Carvedilol is a third generation non-cardioselective β-blocker used in the treatment of hypertension and demonstrated a potential in the treatment of cardiovascular diseases such as myocardial infarction and arrhythmias. For any drug to be therapeutically effective, it must enter the systemic circulation and to do so, it should have an optimum aqueous solubility at the site of absorption which is a major hurdle to overcome by a formulation scientist. Carvedilol belongs to BCS (biopharmaceutical classification system) class II drugs, thus having low solubility and poor bioavailability (around 25%). Hence, the purpose of this review is to elaborate on several approaches to increase the solubility, dissolution, and bioavailability of carvedilol.
Micronization, solid dispersions, cyclodextrin inclusion complex, hydrotropy, nanoformulation which include nanocrystals, nanosuspension, nanoemulsions, dendrimers, and polymeric nanoparticles. It also includes methods that have not been used on carvedilol such as cocrystallization and coamorphous technology.
Several approaches have successfully increased solubility and bioavailability of carvedilol and several other unexplored methods which have the potential to improve the aqueous solubility of carvedilol but have not been applied till date have also been discussed in the review.
There are various approaches explored to increase the solubility of carvedilol with every technique having certain advantages and drawbacks. Micronization and nanoformulations (dendrimers, nanoemulsion, nanosuspension, nanocrystals, polymeric nanoparticles) are the most widely used technique for solubility enhancement of carvedilol on laboratory scale due to higher solubility and dissolution rate but they have poor industrial applicability due to difficulty in scale-up and low yield. Efforts are being made to carry out different solubility enhancement techniques with good industrial applicability for carvedilol, e.g., cocrystals. Cocrystals and coamorphous approach for poorly soluble drugs having similar properties to carvedilol have shown good solubility, dissolution, and bioavailability compared to few techniques discussed in this review, and are being widely explored to overcome the drawbacks associated with its method of preparation by carrying out certain advancements (e.g., hot melt extrusion and sonocrystallization) to produce carvedilol cocrystals and coamorphous compound with unique properties in future development.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
Frishman WH, Henderson LS, Lukas MA. Controlled-release carvedilol in the management of systemic hypertension and myocardial dysfunction. Vasc Health Risk Manag. 2008;4(6):1387.
Freemantle N, Cleland J, Young P, Mason J, Harrison J. β Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999;318(7200):1730–7.
Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and enhancement techniques. ISRN Pharm 2012;2012.
Kalimuthu S, Yadav AV. Formulation and evaluation of carvedilol loaded eudragit E100 nanoparticles. Int J PharmTech Res. 2009;1:179–83.
Jamakandi VG. Formulation and evaluation of immediate release tablet of carvedilol using liquisolid compacts technique for solubility enhancement. Asian J Pharm (AJP). 2016;10(03).
Campoli RD, Sorkin E. Carvedilol: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy. Drugs. 1993;45:232–58.
Drugbank.ca. Carvedilol—DrugBank. 2017. [online] Available at: https://www.drugbank.ca/drugs/DB01136#pharmacology [Accessed 24 Jul 2017].
Arzani G, Haeri A, Daeihamed M, Bakhtiari-Kaboutaraki H, Dadashzadeh S. Niosomal carriers enhance oral bioavailability of carvedilol: effects of bile salt-enriched vesicles and carrier surface charge. Int J Nanomedicine. 2015;10:4797.
Zoghbi A, Wang B. Carvedilol solubility enhancement by inclusion complexation and solid dispersion. J Drug Deliv Ther. 2015;5(2):1–8.
Nollenberger, T. Using polymers to enhance solubility of poorly soluble drugs. 2017 [online] Pharmtech.com. Available at: http://www.pharmtech.com/using-polymers-enhance-solubility-poorly-soluble-drugs [Accessed 25 Jul 2017].
Chu K, Lee E, Jeong S, Park E. Effect of particle size on the dissolution behaviors of poorly water-soluble drugs. Arch Pharm Res. 2012;35(7):1187–95.
Chatterjee B, Pal TK. Development and in vitro evaluation of micronized sustained release matrix tablet of carvedilol. Int J Pharm Sci Res. 2010;1:96–102.
