Research Article Pharmaceutics, Drug Delivery and Pharmaceutical Technology| Volume 108, ISSUE 6, P2112-2118, June 01, 2019

Development and Validation of a Discriminatory Dissolution Method for Rifaximin Products

Published:January 24, 2019DOI:


      The commercial product of rifaximin (RFX) contains α form. The α form can change to β form on exposure to high humidity that can occur during manufacturing, stability, and in-use period. It is critical to maintain α form of the drug in a drug product to avoid variability in clinical response. U.S. Food and Drug Administration dissolution method was found to be nondiscriminatory for RFX formulations containing either 100% α or β form. The objective of this study was to develop a discriminatory dissolution method that can detect low levels of α to β transformation in RFX products. Formulations containing a variable fraction of α and β forms were prepared by using direct compression method. Dissolution parameters investigated were type of dissolution medium (water and phosphate buffer), volume (500, 900, and 1000 mL), and paddle speed (50, 75, and 150 rpm). Dissolution in water with 0.2% sodium lauryl sulfate was less than 80% and nondiscriminatory. However, dissolution tested in a phosphate buffer pH 7.4 with 0.2% sodium lauryl sulfate at 50 rpm was discriminatory with more than 17.5% difference in dissolution profile between formulations containing α and β forms. The developed method can detect polymorphic transformation if there is 25% or more β form conversion.


