Sulfasalazine in ionic liquid form with improved solubility and exposure

Shadid, Mohammad; Gurău, Gabriela; Shamshina, Julia L.; Chuang, Bei-Ching; Hailu, Shumet; Guan, Emily; Chowdhury, S. K.; Wu, Jieyu; Rizvi, Syed A. A.; Griffin, R. J.; Rogers, Robin D.

doi:10.1039/c5md00290g

Cited by 64 publications

(49 citation statements)

References 30 publications

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“…37 It is also well known that the aqueous solubilities of choline-based salts of APIs are substantially higher than those of the neutral parent drugs; for example, in a recent study, we showed that choline sulfasalazine not only exhibited increased solubility but also bioavailability and improved oral exposure (compared to those of the nonmodified drug). 29…”

Section: Resultsmentioning

confidence: 99%

Acyclovir as an Ionic Liquid Cation or Anion Can Improve Aqueous Solubility

et al. 2017

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Six ionic liquid (IL)-forming ions (choline, tetrabutylphosphonium, tetrabutylammonium, and trimethylhexadecylammonium cations, and chloride and docusate anions) were paired with acyclovir as the counterion to form four low melting solid salts and two waxes; five of these compounds could be classified as ILs. All of the newly synthesized acyclovir ILs exhibited increased aqueous solubilities by at least 2 orders of magnitude when compared to that of neutral acyclovir. For three of the prepared compounds, the solubilities in simulated body fluids (phosphate-buffered saline, simulated gastric, and simulated intestinal fluids) were also greatly enhanced when compared to that of neutral acyclovir. Acyclovir in its anionic form was more water- or buffer-soluble than acyclovir in its cationic form, though this might be the effect of the particular ions, indicating that the solubilities can be finely tuned by proper choice of the cationic or anionic form of acyclovir and the counterion paired with it.

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Section: Resultsmentioning

confidence: 99%

Acyclovir as an Ionic Liquid Cation or Anion Can Improve Aqueous Solubility

et al. 2017

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“…Active pharmaceutical ingredient-ionic liquids (API-ILs) comprise a drug and an appropriate counterion. For the formation of an IL, there are a wide range of cation-anion combinations available and previous studies have shown that different API-ILs can result in improvements in drug solubility, stability, bioavailability, and membrane permeability [1,[19][20][21][22][23]. The flexibility of counterion choice enables selection of an appropriate counterion for specific drug delivery systems.…”

Section: Introductionmentioning

confidence: 99%

Ionic Liquid Forms of the Antimalarial Lumefantrine in Combination with LFCS Type IIIB Lipid-Based Formulations Preferentially Increase Lipid Solubility, In Vitro Solubilization Behavior and In Vivo Exposure

et al. 2019

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Lipid based formulations (LBFs) are commonly employed to enhance the absorption of highly lipophilic, poorly water-soluble drugs. However, the utility of LBFs can be limited by low drug solubility in the formulation. Isolation of ionizable drugs as low melting, lipophilic salts or ionic liquids (ILs) provides one means to enhance drug solubility in LBFs. However, whether different ILs benefit from formulation in different LBFs is largely unknown. In the current studies, lumefantrine was isolated as a number of different lipophilic salt/ionic liquid forms and performance was assessed after formulation in a range of LBFs. The solubility of lumefantrine in LBF was enhanced 2-to 80-fold by isolation as the lumefantrine docusate IL when compared to lumefantrine free base. The increase in drug loading subsequently enhanced concentrations in the aqueous phase of model intestinal fluids during in vitro dispersion and digestion testing of the LBF. To assess in vivo performance, the systemic exposure of lumefantrine docusate after administration in Type II-MCF, IIIB-MCF, IIIB-LCF, and IV formulations was evaluated after oral administration to rats. In vivo exposure was compared to control lipid and aqueous suspension formulations of lumefantrine free base. Lumefantrine docusate in the Type IIIB-LCF showed significantly higher plasma exposure compared to all other formulations (up to 35-fold higher). The data suggest that isolation of a lipid-soluble IL, coupled with an appropriate formulation, is a viable means to increase drug dose in an oral formulation and to enhance exposure of lumefantrine in vivo.