Mogal SA, Gurjar PN, Yamgar DS, Kamod AC. Solid dispersion technique for improving solubility of some poorly soluble drugs. Pharm Lett. 2012;4(5):1574–86.
Gala U, Pham H, Chauhan H. Pharmaceutical applications of eutectic mixtures. J Dev Drugs. 2013;2:1–2.
Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971;60(9):1281–302.
Sharma A, Jain CP, Tanwar YS. Preparation and characterization of solid dispersions of carvedilol with poloxamer 188. J Chil Chem Soc. 2013;58(1):1553–7.
Planinšek O, Kovačič B, Vrečer F. Carvedilol dissolution improvement by preparation of solid dispersions with porous silica. Int J Pharm. 2011;406(1):41–8.
Ayoub M, Hasan A, El Nahas H, Ghazy FE. Enhancing oral bioavailability of carvedilol using solid dispersion technique. Int J Pharm Pharm Sci. 2016;8(7):193–9.
Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov. 2004;3(12):1023.
Nekkanti V, Muniyappan T, Karatgi P, Hari MS, Marella S, Pillai R. Spray-drying process optimization for manufacture of drug–cyclodextrin complex powder using design of experiments. Drug Dev Ind Pharm. 2009;35(10):1219–29.
Wen X, Tan F, Jing Z, Liu Z. Preparation and study the 1: 2 inclusion complexes of carvedilol with β-cyclodextrin. J Pharm Biomed Anal. 2004;34(3):517–23.
Moriwaki C, Costa GL, Ferracini CN, de Moraes FF, Zanin GM, Pineda EA, et al. Enhancement of solubility of albendazole by complexation with β-cyclodextrin. Braz J Chem Eng. 2008;25(2):255–67.
Chaudhary VB, Patel JK. Cyclodextrin inclusion complex to enhance solubility of poorly water-soluble drugs: a review. Int J Pharm Sci Res. 2013;4(1):68.
Vemula VR, Lagishetty V, Lingala S. Solubility enhancement techniques. Int J Pharm Sci Rev Res. 2010;5(1):41–51.
Chowdary KP, Kumar AP. Recent research on formulation development of BCS class II drugs—a review. Int Res J Pharm Appl Sci. 2013;3:173–81.
Perrut M, Jung J, Leboeuf F. Enhancement of dissolution rate of poorly-soluble active ingredients by supercritical fluid processes: Part I: Micronization of neat particles. Int J Pharm. 2005;288(1):3–10.
Patil JS, Kadam DV, Marapur SC, Kamalapur MV. Inclusion complex system: a novel technique to improve the solubility and bioavailability of poorly soluble drugs: a review. Int J Pharm Sci Rev Res. 2010;2(2):29–33.
Sapana BB, Shashikant DN. Preparation and characterisation of [beta]-cyclodextrin nebivolol inclusion complex. Int J Pharm Sci Res. 2015;6(5):2205.
Hirlekar R, Kadam V. Preparation and characterization of inclusion complexes of carvedilol with methyl-β-cyclodextrin. J Incl Phenom Macrocycl Chem. 2009;63(3–4):219–24.
Nidhi K, Indrajeet S, Khushboo M, Gauri K, Sen DJ. Hydrotropy: a promising tool for solubility enhancement: a review. Int J Drug Dev Res. 2011;
Chikhle H, Pandey V, Ganeshpurkar A, Dubey N, Bansal D. Solubility enhancement of carvedilol using mixed hydrotropy. Asian J Biomater Res. 2016;2(2):62–5.
Yadollahi R, Vasilev K, Simovic S. Nanosuspension technologies for delivery of poorly soluble drugs. J Nanomater. 2015;2015:1–13.
Junghanns JU, Müller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3(3):295.
Junyaprasert VB, Morakul B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J Pharm Sci. 2015;10(1):13–23.
Chi Lip Kwok P, Chan HK. Nanotechnology versus other techniques in improving drug dissolution. Curr Pharm Des. 2014;20(3):474–82.
