Advancing Ticagrelor Bioavailability: A Comprehensive Review of Solubility Enhancement Techniques

Main Article Content

Muhammad Luthfi Shidik
Tania Miranda Sarlie
Rachmat Mauludin
Saleh Wikarsa
Yuda Prasetya Nugraha

Abstract

Ticagrelor (TICA) inhibits platelet activity by reversibly binding to the P₂Y₁₂  receptor, it is classified as a BCS class IV drug with low solubility and permeability. BCS Class IV drugs have a major challenge due to their reduced rate of dissolution, which leads to poor bioavailability. The absolute bioavailability of TICA after oral administration is ~36%. Various techniques, including particle size reduction, solid dispersion, lipid-based formulation, co-crystals, and polymeric micelles can increase solubility. This article discusses the methodology used to increase the solubility of ticagrelor, thereby emphasizing the research that has been conducted and documented. The increased bioavailability of ticagrelor is apparent when formulated as a solid dispersion (SD), self- microemulsifying drug delivery system (SMEDDS), self-nanoemulsifying drug delivery system (SNEDDS), nanostructured lipid carriers (NLC), suspensions, and co-crystals. Among these approaches, co-crystals and solid dispersions are highly recommended for improving the solubility of ticagrelor. This review provides insights into formulation strategies for improving ticagrelor solubility, guiding future research on its bioavailability and efficacy

Article Details

How to Cite
Shidik, M. L., Tania Miranda Sarlie, Rachmat Mauludin, Saleh Wikarsa, & Yuda Prasetya Nugraha. (2025). Advancing Ticagrelor Bioavailability: A Comprehensive Review of Solubility Enhancement Techniques. Jurnal Sains Farmasi & Klinis, 12(1), 50–62. https://doi.org/10.25077/jsfk.12.1.50-62.2025
Section
Review Articles

References

[1]. Roffman DS. Developments in oral antiplatelet agents for the treatment of acute coronary syndromes: Clopidogrel, prasugrel, and ticagrelor. In: Journal of Pharmacy Practice. SAGE Publications Inc.; 2016. p. 239–49. https://doi.org/10.1177/0897190014568383

[2]. Herron GC, Bates ER. Review of the Ticagrelor Trials Evidence Base. J Am Heart Assoc. 2024;13(11). https://doi.org/10.1161/JAHA.123.031606,

[3]. Štambuk K. The Ticagrelor Era. Cardiologia Croatica. 2022;17(3–4):76–80. https://doi.org/10.15836/CCAR2022.76

[4]. Wang L, Zhao Y, Zhang S, Zhang T, Song J, Yun Y, et al. Ticagrelor vs. clopidogrel in dual antiplatelet therapy after coronary artery bypass surgery: a meta-analysis. Front Cardiovasc Med. 2025;12. https://doi.org/10.3389/FCVM.2025.1542437/PDF

[5]. Sohn JS, Choi JS. A study on the improved dissolution and permeability of ticagrelor with sodium oleate in a ternary system. J Mol Liq. 2022;361. https://doi.org/10.1016/j.molliq.2022.119685

[6]. Fda. BRILINTA® (ticagrelor) tablets, for oral use. Available from: www.fda.gov/medwatch.

[7]. Na YG, Byeon JJ, Wang M, Huh HW, Son GH, Jeon SH, et al. Strategic approach to developing a self-microemulsifying drug delivery system to enhance antiplatelet activity and bioavailability of ticagrelor. Int J Nanomedicine. 2019;14:1193–212. https://doi.org/10.2147/IJN.S190426

[8]. Markovic M, Zur M, Ragatsky I, Cvijić S, Dahan A. Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide. Pharmaceutics. 2020;12(12):1–16. https://doi.org/10.3390/pharmaceutics12121175

[9]. Shahid N, Erum A, Zaman M, Tulain UR, Shoaib Q ul ain, Malik NS, et al. Synthesis and evaluation of chitosan based controlled release nanoparticles for the delivery of ticagrelor. Des Monomers Polym. 2022;25(1):55–63. https://doi.org/10.1080/15685551.2022.2054117

[10]. Inam M, Wu J, Shen J, Phan CU, Tang G, Hu X. Preparation and characterization of novel pharmaceutical co-crystals: Ticagrelor with nicotinamide. Crystals (Basel). 2018;8(9). https://doi.org/10.3390/cryst8090336

[11]. Chen K, Xia T, Shao D, Zhou G, Shen J, Yang Z. Solubility Measurement and Mathematical Correlation of Ticagrelor in Different Pure Solvents. J Chem Eng Data. 2020;65(7):3560–5. https://doi.org/10.1021/acs.jced.0c00127

