SYNTHESIS AND CHARACTERIZATION OF NOVEL AMINO ACID PRODRUG OF FAMOTIDINE
Keywords:
Famotidine, Amino acid prodrug, Characterization, Aqueous solubilityAbstract
Objective: Famotidine an H2 receptor antagonist is the drug of choice to treat ulcers in stomach (gastric and duodenal), erosive esophagitis (heartburn or acid indigestion) and gastroesophageal reflux disease (GERD). Drug molecules with limited aqueous solubility are becoming very common in the research and development portfolios of discovery focused pharmaceutical companies. Prodrugs are an established concept to overcome barriers like poor solubility to drug's usefulness. Polar Amino acids which are biocompatible and easily ionisable were chosen as promoiety for the formation of prodrugs. Aqueous solubility is an important parameter to enhance the bioavailability of the drug. Hence the present study aims to enhance aqueous solubility and in turn bioavailability by prodrug approaches.
Methods: Synthesis of novel amino acid prodrug of famotidine was done by microwave irradiation technique. The synthesized amino acid prodrug was characterized by IR, NMR, Mass and DSC.
Results: In vitro chemical hydrolysis profiles revealed that the synthesized amino acid derivative of famotidine was chemically stable in Simulated Gastric fluid pH 1.2 and Simulated Intestinal Fluid pH 7.4. Decrease in Log P value,-0.39 of amino acid prodrug compared to-0.60 of famotidine was observed.
Conclusion: Hence a novel amino acid prodrug of famotidine with better solubility and bioavailability was synthesized and characterized.
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Patel AR, Vavia PR. Preparation and evaluation of taste masked famotidine formulation using Drug/β-cyclodextrin/Polymer ternary complexation approach. AAPS Pharm Sci Tech 2008;9:544-50.
Hassan MA, Suleiman MS, Najib NM. Improvement of the in vitro dissolution characteristics of famotidine by inclusion in β-cyclodextrin. Int J Pharm 1990;58:19-24.
Dobetti L. Fast disintegrating tablets. US Patent No. B1 6,596,311, (Eurand International); 2003.
Brown D. Orally disintegrating tablets-taste over speed. Drug Delivery Technol 2003;3:58-61.
Seager HJ. Drug-delivery products and the Zydis fast-dissolving dosage form. Pharm Pharmacol 1998;50:375-82.
Bundgaard H. editor. Design of Prodrug. (Amsterdam): Elsevier; 1985.
Shargel L, Andrew Y, Susanna WP. Applied Biopharmaceutics and Pharmacokinetics. 6th ed. (USA): Mcgraw-Hill; 2012.
Balvinder SV, Kristiina MH, Krista L, Jarkko R. Amino acids as promoieties in prodrug design and development. Adv Drug Delivery Rev 2013;65:1370-85.
Zeng H, Li Y, Shao H. Simple and efficient method for N-Boc protection of amines using peg-400 as a reaction medium under mild conditions. Synth Commun 2012;42:25-32.
Khalafi NA, Mokhtari B, Rad MNS. Direct preparation of primary amides from carboxylic acids and urea using imidazole under microwave irradiation. Tetrahedron Lett 2003;44:7325-8.
Liu YS, Zhao C, Bergbreiter DE, Romo D. Simultaneous deprotection and purification of BOC amines based on ionic resin capture. J Org Chem 1998;63:3471-3.
Tang PW. Boric acid catalyzed amide formation from carboxylic acids and amines: N-Benzyl-4-Phenylbutyramide. Org Synth 2005;81:262.
Han G, Tamaki M, Hruby VJ. Fast, efficient and selective deprotection of the tert-butoxycarbonyl (Boc) group using HCl/dioxane (4 m). J Pept Res 2001;58:338-41.
Vijayaraj S, Omshanthi B, Anitha S, Sampathkumar KP. Synthesis and characterization of novel sulphoxide prodrug of famotidine. Indian J Pharm Educ 2014;48:35-44.
OECD. Guidelines for the Testing of Chemicals; 1981. p. 1-13.
Baka E, Comer JEA, Takacs NK. Study of equilibrium solubility measurement by saturation shake-flask method using hydrochloro thiazide as model compound. J Pharm Biomed Anal 2008;46:335–41.
Mahdi MF, Alsaad HN. Design, Synthesis and hydrolytic behavior of mutual prodrugs of NSAIDs with Gabapentin using glycol spacers. Pharmaceuticals 2012;5:1080-91.
Balvinder V, Jarkko R. Amino acid prodrugs for oral delivery: challenges and opportunities. Ther Delivery 2011;2:959-62.
Anastas PT, Warner JC. Green Chemistry: Theory and Practice. New York: Oxford University Press; 1998.