Gao Y, Wang J, Wang Y, Yin Q, Glennon B, Zhong J, et al. Crystallization methods for preparation of nanocrystals for drug delivery system. Curr Pharm Des. 2015;21(22):3131–9.
Kulkarni SA, Myerson AS. Methods for crystals preparation. In Engineering Crystallography: From Molecule to Crystal to Functional Form 2017 (pp. 275–287). Springer, Dordrecht.
Gulsun T, Gursoy RN, Levent O. Nanocrystal technology for oral delivery of poorly water-soluble drugs. FABAD J Pharm Sci. 2009;7:34(5).
Janakiraman AK, Sumathi B, Saleem TM, Ramkanth S, Kumar PO, Venkatachalam G. Design and evaluation of carvedilol nanocrystals sustained release tablets. J Appl Pharm Sci. 2017;7(04):061–8.
Liu D, Pan H, He F, Wang X, Li J, Yang X, et al. Effect of particle size on oral absorption of carvedilol nanosuspensions: in vitro and in vivo evaluation. Int J Nanomedicine. 2015;10:6425.
Patil SK, Wagh KS, Parik VB, Akarte AM, Baviskar DT. Strategies for solubility enhancement of poorly soluble drugs. Int J Pharm Sci Rev Res. 2011;8(2):74–80.
Chung NO, Lee MK, Lee J. Mechanism of freeze-drying drug nanosuspensions. Int J Pharm. 2012;437(1):42–50.
Bouchemal K, Briançon S, Perrier E, Fessi H. Nano-emulsion formulation using spontaneous emulsification: solvent, oil and surfactant optimisation. Int J Pharm. 2004;280(1):241–51.
Jasmina H, Džana O, Alisa E, Edina V, Ognjenka R. Preparation of nanoemulsions by high-energy and low energy emulsification methods. InCMBEBIH 2017 2017 (pp. 317–322). Springer, Singapore.
Chidi E, Ikenna NE, Zainab A, John F. Universal Journal of Pharmaceutical Research Development And Evaluation Of Nanoemulsion Formulations For Improved Oral Delivery Of Carvedilol. Univ J Pharm Res. 2017;2(1):2456–8058.
Madaan K, Kumar S, Poonia N, Lather V, Pandita D. Dendrimers in drug delivery and targeting: drug-dendrimer interactions and toxicity issues. J Pharm Bioallied Sci. 2014;6(3):139.
Sharma M, Sharma R, Jain D. Nanotechnology based approaches for enhancing oral bioavailability of poorly water soluble antihypertensive drugs. Scientifica. 2016;2016:1–11.
Hart ML, Do DP, Ansari RA, Rizvi SA. Brief overview of various approaches to enhance drug solubility. J Dev Drugs. 2013;2(3):100011.
Ornelas C, Pennell R, Liebes LF, Weck M. Construction of a well-defined multifunctional dendrimer for theranostics. Org Lett. 2011;13(5):976–9.
Zheng X, Wang T, Jiang H, Li Y, Jiang T, Zhang J, et al. Incorporation of carvedilol into PAMAM-functionalized MWNTs as a sustained drug delivery system for enhanced dissolution and drug-loading capacity. Asian J Pharm Sci. 2013;8(5):278–86.
Mohanraj VJ, Chen Y. Nanoparticles—a review. Trop J Pharm Res. 2006;5(1):561–73.
Nagavarma BV, Yadav HK, Ayaz A, Vasudha LS, Shivakumar HG. Different techniques for preparation of polymeric nanoparticles—a review. Asian J Pharm Clin Res. 2012;5(3):16–23.
Khan S, Ali W, Rahman NU, Shah SM, Khan J, Shah SM, et al. Self-assembled biodegradable polymeric nanoparticles with improved solubility of carvedilol: preparation, characterisation and in vitro release kinetics. Int J Pharm Sci Res. 2016;7(10):3971.
Sanjay AN, Manohar SD, Bhanudas SR. Pharmaceutical cocrystallization: a review. J Adv Pharm Educ Res 2014;4(4).