[12]. Kumari L, Choudhari Y, Patel P, Gupta G Das, Singh D, Rosenholm JM, et al. Advancement in Solubilization Approaches: A Step towards Bioavailability Enhancement of Poorly Soluble Drugs. Vol. 13, Life. MDPI; 2023. https://doi.org/10.3390/life13051099

[13]. Srivastava A, Khan MA, Bedi S, Bhandari U. A Review on Different Solubility Enhancement Techniques of Ticagrelor. Int J Pharm Investig. 2022;13(1):01–6. https://doi.org/10.5530/223097131574

[14]. Dhaval M, Dudhat K, Soniwala M, Dudhrejiya A, shah S, Prajapati B. A review on stabilization mechanism of amorphous form based drug delivery system. Vol. 37, Materials Today Communications. Elsevier Ltd; 2023. https://doi.org/10.1016/j.mtcomm.2023.107411

[15]. Kabil MF, Abo Dena AS, El-Sherbiny IM. Ticagrelor. In: Profiles of Drug Substances, Excipients and Related Methodology. Academic Press Inc.; 2022. p. 91–111. https://doi.org/10.1016/bs.podrm.2021.10.003

[16]. Ren Y, Shen J, Yu KX, Phan CU, Chen GX, Liu JY, et al. Impact of crystal habit on solubility of ticagrelor. Crystals (Basel). 2019;9(11). https://doi.org/10.3390/cryst9110556

[17]. Agarwal et al. - 2017 - Crystalline form of ticagrelor.

[18]. Rizea-Savu S, Duna SN, Ghita A, Iordachescu A, Garlea I, Chirila M. Pharmacokinetics and Bioequivalence of a Generic Ticagrelor 90-mg Formulation Versus the Innovator Product in Healthy White Subjects Under Fasting Conditions. Clin Pharmacol Drug Dev. 2024;14(1). https://doi.org/10.1002/CPDD.1471,

[19]. Teng R. Ticagrelor: Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Profile: An Update. Clin Pharmacokinet. 2015;54(11):1125–38. https://doi.org/10.1007/S40262-015-0290-2

[20]. Ticagrelor. Meyler’s Side Effects of Drugs. 2016;962–3. https://doi.org/10.1016/B978-0-444-53717-1.01719-4

[21]. Hassane SY, Secrétan PH, Henriet T, Bernard M, Amrani F, Akrout W, et al. Identification of the major degradation pathways of ticagrelor. J Pharm Biomed Anal. 2015;105:74–83. https://doi.org/10.1016/j.jpba.2014.11.046

[22]. EUROPEAN PHARMACOPOEIA 11.0 [Internet]. Available from: www.webofpharma.com

[23]. Xie B, Liu Y, Li X, Yang P, He W. Solubilization techniques used for poorly water-soluble drugs. Acta Pharm Sin B. 2024;14(11). https://doi.org/10.1016/j.apsb.2024.08.027

[24]. Sun J, Wang F, Sui Y, She Z, Zhai W, Wang C, et al. Effect of particle size on solubility, dissolution rate, and oral bioavailability: Evaluation using coenzyme Q10 as naked nanocrystals. Int J Nanomedicine. 2012;7:5733–44. https://doi.org/10.2147/IJN.S34365

[25]. Zi P, Zhang C, Ju C, Su Z, Bao Y, Gao J, et al. Solubility and bioavailability enhancement study of lopinavir solid dispersion matrixed with a polymeric surfactant - Soluplus. European Journal of Pharmaceutical Sciences. 2019;134:233–45. https://doi.org/10.1016/j.ejps.2019.04.022

[26]. Kim DS, Cho JH, Park JH, Kim JS, Song ES, Kwon J, et al. Self-microemulsifying drug delivery system (SMEDDS) for improved oral delivery and photostability of methotrexate. Int J Nanomedicine. 2019;14:4949–60. https://doi.org/10.2147/IJN.S211014

[27]. Krstić M, Medarević Đ, Đuriš J, Ibrić S. Self-nanoemulsifying drug delivery systems (SNEDDS) and self-microemulsifying drug delivery systems (SMEDDS) as lipid nanocarriers for improving dissolution rate and bioavailability of poorly soluble drugs. Lipid Nanocarriers for Drug Targeting. 2018;473–508. https://doi.org/10.1016/B978-0-12-813687-4.00012-8

