Transformation of acidic poorly water soluble drugs into ionic liquids

Balk, Anja; Wiest, Johannes; Widmer, Toni; Galli, Bruno; Holzgrabe, Ulrike; Meinel, Lorenz

doi:10.1016/j.ejpb.2015.04.034

Cited by 77 publications

(46 citation statements)

References 40 publications

(53 reference statements)

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“…The fact that the dissolution of the unformulated lipophilic salts was incomplete, even at relatively low doses/low concentrations (below saturated solubility values in all cases and under sink conditions in some cases), suggests that other factors such as salt wettability and dispersibility played a role in their slow dissolution properties. Thus, while there is growing interest in preparing low melting, lipophilic salt forms of pharmaceutical compounds, 13,24,25 the results presented here highlight the importance of matching the properties of the salts with an appropriate formulation. In this study, despite high aqueous solubilities in some cases, the new lipophilic salts exhibited very slow rates of dissolution.…”

Section: Aqueous Solution Behavior Of Unformulated and Lipid Formulatmentioning

confidence: 93%

“…Lipophilic salts of water-soluble drugs have been previously described. 11,13,14 In these cases, the altered salt form was employed to improve aqueous solubility, to provide for controlled release, or to facilitate dual pharmacological functions (where the counterion also had pharmacological activity). In contrast, the potential for lipophilic salt forms to facilitate the use of lipid formulations for water-soluble drugs, as a means to, for example, increase drug loading, has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations

Williams

Ford

Lim

et al. 2018

Journal of Pharmaceutical Sciences

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Higher lipid solubility of lipophilic salt forms creates new product development opportunities for high-dose liquid-filled capsules. The purpose of this study is to determine if lipophilic salts of Biopharmaceutical Classification System (BCS) Class I amlodipine and BCS Class III fexofenadine, ranitidine, and metformin were better lipid formulation candidates than existing commercial salts. Lipophilic salts were prepared from lipophilic anions and commercial HCl or besylate salt forms, as verified by H-NMR. Thermal properties were assessed by differential scanning calorimetry and hot-stage microscopy. X-ray diffraction and polarized light microscopy were used to confirm the salt's physical form. All lipophilic salt forms were substantially more lipid-soluble (typically>10-fold) when compared to commercial salts. For example, amlodipine concentrations in lipidic excipients were limited to <5-10 mg/g when using the besylate salt but could be increased to >100 mg/g when using the docusate salt. Higher lipid solubility of the lipophilic salts of each drug translated to higher drug loadings in lipid formulations. In vitro tests showed that lipophilic salts solubilized in a lipid formulation resulted in dispersion behavior that was at least as rapid as the dissolution rates of conventional salts. This study confirmed the applicability of forming lipophilic salts of BCS I and III drugs to promote the utility of lipid-based delivery systems.

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Section: Aqueous Solution Behavior Of Unformulated and Lipid Formulatmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations

Williams

Ford

Lim

et al. 2018

Journal of Pharmaceutical Sciences

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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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“…These protic ionic liquids carrier composites exhibited rapid dissolution and better bioavailability in capsule forms (Wang et al, 2018a). The water-soluble acidic active pharmaceutical ingredients such as diclofenac, ibuprofen, ketoprofen, naproxen, sulfadiazine, sulfamethoxazole, and tolbutamide were converted into tetrabutylphosphonium ionic liquids and the results were quite encouraging compared with their respective free acid forms (Balk et al, 2015). A library of 36 counter ions as halide salts was prepared to map the pharmaceutical design space for ionic liquid of Selurampanel (Wiest et al, 2017).…”

Section: Ionic Liquidsmentioning

confidence: 99%

Oral Drug Delivery Technologies—A Decade of Developments

Kaur

Arora

Kumar

2019

J Pharmacol Exp Ther

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Advanced drug delivery technologies, in general, enable drug reformulation and administration routes, together contributing to life-cycle management and allowing the innovator to maintain the product monopoly. Over the years, there has been a steady shift from mere life-cycle management to drug repurposingapplying delivery technologies to tackle solubility and permeability issues in early stages or safety and efficacy issues in the late stages of drug discovery processes. While the drug and the disease in question primarily drive the choice of route of administration, the oral route, for its compliance and safety attributes, is the most preferred route, particularly when it comes to chronic conditions, including pain, which is not considered a disease but a symptom of a primary cause. Therefore, the attempt of this review is to take a stock of the advances in oral delivery technologies that are applicable for injectable to oral transformation, improve risk-benefit profiles of existing orals, and apply them in the early discovery program to minimize the drug attrition rates.

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Transformation of acidic poorly water soluble drugs into ionic liquids

Cited by 77 publications

References 40 publications

Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations

Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations

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

Oral Drug Delivery Technologies—A Decade of Developments

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