Patole T, Deshpande A. Co-crystallization—a technique for solubility enhancement. Int J Pharm Sci Res. 2014;5(9):3566.
Jampílek J, Dohnal J. Investigation of carbohydrates and their derivatives as crystallization modifiers. InCarbohydrates-Comprehensive Studies on Glycobiology and Glycotechnology 2012. InTech.
Kotak U, Prajapati V, Solanki H, Jani G, Jha P. Co-crystallization technique its rationale and recent progress. World J Pharm Pharm Sci. 2015;4(4):1484–508.
Prasad RV, Rakesh MG, Jyotsna RM, Mangesh ST, Anita PS, Mayur PK. Pharmaceutical cocrystallization: a review. Int J Pharm Chem Sci. 2012;1(3):725–36.
Mounika P, Raj SV, Divya G, Gowramma A, Vijayamma G, Rangampet A, et al. Preparation and characterization of novel co-crystal forms of fexofenadine. Int J Innov Pharm Res. 2015;6(1):458–63.
Yamamoto K, Tsutsumi S, Ikeda Y. Establishment of cocrystal cocktail grinding method for rational screening of pharmaceutical cocrystals. Int J Pharm. 2012;437(1):162–71.
(23b) Slurry crystallization of water-insoluble drug substance—overcoming challenges in solubility and miscibility requirements for solvents and anti-solvents | AIChE Academy [Internet]. Aiche.org. 2017 [Accesed on 7 Oct 2017]. Available from: https://www.aiche.org/conferences/aiche-annual-meeting/2012/proceeding/paper/23b-slurry-crystallization-water-insoluble-drug-substance-overcoming-challenges-solubility-and
Shewale S, Shete AS, Doijad RC, Kadam SS, Patil VA, Yadav AV. Formulation and solid-state characterization of nicotinamide-based co-crystals of fenofibrate. Indian J Pharm Sci. 2015;77(3):328.
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.
Dhumal RS, Kelly AL, York P, Coates PD, Paradkar A. Cocrystallization and simultaneous agglomeration using hot melt extrusion. Pharm Res. 2010;27(12):2725–33.
Yadav S, Gupta PC, Sharma N, Kumar J. Cocrystals: an alternative approach to modify physicochemical properties of drugs. Int J Pharm Chem Biol Sci. 2015;5(2).
Sanjay AN, Manohar SD, Bhanudas SR. Pharmaceutical cocrystallization: a review. J Adv Pharm Educ Res 2014;4(4).
Aher S, Dhumal R, Mahadik K, Paradkar A, York P. Ultrasound assisted cocrystallization from solution (USSC) containing a non-congruently soluble cocrystal component pair: caffeine/maleic acid. Eur J Pharm Sci. 2010;41(5):597–602.
Dengale SJ, Grohganz H, Rades T, Löbmann K. Recent advances in co-amorphous drug formulations. Adv Drug Deliv Rev. 2016;100:116–25.
Jensen KT, Löbmann K, Rades T, Grohganz H. Improving co-amorphous drug formulations by the addition of the highly water soluble amino acid, proline. Pharmaceutics. 2014;6(3):416–35.
Chein W, Lamey K, Malofiy J, Oh C. Carvedilol formulations. WO 2003092625 A2, 2003
Oh C, Oh Choon K. Novel composition of carvedilol. United States patent application US 10/491,195. 2004 Oct 1.
Liversidge G, Jenkins S. Carvedilol phosphate solid dispersion. CA 2643492 A1, 2007.
Gary Liversidge, Scott Jenkins. Nanoparticle formulation of carvedilol. EP1996161A2, 2008
Parthasaradhi R, Rathnakar R, Muralidhara R, Subash C, Vamsi K. Carvedilol phosphate solid dispersion. WO 2014108921 A3, 2015.
About this article
Cite this article
Fernandes, G.J., Kumar, L., Sharma, K. et al. A Review on Solubility Enhancement of Carvedilol—a BCS Class II Drug. J Pharm Innov 13, 197–212 (2018). https://doi.org/10.1007/s12247-018-9319-z
- Solubility enhancement
- Solid dispersion
- Cyclodextrin inclusion complex