Author(s): Gunjan Vyas, Shah Jigar, Shery Jacob


DOI: 10.52711/0974-360X.2024.00010   

Address: Gunjan Vyas1, Shah Jigar1*, Shery Jacob2
1Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad - 382481, Gujarat, India.
2Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, United Arab Emirates.
*Corresponding Author

Published In:   Volume - 17,      Issue - 1,     Year - 2024

Biopharmaceutical Classification System II drug, Ranolazine exhibits pH-dependent solubility and thus shows variable absorption along the gastrointestinal tract. Due to poor aqueous solubility particularly in basic pH, an attempt has been made to improve solubility through the cocrystallization technique. Cocrystals of Ranolazine with Nicotinamide have been synthesized at different molar ratios (1:1, 1:2, 1:3 2:1, and 3:1) through solvent-assisted grinding, slurry preparation, and solvent evaporation method and subsequently characterized by different analytical methodologies. Conformational characterization studies have been performed using techniques like melting point analysis, powder X-ray diffraction, and differential scanning calorimetry. Saturation solubility of Ranolazine alone along with cocrystals prepared in different molar ratios was conducted in water and buffers of different pH (1.2, 4.5, and 6.8) to establish enhancement in solubility. Ranolazine: Nicotinamide 1:2 cocrystals were found to be stable in accelerated and long-term stability conditions. In-vivo study performed in rats to demonstrate enhanced bioavailability. Ranolazine cocrystals with Nicotinamide were shown to have enhanced solubility in basic pH and improved peak plasma concentration, the area under the curve, and relative bioavailability by 2-folds.

Cite this article:
Gunjan Vyas, Shah Jigar, Shery Jacob. Enhancement of Physicochemical and Pharmacokinetic Characteristics of Ranolazine drug substance using Cocrystalization Technique. Research Journal of Pharmacy and Technology. 2024; 17(1):59-6. doi: 10.52711/0974-360X.2024.00010

Gunjan Vyas, Shah Jigar, Shery Jacob. Enhancement of Physicochemical and Pharmacokinetic Characteristics of Ranolazine drug substance using Cocrystalization Technique. Research Journal of Pharmacy and Technology. 2024; 17(1):59-6. doi: 10.52711/0974-360X.2024.00010   Available on:

1.    Patel Vishakha D, Raj Hasumati A, Gheewala Nirav. Pharmacology of Combined Amiodarone Hydrochloride and Ranolazine Therapy in Atrial Fibrillation. Asian J. Res. Pharm. Sci. 2015; 5(4): 234-238. DOI: 10.5958/2231-5659.2015.00034.X
2.    Jerling M., Clinical pharmacokinetics of Ranolazine. Clin Pharmacokinet. 2006; 45(5): 469–91. DOI:10.2165/00003088-200645050-00003159669
3.    Bawankar DL, Deshmane SV, More SM, Channawar MA, Chandewar AV, Shreekanth J.. Design and Characterization of Extended Release Ranolazine Matrix Tablet. Research J. Pharm. and Tech. 2009; 2(4): 756-761.
4.    Wolff AA, Baker F, Landridge J. Sustained release Ranolazine formulations. United State Patent, US 6396062B1, 1998-09-10
5.    Reddy BM, Weintraub HS, Schwartzbard AZ., Ranolazine: a new approach to treating an old problem. Tex Heart Inst J. 2010; 37(6): 641–7. PMID: 21224931; PMCID: PMC3014127
6.    O.M. Bagade, D.R. Kad, D.N. Bhargude, D.R. Bhosale and S.K. Kahane. Consequences and Impose of Solubility Enhancement of Poorly Water Soluble Drugs. Research J. Pharm. and Tech. 2014; 7(5): 598-607.
7.    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. DOI: 10.4103/0250-474X.57283
8.    Shan N, Zaworotko MJ, Abraham DJ, Polymorphic crystal forms and cocrystals in drug delivery (crystal engineering). In Burger’s medicinal chemistry and drug discovery, edited by Donald J. Abraham and David P. Rotella 2003. 7th ed: pp. 187-218
9.    Aitipamula S, Banerjee R, Bansal AK, Biradha K, Cheney ML, Choudhury AR, Desiraju GR, Dikundwar AG, Dubey R, Duggirala N, Ghogale PP. Polymorphs, salts, and cocrystals: what’s in a name? Crystal Growth & Design. 2012; 12(5): 2147-52.
10.    Matthew L. Peterson, Magali B. Hickey, Michael J. Zaworotko and Örn Almarsson, Expanding the scope of crystal form evaluation in pharmaceutical science, Journal of Pharmaceutical Sciences. 2006; 9(3): 317-326. PMID: 17207415
11.    Swapnil R. Lahamage, Avinash B. Darekar, Ravindra B. Saudagar. Pharmaceutical Co-Crystallization. Asian J. Res. Pharm. Sci. 2016; 6(1): 51-58. DOI: 10.5958/2231-5659.2016.00008.4
12.    Margaret C. Etter, Hydrogen Bonds as Design Elements in Organic Chemistry, The Journal of Physical Chemistry 1991; 95(12): 4601-4610.
13.    Peddy Vishweshwar, Jennifer A. Mcmahon, Joanna, A. Bis, Michael J. Zaworotko, Pharmaceutical Co-Crystals, J Pharm Sci. 2006; 95(3): 499-516. doi: 10.1002/jps.20578. PMID: 16444755
14.    Ramu Samineni, Jithendra Chimakurthy, Sumalatha. K, Dharani G, Rachana J, Manasa K, Anitha P. Co-Crystals: A Review of Recent Trends in Co Crystallization of BCS Class II Drugs. Research J. Pharm. and Tech. 2019; 12(7): 3117-3124. DOI: 10.5958/0974-360X.2019.00527.4
15.    Naír Rodríguez-Hornedoa, Sarah J. Nehma, Adivaraha Jayasankara. Cocrystals: Design, Properties, and Formation Mechanisms. In Encyclopedia of Pharmaceutical Technology, edited by James Swarbrick 2006, 3rd ed: pp. 615-635
16.    Anderson JR, Nawarskas JJ., Ranolazine. A metabolic modulator for the treatment of chronic stable angina Cardiol Rev. 2005; 13(4): 202-10. DOI: 10.1023/a:1016212804288
17.    Bidada J, Gonjari I, Bhusari A, Raut C, Dhule A. Development of extended release matrix tablets of Ranolazine containing polyacrylic and ethylcellulose polymers. Der Pharm Lett 2011; 3(4): 215-26. Available at
18.    Amit J. Raval, Madhabhai M. Patel. Techniques to Improve Bioavailability of Poorly Water Soluble Drugs – A review. Research J. Pharma. Dosage Forms and Tech. 2011; 3(5): 182-192.
19.    B.A. Bhairav, J.K. Bachhav, R.B. Saudagar. Review on Solubility Enhancement Techniques. Asian J. Pharm. Res. 2016; 6(3): 147-152. 10.5958/2231-5691.2016.00025.3
20.    Amidon GL., Lennernas 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. Pharm. Res. 1995; 12: 413−420. DOI: 10.1023/a:1016212804288