[28]. Huang Z, Staufenbiel S, Bodmeier R. Combination of co-crystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs. Pharm Res. 2022;39(5):949–61. https://doi.org/10.1007/S11095-022-03243-9/FIGURES/11

[29]. Rani S, Mishra S, Sharma M, Nandy A, Mozumdar S. Solubility and stability enhancement of curcumin in Soluplus® polymeric micelles: a spectroscopic study. J Dispers Sci Technol. 2020;41(4):523–36. https://doi.org/10.1080/01932691.2019.1592687

[30]. Park JJ, Meghani N, Choi JS, Lee BJ. Development and evaluation of decorated aceclofenac nanocrystals. Colloids Surf B Biointerfaces. 2016;143:206–12. https://doi.org/10.1016/j.colsurfb.2016.03.022

[31]. Wang H, Qi J, Li Y, Tang Y, Li C, Li J, et al. Pharmacodynamics and pharmacokinetics of ticagrelor vs. clopidogrel in patients with acute coronary syndromes and chronic kidney disease. Br J Clin Pharmacol. 2018;84(1):88–96. https://doi.org/10.1111/BCP.13436,

[32]. Liu X, Feng X, Williams RO, Zhang F. Characterization of amorphous solid dispersions. Vol. 48, Journal of Pharmaceutical Investigation. Springer Netherlands; 2018. p. 19–41. https://doi.org/10.1007/s40005-017-0361-5

[33]. Chaudhari SP, Dugar RP. Application of surfactants in solid dispersion technology for improving solubility of poorly water soluble drugs. J Drug Deliv Sci Technol. 2017;41:68–77. https://doi.org/10.1016/J.JDDST.2017.06.010

[34]. Kim SJ, Lee HK, Na YG, Bang KH, Lee HJ, Wang M, et al. A novel composition of ticagrelor by solid dispersion technique for increasing solubility and intestinal permeability. Int J Pharm. 2019;555:11–8. https://doi.org/10.1016/j.ijpharm.2018.11.038

[35]. Kini A, Patel SB. Phase behavior, intermolecular interaction, and solid state characterization of amorphous solid dispersion of Febuxostat. Pharm Dev Technol. 2017;22(1):45–57. https://doi.org/10.3109/10837450.2016.1138130,

[36]. Yeom DW, Song YS, Kim SR, Lee SG, Kang MH, Lee S, et al. Development and optimization of a self-microemulsifying drug delivery system for atorvastatin calcium by using D-optimal mixture design. Int J Nanomedicine. 2015;10:3865–78. https://doi.org/10.2147/IJN.S83520,

[37]. Kamboj S, Sharma R, Singh K, Rana V. Aprepitant loaded solid preconcentrated microemulsion for enhanced bioavailability: A comparison with micronized Aprepitant. European Journal of Pharmaceutical Sciences. 2015;78:90–102. https://doi.org/10.1016/J.EJPS.2015.07.008

[38]. Krishnamoorthy B, Habibur Rahman SM, Tamil selvan N, Hari prasad R, Rajkumar M, Siva selvakumar M, et al. Design, formulation, in vitro, in vivo, and pharmacokinetic evaluation of nisoldipine-loaded self-nanoemulsifying drug delivery system. Journal of Nanoparticle Research. 2015;17(1). https://doi.org/10.1007/S11051-014-2818-Z

[39]. Lv X, Zhang S, Ma H, Dong P, Ma X, Xu M, et al. In situ monitoring of the structural change of microemulsions in simulated gastrointestinal conditions by SAXS and FRET. Acta Pharm Sin B. 2018;8(4):655–65. https://doi.org/10.1016/j.apsb.2018.05.008

[40]. Bi X, Liu X, Di L, Zu Q. Improved Oral Bioavailability Using a Solid Self-Microemulsifying Drug Delivery System Containing a Multicomponent Mixture Extracted from Salvia miltiorrhiza. Molecules. 2016;21(4). https://doi.org/10.3390/MOLECULES21040456,

[41]. Beloqui A, Solinís MÁ, Rodríguez-Gascón A, Almeida AJ, Préat V. Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomedicine. 2016;12(1):143–61. https://doi.org/10.1016/J.NANO.2015.09.004,

[42]. Son GH, Na YG, Huh HW, Wang M, Kim MK, Han MG, et al. Systemic design and evaluation of ticagrelor-loaded nanostructured lipid carriers for enhancing bioavailability and antiplatelet activity. Pharmaceutics. 2019;11(5). https://doi.org/10.3390/pharmaceutics11050222

