation. Int J PharmaTech Res. 2015;8(10):166–170.
  11. Sathisaran I, Dalvi SV. Engineering cocrystals of poorly water-soluble drugs to enhance dissolution in aqueous medium. Pharmaceutics. 2018;10(3):108.
  12. Swapna B, Maddileti D, Nangia A. Cocrystals of the tuberculosis drug isoniazid. Cryst Growth Des. 2014;14(11):5991–6005.
  13. Huang Y, Zhou L, Yang W, Li Y, Yin Q. Preparation of theophylline–benzoic acid cocrystal and on-line monitoring by Raman spectroscopy. Crystals. 2019;9(7):329–344.
  14. Germann LS, Arhangelskis M, Etter M, Dinnebier RE, Friščić T. Challenging the Ostwald rule of stages in mechanochemical cocrystallisation. Chem Sci. 2020;11(39):10092–10100.
  15. 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):806–817.
  16. Douroumis D, Ross SA, Nokhodchi A. Advanced methodologies for cocrystal synthesis. Adv Drug Deliv Rev. 2017;117:178–195.
  17. Guo M, Sun X, Chen J, Cai T. Pharmaceutical cocrystals: a review of preparations, physicochemical properties and applications. Acta Pharm Sin B. 2021;11(8):2537–2564.
  18. Fonseca JDC, Tenorio Clavijo JC, Alvarez N, Ellena J, Ayala AP. Novel solid solution of the antiretroviral drugs lamivudine and emtricitabine. Cryst Growth Des. 2018;18(6):3441–3448.
  19. Kuminek G, Cao F, Bahia de Oliveira da Rocha A, Gonçalves Cardoso S, Rodríguez-Hornedo N. Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5. Adv Drug Deliv Rev. 2016;101:143–166.
  20. Cappuccino C, Spoletti E, Renni F, Muntoni E, Keiser J, Voinovich D, et al. Co-crystalline solid solution affords a high-soluble and fast-absorbing form of praziquantel. Mol Pharm. 2023;20(4):2009–2016.
  21. Suresh K, Minkov VS, Namila KK, Derevyannikova E, Losev E, Nangia A, et al. Novel cocrystals of sulfacetamide with aromatic acids. Cryst Growth Des. 2015;15(7):3498–3510.
  22. Kumar S, Nanda A. Pharmaceutical cocrystals: an overview. Indian J Pharm Sci. 2017;79(6):858–871.
  23. United States Pharmacopeia and National Formulary. USP 39–NF 34. Rockville, MD: United States Pharmacopeial Convention; 2016.
  24. Raghuram Reddy K, Kothur AS, Swetha NPB. A review on pharmaceutical co-crystals. Int J Pharm Res Dev. 2012;4(2):84–92.
  25. Brahamdutt CM, Kumar S, Bhatia M, Budhwar V. Co-crystals of active pharmaceutical ingredients. Int Res J Pharm. 2016;7(10):27–35.
  26. Cheney ML, Weyna DR, Shan N, Hanna M, Wojtas L, Zaworotko MJ. Coformer selection in pharmaceutical cocrystal development. J Pharm Sci. 2011;100(6):2172–2181.
  27. Kavanagh ON, Croker DM, Walker GM, Zaworotko MJ. Pharmaceutical cocrystals: from serendipity to design to application. Drug Discov Today. 2019;24(3):796–804.
  28. Rodrigues M, Baptista B, Lopes JA, Sarraguça MC. Pharmaceutical cocrystallization techniques. Int J Pharm. 2018;547(1–2):404–420.
  29. Kras W, Carletta A, Montis R, Sullivan RA, Cruz-Cabeza AJ. Switching polymorph stabilities with impurities reveals thermodynamic and kinetic drivers of polymorphism. Commun Chem. 2021;4(1):1–7.
  30. Cerreia Vioglio P, Chierotti MR, Gobetto R. Pharmaceutical aspects of salt and cocrystal forms of APIs and characterisation challenges. Adv Drug Deliv Rev. 2017;117:86–110.
  31. Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B. 2015;5(5):442–453.
  32. Yan Y, Chen JM, Lu TB. Simultaneously improving the solubility and permeability of acyclovir by crystal engineering approach. CrystEngComm. 2015;17(3):612–620.
  33. Seefeldt K, Miller J, Alvarez-Núñez F, Rodríguez-Hornedo N. Crystallization pathways and kinetics of carbamazepine–nicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy, and calorimetry studies. J Pharm Sci. 2007;96(5):1147–1158.
  34. Fischer F, Scholz G, Benemann S, Rademann K, Emmerling F. Evaluation of the formation pathways of cocrystal polymorphs in liquid-assisted syntheses. CrystEngComm. 2014;16(39):8272–8278.
  35. Seera R, Cherukuvada S, Guru Row TN. Evolution of cocrystals from solid solutions in benzoic acid–fluorobenzoic acid combinations. Cryst Growth Des. 2021;21(8):4607–4618.
  36. Chadwick K, Davey R, Cross W. How does grinding produce co-crystals? Insights from the case of benzophenone and diphenylamine. CrystEngComm. 2007;9(9):732–734.
