Crystal forms of rifaximin and their effect on pharmaceutical properties

Viscomi, G. C.; Campana, Manuela; Barbanti, M.; Grepioni, Fabrizia; Polito, Marco; Confortini, Donatella; Rosini, Goffredo; Righi, Paolo; Cannata, V.; Braga, Dario

doi:10.1039/b717887e

Cited by 53 publications

(61 citation statements)

References 27 publications

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“…Five distinct crystal forms of rifaximin (a, b, g, d, and ") have been identified and characterized. Rifaximin in any form can be defined as practically water-insoluble, but at a concentration of less than 0.1 mg/ml water [Viscomi et al 2008]. Reportedly, an extremely high fecal concentration of rifaximin after oral ingestion was determined after the no physiologic dissolution of rifaximin from stool specimens using an organic solvent [Jiang et al 2000].…”

Section: Clostridium Difficile Infectionmentioning

confidence: 99%

Rifaximin for the treatment of acute infectious diarrhea

Hong

Kim

2011

Therap Adv Gastroenterol

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Rifaximin is a nonabsorbable rifamycin derivative with an excellent safety profile and a broad spectrum of antimicrobial activity against a variety of enteropathogens causing acute infectious diarrhea. After oral ingestion, its bioavailability is known to be less than 0.4%, and it has a low potential for significant drug interactions. In the treatment of travelers' diarrhea caused by noninvasive diarrheagenic Escherichia coli, it has been demonstrated that rifaximin significantly shortens the duration of diarrhea and has an efficacy similar to that of ciprofloxacin. Moreover, according to two randomized placebo-controlled trials, prophylactic treatment with rifaximin reduced the risk of developing travelers' diarrhea by more than 50% compared with the placebo group. For the treatment of acute diarrhea unrelated to travel, a short course of rifaximin significantly reduced the duration of diarrhea, and its overall efficacy was comparable to that of ciprofloxacin. The discrepancy between the in vitro and in vivo antimicrobial activities of rifaximin, however, and the clinical implication of the rapid appearance of bacterial resistance, must be further elucidated. In conclusion, this gut-selective antibiotic seems to be a promising option for the treatment of acute infectious diarrhea secondary to noninvasive E. coli and also appears to be effective in chemoprophylaxis for travelers' diarrhea.

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Section: Clostridium Difficile Infectionmentioning

confidence: 99%

Rifaximin for the treatment of acute infectious diarrhea

Hong

Kim

2011

Therap Adv Gastroenterol

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“…In this instance, polarity of the solvent kinetically biases the molecule in to one specific molecular packing. Other environmental factors that can influence the synthesized crystal structure include temperature [26,29,44,75], pressure [76][77][78][79][80][81], humidity [47,56,82,83], impurities [84][85][86], impeller speed, and other shear forces [27,52,75,85,87].…”

Section: Improving Materials Performance Through Crystal Polymorphismmentioning

confidence: 99%

“…Properties than can change between polymorphs include density [11,20,31], compressibility [32], hardness [33,34], gel strength [35], flexibility [36], conductivity [26][27][28][29][30][37][38][39], explosivity [20,[22][23][24], catalytic activity [40,41], transparency [42,43], weather resistance [25,44], heat capacity [20], melting point [32,45,46], vapor pressure [46], stability [25,29], solubility [14,[47][48][49], bioavailability [14,33,48,[50][51][52][53][54], and dissolution rate [47,55,56].…”

Section: What Is Polymorphism?mentioning

confidence: 99%

“…The scientifically alluring aspect of polymorphic solids is that a material's properties can be greatly influenced by the specific crystal structure that it is currently adopting. In the example [14,33,48,[50][51][52][53][54], and dissolution rate [47,55,56].…”

Section: Introductionmentioning

confidence: 99%

“…A complicating factor in the search for commercially viable solid phases is that the stable forms of a material can change based on external factors such as temperature [18,46,[92][93][94][95][96][97][98][99][100][101][102][103], pressure [76][77][78][79][80][81] and humidity [47,82,83,200]. A complete experimental mapping of all possible solid forms for a given material would therefore require screening at every condition the material will encounter.…”

Section: Introductionmentioning

confidence: 99%

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Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Dybeck

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AcknowledgementsI would like to acknowledge the guidance and support provided by my advisor MichaelShirts. I would also like to thank Levi Naden, Natalie Schieber, Nate Abraham and the entire Shirts group for their help and technical support during my research. I also would like to acknowledge the UVA high performance computing team for the computational resources necessary to complete this work. Finally, I would like to acknowledge the endless love and support that my friends and family provided me during this challenging Ph.D. journey.iii AbstractThe presence of multiple stable crystal structures in solid organic materials can limit their commercial viability when two or more observable polymorphs exhibit markedly different physical properties. Unintended restructuring events have hindered pharmaceutical solid form development in numerous therapeutic candidates and have led to costly market recalls.Conversely, intentional synthesis of a metastable form has led to significantly more favorable performance in numerous materials.Current computational methods for predicting polymorphic behavior evaluate candidate crystal structures based on the minimized lattice energy. However, these static lattice energybased approaches generate far more lattice energy minima than there are experimentally observed structures. Thermal motion of the crystals under working conditions has the potential to explain why many of these lattice minima are not observed experimentally. Lattice minima that are identified from a static crystal structure prediction can ultimately be unstable at experimental conditions through either temperature-mediated stability reranking, kinetic interconversion of multiple minima, or inaccuracies of the energy function in producing the real crystal ensemble.In this work, we explore the role of thermal motion in eliminating candidate crystal structures using fully atomistic molecular dynamics simulations. Enthalpically favorable structures with low entropy will become unfavorable at high temperatures through temperaturemediated stability reranking. Our simulations correctly identify the high temperature solid form as having a larger entropy than the low temperature form in twelve small molecule organic systems with known temperature-mediated transformations. The estimated entropy differences in the classical point-charge potential are significantly closer to experimental measurements than estimated enthalpy differences. This result suggests that entropy difference estimates are less sensitive to the complexity of the simulation potential than the corresponding enthalpy estimates. We additionally find that a cheaper harmonic approximation provides a sufficient estimate of entropic contributions in small rigid molecules. However, entropies with iv the harmonic approximation diverge from molecular dynamics-derived entropies in systems with multiple rotatable degrees of freedom or dynamically disordered crystalline structures.We additionally probe the sensitivity of the stability estimates to the energy function ...

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Dealing with Crystal Forms (The Kingdom of Serendip?)

Braga

D’Agostino

Dichiarante³

et al. 2011

Chemistry An Asian Journal

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The variety of crystal forms that may be associated with one specific molecule of interest can be extremely large: in addition to polymorphs, all sorts of crystalline solids can be obtained, from molecular and ionic co-crystals to hydrates/solvates, to, needless to say, polymorphs of all these new crystal forms. Lack of predictability of crystallization experiments, far from representing a failure or a nuisance, should encourage in the crystal maker the same attitude shown by the three princes of Serendip (who were making unexpected discoveries by virtue of their "sagacity and readiness of mind") to be ready to pick new avenues as the crystal experiments will yield something unplanned for.

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Crystal forms of rifaximin and their effect on pharmaceutical properties

Cited by 53 publications

References 27 publications

Rifaximin for the treatment of acute infectious diarrhea

Rifaximin for the treatment of acute infectious diarrhea

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Dealing with Crystal Forms (The Kingdom of Serendip?)

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