[43]. Mohammadi MR, Nojoomi A, Mozafari M, Dubnika A, Inayathullah M, Rajadas J. Nanomaterials engineering for drug delivery: a hybridization approach. J Mater Chem B. 2017;5(22):3995–4018. https://doi.org/10.1039/C6TB03247H

[44]. Poovi G, Damodharan N. Lipid nanoparticles: A challenging approach for oral delivery of BCS Class-II drugs. Futur J Pharm Sci. 2018;4(2):191–205. https://doi.org/10.1016/J.FJPS.2018.04.001

[45]. Nguyen VH, Thuy VN, Van TV, Dao AH, Lee BJ. Nanostructured lipid carriers and their potential applications for versatile drug delivery via oral administration. OpenNano. 2022;8:100064. https://doi.org/10.1016/J.ONANO.2022.100064

[46]. Gan L, Zhang C, Wu F, Li H, Zhang WP, Zhang Q. Microencapsulated nanostructured lipid carriers as delivery system for rutin. Materials Technology. 2018;33(5):357–63. https://doi.org/10.1080/10667857.2018.1446406

[47]. Franco V, Gershkovich P, Perucca E, Bialer M. The Interplay Between Liver First-Pass Effect and Lymphatic Absorption of Cannabidiol and Its Implications for Cannabidiol Oral Formulations. Clin Pharmacokinet. 2020;59(12):1493–500. https://doi.org/10.1007/S40262-020-00931-W,

[48]. Rizvi SZH, Shah FA, Khan N, Muhammad I, Ali KH, Ansari MM, et al. Simvastatin-loaded solid lipid nanoparticles for enhanced anti-hyperlipidemic activity in hyperlipidemia animal model. Int J Pharm. 2019;560:136–43. https://doi.org/10.1016/J.IJPHARM.2019.02.002

[49]. Lu S, Yu PP, He JH, Zhang SS, Xia YL, Zhang WL, et al. Enhanced dissolution and oral bioavailability of lurasidone hydrochloride nanosuspensions prepared by antisolvent precipitation-ultrasonication method. RSC Adv. 2016;6(54):49052–9. https://doi.org/10.1039/C6RA08392G

[50]. Huang S, Zhang Q, Li H, Sun Y, Cheng G, Zou M, et al. Increased bioavailability of efonidipine hydrochloride nanosuspensions by the wet-milling method. European Journal of Pharmaceutics and Biopharmaceutics. 2018;130:108–14. https://doi.org/10.1016/J.EJPB.2018.06.022,

[51]. Wang H, Xiao Y, Wang H, Sang Z, Han X, Ren S, et al. Development of daidzein nanosuspensions: Preparation, characterization, in vitro evaluation, and pharmacokinetic analysis. Int J Pharm. 2019;566:67–76. https://doi.org/10.1016/J.IJPHARM.2019.05.051,

[52]. Gajera BY, Shah DA, Dave RH. Development of an amorphous nanosuspension by sonoprecipitation-formulation and process optimization using design of experiment methodology. Int J Pharm. 2019;559:348–59. https://doi.org/10.1016/j.ijpharm.2019.01.054

[53]. Na YG, Pham TMA, Byeon JJ, Kim MK, Han MG, Baek JS, et al. Development and evaluation of TPGS/PVA-based nanosuspension for enhancing dissolution and oral bioavailability of ticagrelor. Int J Pharm. 2020;581. https://doi.org/10.1016/j.ijpharm.2020.119287

[54]. Mishra B, Sahoo J, Dixit PK. Enhanced bioavailability of cinnarizine nanosuspensions by particle size engineering: Optimization and physicochemical investigations. Materials Science and Engineering C. 2016;63:62–9. https://doi.org/10.1016/j.msec.2016.02.046

[55]. Bartos C, Ambrus R, Katona G, Sovány T, Gáspár R, Márki Á, et al. Transformation of Meloxicam containing nanosuspension into surfactant-free solid compositions to increase the product stability and drug bioavailability for rapid analgesia. Drug Des Devel Ther. 2019;13:4007–20. https://doi.org/10.2147/DDDT.S220876,

[56]. Mishra B, Sahoo J, Dixit PK. Formulation and process optimization of naproxen nanosuspensions stabilized by hydroxy propyl methyl cellulose. Carbohydr Polym. 2015;127:300–8. https://doi.org/10.1016/J.CARBPOL.2015.03.077,