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“…If one were to focus on API-ILs that melt below body temperature of 37 °C, one would have pure liquid salt forms of APIs allowing for all the advantages that salt forms provide from a pharmaceutical standpoint, but without being subject to problems of the solid state such as polymorphism . API-ILs are easily accessible, and have shown to be effective in the development of novel forms of antimicrobial, fungicidal, and pain-relieving medicines [ 46 , 47 , 48 , 49 , 50 ].…”

Section: What About Api Ionic Liquids (Api-ils) As Alternative To mentioning

confidence: 99%

“…Through a rational combination of discrete cationic and anionic derivatives of approved APIs, API-ILs allow tuning the biological, chemical, and physical properties of the drugs while maintaining their biological activity, by design. Among the most impressive examples of solubility increase are choline-based API-ILs: Choline sulfasalazine, which demonstrated 4000-fold solubility enhancement compared to sulfasalazine [ 46 ]; choline acyclovir, which showed a 450 times solubility improvement [ 47 ]; choline nalidixate, the water solubility of which is 5000 times higher than that of the parent drug; and choline niflumate, where water solubility is as much as 56,000 times higher than that of the parent API [ 48 ]. We will not go into examples of API-ILs in detail here, as one can find extensive reviews and book chapters on the subject [ 8 , 49 , 50 ].…”

Section: What About Api Ionic Liquids (Api-ils) As Alternative To mentioning

confidence: 99%

Are Myths and Preconceptions Preventing Us from Applying Ionic Liquid Forms of Antiviral Medicines to the Current Health Crisis?

Shamshina

2020

IJMS

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At the moment, there are no U.S. Food and Drug Administration (U.S. FDA)-approved drugs for the treatment of COVID-19, although several antiviral drugs are available for repurposing. Many of these drugs suffer from polymorphic transformations with changes in the drug’s safety and efficacy; many are poorly soluble, poorly bioavailable drugs. Current tools to reformulate antiviral APIs into safer and more bioavailable forms include pharmaceutical salts and cocrystals, even though it is difficult to classify solid forms into these regulatory-wise mutually exclusive categories. Pure liquid salt forms of APIs, ionic liquids that incorporate APIs into their structures (API-ILs) present all the advantages that salt forms provide from a pharmaceutical standpoint, without being subject to solid-state matter problems. In this perspective article, the myths and the most voiced concerns holding back implementation of API-ILs are examined, and two case studies of API-ILs antivirals (the amphoteric acyclovir and GSK2838232) are presented in detail, with a focus on drug property improvement. We advocate that the industry should consider the advantages of API-ILs which could be the genesis of disruptive innovation and believe that in order for the industry to grow and develop, the industry should be comfortable with a certain element of risk because progress often only comes from trying something different.

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Sulfasalazine in ionic liquid form with improved solubility and exposure

Abstract: An ionic liquid form of sulfasalazine demonstrates improved solubility (4000×), bioavailability (2.5×), andin vivoexposure over the neutral drug.

Cited by 64 publications

References 30 publications

Acyclovir as an Ionic Liquid Cation or Anion Can Improve Aqueous Solubility

Acyclovir as an Ionic Liquid Cation or Anion Can Improve Aqueous Solubility

Ionic Liquid Forms of the Antimalarial Lumefantrine in Combination with LFCS Type IIIB Lipid-Based Formulations Preferentially Increase Lipid Solubility, In Vitro Solubilization Behavior and In Vivo Exposure

Are Myths and Preconceptions Preventing Us from Applying Ionic Liquid Forms of Antiviral Medicines to the Current Health Crisis?

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