  37. Lien Nguyen K, Friščić T, Day GM, Gladden LF, Jones W. Terahertz time-domain spectroscopy and the quantitative monitoring of mechanochemical cocrystal formation. Nat Mater. 2007;6(3):206–209.
  38. Friščić T, Jones W. Recent advances in understanding the mechanism of cocrystal formation via grinding. Cryst Growth Des. 2009;9(3):1621–1637.
  39. Jayasankar A, Somwangthanaroj A, Shao ZJ, Rodríguez-Hornedo N. Cocrystal formation during cogrinding and storage is mediated by amorphous phase. Pharm Res. 2006;23(10):2381–2392.
  40. Rehder S, Klukkert M, Lobmann KA, Strachan CJ, Sakmann A, Gordon K, et al. Investigation into the formation process of two piracetam cocrystals during grinding. Pharmaceutics. 2011;3(4):706–722.
  41. Karki S, Friščić T, Jones W. Control and interconversion of cocrystal stoichiometry in grinding: stepwise mechanism for the formation of a hydrogen-bonded cocrystal. CrystEngComm. 2009;11(3):470–481.
  42. Halasz I, Puškarić A, Kimber SAJ, Beldon PJ, Patel AM, Jones W, et al. Real-time in situ powder X-ray diffraction monitoring of mechanochemical synthesis of pharmaceutical cocrystals. Angew Chem Int Ed. 2013;52(44):11538–11541.
  43. Ahuja D, Ramisetty KA, Sumanth PK, Crowley CM, Lusi M, Rasmuson AC. Microwave-assisted slurry conversion crystallization: the case of carbamazepine cocrystals. CrystEngComm. 2020;22(8):1381–1394.
  44. Rodríguez-Hornedo N, Nehm SJ, Seefeldt KF, Pagán-Torres Y, Falkiewicz CJ. Reaction crystallization of pharmaceutical molecular complexes. Mol Pharm. 2006;3(3):362–367.
  45. Machado TC, Kuminek G, Cardoso SG, Rodríguez-Hornedo N. pH impact on cocrystal solubility and thermodynamic stability with ionizable coformer or API. Eur J Pharm Sci. 2020;152:105422.
  46. Cao F, Amidon GL, Rodriguez-Hornedo N, Amidon GE. Mechanistic analysis of cocrystal dissolution as a function of pH and micellar solubilization. Mol Pharm. 2016;13(3):1030–1046.
  47. Maya P, Lipert N, Rodríguez-Hornedo N. Crystallization of cocrystals by slurry conversion. Mol Pharm. 2015;12(9):3535–3546.
  48. Dai XL, Yao J, Wu C, Deng JH, Mo YH, Lu TB, et al. Cocrystal and salt of febuxostat with piperazine: reducing the gastrointestinal toxicity. Cryst Growth Des. 2020;20(8):5160–5168.
  49. Huang S, Xue Q, Xu J, Ruan S, Cai T. Simultaneously improving the physicochemical properties and bioavailability of apigenin and daidzein by co-crystallization with theophylline. J Pharm Sci. 2019;108(9):2982–2993.
  50. Trask AV, Motherwell WDS, Jones W. Solvent-drop grinding: green polymorph control of cocrystallisation. Cryst Growth Des. 2005;5(3):1013–1021.
  51. Oburn SM, Ray OA, Macgillivray LR. Cocrystallization enables the isolation of a light-stable, complete solid-state photoproduct. Cryst Growth Des. 2018;18(4):2495–2501.
  52. Vidovic S, Vladić J, Nastic N, Jokić S. Supercritical fluid techniques in drug co-crystal engineering. In: Innovative Food Processing Technologies. 2020:705–721.
  53. European Medicines Agency. Reflection paper on the use of cocrystals of active substances in medicinal products. EMA/CHMP/NCE/2014. London: EMA; 2015. Available from: https://www.ema.europa.eu
  54. Huang S, Xu J, Peng Y, Guo M, Cai T. Tuning photoluminescence and dissolution of phloretin through cocrystallization. Cryst Growth Des. 2019;19(12):6837–6844.
  55. Raghuram M, Alam MS, Prasad M, Khanduri CH. Physicochemical characterization of pharmaceutical cocrystals. Tetrahedron Lett. 2014;55(2):279–282.
  56. Thomas SP, Sathishkumar R, Guru Row TN. Organic alloys and drug–drug cocrystal of three common analgesic drugs: aspirin, paracetamol and ibuprofen. Chem Commun. 2015;51(72):14255–14258.
  57. Romasanta AKS, Braga D, Duarte MT, Grepioni F. Changing properties by making pharmaceutical cocrystals: the case of zidovudine and lamivudine. CrystEngComm. 2017;19(4):653–660.
  58. Lusi M, Vitorica-Yrezabal IJ, Zaworotko MJ. Expanding the scope of molecular mixed crystals enabled by three component solid solutions. Cryst Growth Des. 2015;15(8):4098–4103.
  59. Trask AV, Motherwell WDS, Jones W. Physical stability enhancement of theophylline via cocrystallisation. Int J Pharm. 2006;320(1–2):114–123.
Regular Issue Subscription Review Article
Volume 14
Issue 03
Received 24/04/2026
Accepted 08/05/2026
Published 18/05/2026
Publication Time 24 Days
110

Login


My IP

PlumX Metrics