[57]. Ullah M, Ullah H, Murtaza G, Mahmood Q, Hussain I. Evaluation of influence of various polymers on dissolution and phase behavior of carbamazepine-succinic acid cocrystal in matrix tablets. Biomed Res Int. 2015;2015. https://doi.org/10.1155/2015/870656,

[58]. Emami S, Siahi-Shadbad M, Adibkia K, Barzegar-Jalali M. Recent advances in improving oral drug bioavailability by cocrystals. BioImpacts. 2018;8(4):305–20. https://doi.org/10.15171/BI.2018.33,

[59]. Li L, Pang Z, Ma K, Gao Y, Zheng D, Wei Y, et al. Effect of Coformer Selection on In Vitro and In Vivo Performance of Adefovir Dipivoxil Cocrystals. Pharm Res. 2021;38(10):1777–91. https://doi.org/10.1007/S11095-021-03116-7,

[60]. Bavishi DD, Borkhataria CH. Spring and parachute: How cocrystals enhance solubility. Vol. 62, Progress in Crystal Growth and Characterization of Materials. Elsevier Ltd; 2016. p. 1–8. https://doi.org/10.1016/j.pcrysgrow.2016.07.001

[61]. Devhare LD, Kore PK. A Recent Review on Bioavailability and Solubility Enhancement of Poorly Soluble Drugs by Physical and Chemical Modifications [Internet]. Available from: https://ssrn.com/abstract=4455504

[62]. Triboandas H, Pitt K, Bezerra M, Ach-Hubert D, Schlindwein W. Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools. Pharmaceutics. 2022;14(11). https://doi.org/10.3390/pharmaceutics14112398

[63]. Yang X, Gao P, Jiang Z, Luo Q, Mu C, Cui M. Preparation and Evaluation of Self-emulsifying Drug Delivery System (SEDDS) of Cepharanthine. AAPS PharmSciTech. 2021;22(7). https://doi.org/10.1208/s12249-021-02085-9

[64]. Sarabia-Vallejo Á, Caja M del M, Olives AI, Martín MA, Menéndez JC. Cyclodextrin Inclusion Complexes for Improved Drug Bioavailability and Activity: Synthetic and Analytical Aspects. Vol. 15, Pharmaceutics. Multidisciplinary Digital Publishing Institute (MDPI); 2023. https://doi.org/10.3390/pharmaceutics15092345

[65]. Sherje AP, Jadhav M. β-Cyclodextrin-based inclusion complexes and nanocomposites of rivaroxaban for solubility enhancement. J Mater Sci Mater Med. 2018;29(12):1–8. https://doi.org/10.1007/S10856-018-6194-6/METRICS

[66]. Fu Q, Lu HD, Xie YF, Liu JY, Han Y, Gong NB, et al. Salt formation of two BCS II drugs (indomethacin and naproxen) with (1R, 2R)-1,2-diphenylethylenediamine: Crystal structures, solubility and thermodynamics analysis. J Mol Struct. 2019;1185:281–9. https://doi.org/10.1016/j.molstruc.2019.02.104

[67]. Wang Z, Li S, Li Q, Wang W, Liu M, Yang S, et al. A Novel Cocrystal of Daidzein with Piperazine to Optimize the Solubility, Permeability and Bioavailability of Daidzein. Molecules. 2024;29(8). https://doi.org/10.3390/molecules29081710

[68]. He Z, Wan X, Schulz A, Bludau H, Dobrovolskaia MA, Stern ST, et al. A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity. Biomaterials. 2016;101:296–309. https://doi.org/10.1016/j.biomaterials.2016.06.002

[69]. Yadav M, Sarolia J, Vyas B, Lalan M, Mangrulkar S, Shah P. Amalgamation of Solid Dispersion and Melt Adsorption Technique: Improved In Vitro and In Vivo Performance of Ticagrelor Tablets. AAPS PharmSciTech. 2021;22(8). https://doi.org/10.1208/s12249-021-02138-z

[70]. Aziz A, Zaman M, Khan MA, Jamshaid T, Butt MH, Hameed H, et al. Preparation and Evaluation of a Self-Emulsifying Drug Delivery System for Improving the Solubility and Permeability of Ticagrelor. ACS Omega. 2024;9(9):10522–38. https://doi.org/10.1021/acsomega.3c08700

[71]. Shane NLJ, Chamle AH, Vasantharaju, Pai A, Pai G, Sathyanarayana MB. Fabrication and solid state characterization of ticagrelor co-crystals with improved solubility and dissolution. International Journal of Pharmaceutical Quality Assurance. 2017;8(1):1–8. https://doi.org/10.25258/ijpqa.v8i1.8433