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        • Thomas V.H.
        • Bhattachar S.
        • Hitchingham L.
        • et al.
        The road map to oral bioavailability: an industrial perspective.
        Expert Opin Drug Metab Toxicol. 2006; 2: 591-608
        • Hurst S.
        • Loi C.M.
        • Brodfuehrer J.
        • El-Kattan A.
        Impact of physiological, phys-icochemical and biopharmaceutical factors in absorption and metabolism mechanisms on the drug oral bioavailability of rats and humans.
        Expert Opin Drug Metab Toxicol. 2007; 3: 469-489
        • Bauer J.
        • Spanton S.
        • Henry R.
        • et al.
        Ritonavir: an extraordinary example of conformational polymorphism.
        Pharm Res. 2001; 18: 859-866
        • Corrado B.
        • Giuseppe C.V.
        • Antonio M.
        • Carmelo S.
        Is generic rifaximin still a poorly absorbed antibiotic? A comparison of branded and generic formulations in healthy volunteers.
        Pharmacol Res. 2014; 85: 39-44
        • Kato Y.
        • Kohketsu M.
        Relationship between polymorphism and bioavailability of amobarbital in the rabbit.
        Chem Pharm Bull. 1981; 29: 268-272
        • Kimura N.
        • Fukui H.
        • Takagaki H.
        • Yonemochi E.
        • Terada K.
        Characterisation of polymorphs of a novel quinolinone derivative TA-270 (4-hydroxy-1-methyl-3-octyloxy-sinapinoylamino-2(1H)-quinolinone).
        Chem Pharm Bull. 2001; 49: 1321-1325
        • Ana C.K.
        • Selma G.A.
        • Hérida R.N.S.
        Characterization of polymorphic forms of rifaximin.
        J AOAC Int. 2016; 99: 964-971
        • Aguiar A.J.
        • Krc J.
        • Kinkel A.W.
        • Samyn J.C.
        Effect of polymorphism on the absorption of chloramphenicol from chloramphenicol palmitate.
        J Pharm Sci. 1967; 56: 847-853
        • Pandit J.K.
        • Gupta S.K.
        • Gode K.D.
        • Mishra B.
        Effect of crystal form on the oral absorption of phenylbutazone.
        Int J Pharm. 1984; 21: 129-132
        • Szeleszczuk Ł.
        • Jurczak E.
        • Zielińska-Pisklak M.
        • Harwacki J.
        • Pisklak D.M.
        Comparison of the analytical methods (solid state NMR, FT-IR, PXRD) in the analysis of the solid drug forms with low concentration of an active ingredient - 17-β-estradiol case.
        J Pharm Biomed Anal. 2018; 149: 160-165
        • Rahman Z.
        • Siddiqui A.
        • Khan M.A.
        Assessing the impact of nimodipine devitrification in the ternary cosolvent system through quality by design approach.
        Int J Pharm. 2013; 455: 113-123
        • Zidan A.S.
        • Rahman Z.
        • Sayeed V.
        • Raw A.
        • Yu L.
        • Khan M.A.
        Crystallinity evaluation of tacrolimus solid dispersions by chemometric analysis.
        Int J Pharm. 2012; 423: 341-350
        • Rahman Z.
        • Bykadi S.
        • Siddiqui A.
        • Khan M.A.
        Comparison of X-ray powder diffraction and solid-state nuclear magnetic resonance in estimating crystalline fraction of tacrolimus in sustained-release amorphous solid dispersion and development of discriminating dissolution method.
        J Pharm Sci. 2015; 104: 1777-1786
        • Di Stefano F.D.
        • Rusca A.
        • Loprete L.
        • Dröge M.J.
        • Moro L.
        • Assandri A.
        Systemic absorption of rifamycin SV MMX administered as modified-release tablets in healthy volunteers.
        Antimicrob Agents Chemother. 2011; 55: 2122-2128
      1. Drugs@FDA.
        (Available at:)
        • Slavik R.S.
        • Jewesson P.J.
        Selecting antibacterial for outpatient parenteral antimicrobial therapy: pharmacokinetic–pharmacodynamic considerations.
        Clin Pharmacokinet. 2003; 42: 793-817
        • Scaglione F.
        • Paraboni L.
        Influence of pharmacokinetics/pharmacodynamics of antibacterials in their dosing regimen selection.
        Expert Rev Anti Infect Ther. 2006; 4: 479-490
        • Swidsinski A.
        • Ladhoff A.
        • Pernthaler A.
        • et al.
        Mucosal flora in inflammatory bowel disease.
        Gastroenterology. 2002; 122: 44-54
        • Macfarlane S.
        • Steed H.
        • Macfarlane G.T.
        Intestinal bacteria and inflammatory bowel disease.
        Crit Rev Clin Lab Sci. 2009; 46: 25-54
        • Kyoung S.H.
        • Joo S.K.
        Rifaximin for the treatment of acute infectious diarrhea.
        Ther Adv Gastroenterol. 2011; 4: 227-235
        • Whitehead K.
        • Karr N.
        • Mitragotri S.
        Safe and effective permeation enhancers for oral drug delivery.
        Pharm Res. 2008; 25: 1782-1788
        • Aungst B.J.
        Absorption enhancers: applications and advances.
        AAPS J. 2012; 14: 10-18
        • Viscomi G.
        • Campana M.
        • Braga D.
        • Confortini D.
        • Cannata V.
        • Righi P.
        Polymorphic Forms of Rifaximin, Process for Their Production and Uses Thereof. United States Patent 0272754.
        United States Patent Office, Alexandria, VA2005
        • Gushurst K.S.
        • Yang D.
        • Vlahova P.
        • Stults J.S.
        The United States Patent 8586956.
        United States Patent Office, Alexandria, VA2013
      2. Summary of product characteristic, Lormyx 200mg.
        (Available at:)
      3. Xifaxan (Rifaximin) Tablets [Prescribing Information]. Salix Pharmaceuticals, Palo Alto, CA2004 (Available at:)
        • Gobernado M.
        • Ponce J.
        Rev Esp Quimioter. 2004; 17: 141-153
        • Adachi J.A.
        • DuPont H.L.
        Rifaximin: a novel nonabsorbed rifamycin for gastrointestinal disorders.
        Clin Infect Dis. 2006; 42: 541-547
        • Soro O.
        • Pesce A.
        • Raggi M.
        • Debbia E.A.
        • Schito G.C.
        Selection of rifampicin-resistant Mycobacterium tuberculosis does not occur in the presence of low concentrations of rifaximin.
        Clin Microbiol Infect. 1997; 3: 147-151
      4. Drugs@FDA.
        (Available at:)
        • Viscomi G.C.
        • Campana M.
        • Barbanti M.
        • et al.
        Crystal forms of rifaximin and their effect on pharmaceutical properties.
        CrystEngComm. 2008; 10: 1074-1081
        • Zolnik B.S.
        Dissolution Method Development for Generic Drug Products.
        Regulatory Education for Industry (REdI): GENERIC DRUGS FORUM, Silver Spring, MD2015 (Available at:)
        • Menegola J.
        • Steppe M.
        • Schapoval E.E.S.
        Dissolution test for citalopram in tablets and comparison of in vitro dissolution profiles.
        Eur J Pharm Biopharm. 2007; 67: 524-530
        • ICH Guidance for Industry
        Validation of Analytical Procedures: Methodlogy, Q2B.
        Unites States Patent Office, Alexandria, VA2005: 1996
      5. USP41-NF36: General Chapters: <1225> Validation of Compendial Procedures. United States Pharmacopeia, Rockville, MD2018: 7665-7671
        • U.S. Food and Drug Administration
        FDA Guidance for Industry. Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
        FDA, Silver Spring, MD1997
        • Narendra A.
        • Annapurna M.M.
        • Ravi Kumar K.
        Development and validation of the stability indicating liquid chromatographic method for Rifaximin-an antibiotic.
        J Drug Deliv Ther. 2013; 3: 18-25
        • Annapurna M.M.
        • Sai P.K.B.
        • Venkatesh B.
        • Raj P.J.
        Development and validation of stability-indicating liquid chromatographic assay for rifaximin (an antibiotic) in bulk and pharmaceutical dosage.
        Forms Chem Sci Trans. 2014; 3: 566-575
        • Sudha T.
        • Hemalatha P.V.
        • Ravikumar V.R.
        • Jothi R.
        • Radhakrishnan M.
        Development and validation of RP-HPLC method for the estimation of rifaximin in bulk and in tablet dosage form.
        Asian J Pharm Clin Res. 2009; 2: 112-116
        • U.S. Food and Drug Administration
        FDA draft guidance on rifaximin.
        FDA, Silver Spring, MD2017 (Available at:)
        • USP40.NF35
        Extended Phenytoin Capsules Monogram.
        United States Pharmacopeia, Rockville, MD2018: 5693