API ionic liquids: probing the effect of counterion structure on physical form and lipid solubility

Ford, Leigh; Tay, Erin; Nguyen, Tri‐Hung; Williams, Hywel David; Benameur, Hassan; Scammells, Peter J.; Porter, Christopher John

doi:10.1039/d0ra00386g

Cited by 18 publications

(25 citation statements)

References 52 publications

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“…A recent study by Ford et al, indicates that ionic liquids/lipophilic salts based on branched alkyl sulfonates (such as docusate sodium) as counterions exhibit more lipid solubility than those based on linear alkyl sulfonates as counterions. 40 This may be the reason behind the higher lipid solubility of metformin docusate compared to the other metformin salts with linear fatty acids as counterions. Metformin docusate is the only lipophilic salt of metformin suitable for the development of oral lipid-based formulations.…”

Section: ■ Discussionmentioning

confidence: 99%

“…We continued evaluating the lipid solubility of metformin docusate in lipid vehicles and found that the solubility of metformin docusate is >200 mg/g. A recent study by Ford et al, indicates that ionic liquids/lipophilic salts based on branched alkyl sulfonates (such as docusate sodium) as counterions exhibit more lipid solubility than those based on linear alkyl sulfonates as counterions . This may be the reason behind the higher lipid solubility of metformin docusate compared to the other metformin salts with linear fatty acids as counterions.…”

Section: Discussionmentioning

confidence: 99%

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Synthesis and Characterization of Lipophilic Salts of Metformin to Improve Its Repurposing for Cancer Therapy

et al. 2021

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Epidemiological evidence has accentuated the repurposing of metformin hydrochloride for cancer treatment. However, the extreme hydrophilicity and poor permeability of metformin hydrochloride are responsible for its poor anticancer activity in vitro and in vivo. Here, we report the synthesis and characterization of several lipophilic metformin salts containing bulky anionic permeation enhancers such as caprate, laurate, oleate, cholate, and docusate as counterions. Of various counterions tested, only docusate was able to significantly improve the lipophilicity and lipid solubility of metformin. To evaluate the impact of the association of anionic permeation enhancers with metformin, we checked the in vitro anticancer activity of various lipophilic salts of metformin using drug-sensitive (MYCN-2) and drug-resistant (SK-N-Be2c) neuroblastoma cells as model cancer cells. Metformin hydrochloride showed a very low potency (IC 50 ≈ >100 mM) against MYCN-2 and SK-N-Be2c cells. Anionic permeation enhancers showed a considerably higher activity (IC 50 ≈ 125 μM to 1.6 mM) against MYCN-2 and SK-N-Be2c cells than metformin. The association of metformin with most of the bulky anionic agents negatively impacted the anticancer activity against MYCN-2 and SK-N-Be2c cells. However, metformin docusate showed 700-to 4300-fold improvement in anticancer potency compared to metformin hydrochloride and four-to five-fold higher in vitro anticancer activity compared to sodium docusate, indicating a synergistic association between metformin and docusate. A similar trend was observed when we tested the in vitro activity of metformin docusate, sodium docusate, and metformin hydrochloride against hepatocellular carcinoma (HepG2) and triple-negative breast cancer (MDA-MB-231) cells.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synthesis and Characterization of Lipophilic Salts of Metformin to Improve Its Repurposing for Cancer Therapy

et al. 2021

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“…One of the robust approaches is the application of ILs as a drug delivery method [ 18 , 19 , 20 ]. Moreover, coupling a pharmaceutically active cation with IL-based compounds resulted in improved solubility that permits effective absorption via several barriers to reach target cells [ 21 , 22 ]. This combination is also known as active pharmaceutical ingredient ionic liquids (API-ILs).…”

Section: Introductionmentioning

confidence: 99%

Role and Recent Advancements of Ionic Liquids in Drug Delivery Systems

et al. 2023

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Advancements in the fields of ionic liquids (ILs) broaden its applications not only in traditional use but also in different pharmaceutical and biomedical fields. Ionic liquids “Solutions for Your Success” have received a lot of interest from scientists due to a myriad of applications in the pharmaceutical industry for drug delivery systems as well as targeting different diseases. Solubility is a critical physicochemical property that determines the drug’s fate at the target site. Many promising drug candidates fail in various phases of drug research due to poor solubility. In this context, ionic liquids are regarded as effective drug delivery systems for poorly soluble medicines. ILs are also able to combine different anions/cations with other cations/anions to produce salts that satisfy the concept behind the ILs. The important characteristics of ionic liquids are the modularity of their physicochemical properties depending on the application. The review highlights the recent advancement and further applications of ionic liquids to deliver drugs in the pharmaceutical and biomedical fields.

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“…Recent work suggested a possible advantage, in terms of higher lipid solubility, of longer chain length and chain branching of alkyl sulfate counterions for basic drugs. 28 Lipophilic salts with a melting point < 100 °C are so-called ionic liquids, which are considered favourable in LBFs as a lower hydrophobic burden from the crystal lattice may potentially support a higher dose loading in a LBF. The formulation strategy of lipophilic salts have been applied to a variety of drugs (18 in total 27 ) belonging to all classes of the biopharmaceutics classification system (BCS) such as ceritinib, 22 amlodipine, 23 metformin 23 and itraconazole.…”

Section: Introductionmentioning

confidence: 99%

Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax

Koehl

Henze

Holm

et al. 2022

Journal of Pharmaceutical Sciences

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API ionic liquids: probing the effect of counterion structure on physical form and lipid solubility

Abstract: Structure/property relationship of API IL counterions and salt physicochemical properties are investigated, the results highlight the complex interplay involved.

Cited by 18 publications

References 52 publications

Synthesis and Characterization of Lipophilic Salts of Metformin to Improve Its Repurposing for Cancer Therapy

Synthesis and Characterization of Lipophilic Salts of Metformin to Improve Its Repurposing for Cancer Therapy

Role and Recent Advancements of Ionic Liquids in Drug Delivery Systems

Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax

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