21.    Khadka P, Ro J, Kim H, Kim I, Kim JT, Kim H, Cho JM, Yun G, Lee J. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution, and bioavailability. Asian Journal of Pharmaceutical Sciences. 2014; 9(6): 304-16.
22.    Jacob S, Nair AB. Cyclodextrin complexes: a perspective from drug delivery and formulation. Drug Dev Res. 2018; 79(5): 201– 17. DOI: 10.1002/ddr.21452. PMID: 30188584
23.    Jacob S, Nair AB, Shah J, Gupta S, Boddu SH, Sreeharsha N, Joseph A, Shinu P, Morsy MA. Lipid Nanoparticles as a Promising Drug Delivery Carrier for Topical Ocular Therapy—An Overview on Recent Advances. Pharmaceutics. 2022; 14(3): 533. DOI: 10.1002/ddr.21452
24.    Samavini R, Sandaruwan C, De Silva M, Priyadarshana G, Kottegoda N, Karunaratne V. Effect of citric acid surface modification on the solubility of hydroxyapatite nanoparticles. Journal of agricultural and food chemistry. 2018; 66(13): 3330-7. DOI: 10.1021/acs.jafc.7b05544
25.    Chaudhary S, Nair AB, Shah J, Gorain B, Jacob S, Shah H, Patel V. Enhanced solubility and bioavailability of Dolutegravir by solid dispersion method: In vitro and in vivo evaluation—A potential approach for HIV therapy. AAPS PharmSciTech. 2021; 22(3): 1-2. DOI: 10.1208/s12249-021-01995-y
26.    Zalte A. G., Saudagar R. B.. Preparation and Characterization of Flurbiprofen Co-crystals By Using Factorial Design. Asian J. Research Chem. 2018; 11(1): 166-170.DOI:10.5958/0974-4150.2018.00034.2
27.    Li AY, Xu LL, Chen JM, Lu TB. Solubility and dissolution rate enhancement of triamterene by a cocrystallization method. Crystal Growth & Design. 2015; 15(8): 3785-91.
28.    Dressman, JB, Vertzoni M, Goumas K, Reppa C. Estimating drug solubility in the gastrointestinal tract. Adv. Drug Delivery Rev. 2007; 59: 591−602. DOI: 10.1016/j.addr.2007.05.009
29.    Karimi-Jafari M, Padrela L, Walker GM, Croker DM. Creating cocrystals: A review of pharmaceutical cocrystal preparation routes and applications. Crystal Growth & Design. 2018; 18(10): 6370-87.
30.    Arif Budiman, Sandra Megantara, Putri Saraswati. Synthesize Glibenclamide-Ascorbic Acid Cocrystal Using Solvent Evaporation Method to Increase Solubility and Dissolution Rate of Glibenclamide. Research J. Pharm. and Tech. 2019; 12(12): 5805-5810. DOI: 10.5958/0974-360X.2019.01005.9
31.    Patel Vishakha. D., Raj Hasumati. Ranolazine: A Review on Analytical Method and Its Determination in Synthetic Mixture. Asian J. Pharm. Ana. 2015; 5(4): 214-218. DOI: 10.5958/2231-5675.2015.00034.4
32.    ICH Q1A(R2). Stability testing of new drug substances and products Q1A(R2); Current Step 4 version dated 6 February 2003. Available on
33.    Habibeh Mashayekhi-sardoo, Hossein Kamali, Soghra Mehri, Amirhossein Sahebkar, Mohsen Imenshahidi, Amir Hooshang Mohammadpour, Comparison of pharmacokinetic parameters of ranolazine between diabetic and non-diabetic rats, Iran J Basic Med Sci, 2022; 25(7): DOI: 10.22038/IJBMS.2022.64391.14156
34.    Mani Ganesh, Udhumansha Ubaidulla, Grace Rathnamb, Hyun Tae Jang a. Chitosan-telmisartan polymeric cocrystals for improving oral absorption: In vitro and In vivo evaluation. International Journal of Biological Macromolecules. 2019; 131: 879–885. DOI: 10.1016/j.ijbiomac.2019.03.141
35.    Gozali D. Virtual screening of coformers for atorvastatin co-crystallization and the characterizations of the co-crystals. Int J Pharm Sci Res. 2016; 7(4): 1450. DOI: 10.13040/IJPSR.0975-8232.7(4).1450-55
36.    Sheetal Shewale, A. S. Shete1, R. C. Doijad, S. S. Kadam, V. A. Patil, And A. V. Yadav. Formulation and Solid-State Characterization of Nicotinamide-based Co-crystals of Fenofibrate. Indian J Pharm Sci. 2015; 77(3): 328-334. DOI: 10.4103/0250-474x
37.    Tomaszewska I, Karki S, Shur J, Price R, Fotaki N. Pharmaceutical characterization and evaluation of cocrystals: Importance of in vitro dissolution conditions and type of conformer. Int J Pharm. 2013; 453: 380-8.

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