Influence of lipophilicity on drug–cyclodextrin interactions: A calorimetric study

Waters, Laura J.; Bedford, Susan; Parkes, Gareth M.B.; Mitchell, John C.

doi:10.1016/j.tca.2010.07.031

Cited by 30 publications

(20 citation statements)

References 42 publications

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“…NMR results allowed determination of the OXZ : HP‐β‐CD association constant ( K = 198/M), in good agreement with that determined by phase solubility ( K = 126/M, Figure ), revealing a strong interaction between OXZ and HP‐β‐CD. Oxethazaine is the amino‐amide anaesthetic agent of higher lipophilicity (log P 3.64); since K is directly correlated with lipophilicity (as demonstrated for complex non‐steroid anti‐inflammatory drugs), we expected the highest association constant for OXZ among the amino‐amide group. In accordance, the association constant of OXZ with HP‐β‐CD (pH 7.4 – DOSY‐NMR) is higher than S‐bupivacaine ( K = 91/M), S‐ropivacaine ( K = 55/M) and prilocaine ( K = 41/M).…”

Section: Discussionmentioning

confidence: 91%

Complexation of oxethazaine with 2-hydroxypropyl-β-cyclodextrin: increased drug solubility, decreased cytotoxicity and analgesia at inflamed tissues

Prado

Yokaichiya

Franco

et al. 2017

Journal of Pharmacy and Pharmacology

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Section: Discussionmentioning

confidence: 91%

Complexation of oxethazaine with 2-hydroxypropyl-β-cyclodextrin: increased drug solubility, decreased cytotoxicity and analgesia at inflamed tissues

Prado

Yokaichiya

Franco

et al. 2017

Journal of Pharmacy and Pharmacology

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“…To validate the theoretical expression, stability constants for a model system of β-CD and ibuprofen were determined at four temperatures and seven pH values. Ibuprofen was chosen as a model drug since it is known to form an inclusion complex with β-CD (Castronuovo and Niccoli, 2013;Waters et al, 2010;Xing et al, 2009). Ibuprofen is a monoprotic acid meaning that a neutral form of ibuprofen exists at low pH and an ionized form exists at high pH.…”

Section: Introductionmentioning

confidence: 99%

Correlation between the stability constant and pH for β-cyclodextrin complexes

Samuelsen

Holm

Lathuile

2019

International Journal of Pharmaceutics

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In drug formulations, cyclodextrins are used to increase aqueous solubility and chemical stability of drugs via formation of inclusion complexes. For ionizable drug molecules, the complexation strength depends on pH. Increased ionization leads to a more soluble drug, but also results in destabilization of cyclodextrin complexes. Therefore, formulation scientists aim to find a balance between increased drug solubility and high complexation strength. In this work, a theoretical expression for the dependency between the stability constant and pH is presented, allowing the accurate prediction of the stability constant at any pH. The theoretical expression requires three out of four input parameters; the pKa of the free guest molecule, the pKa of the complex, and the stability constants for the neutral and fully ionized complex. Stability constants for β-cyclodextrin and ibuprofen complexes were determined by isothermal titration calorimetry at seven pH values (2.5-5.5) and four temperatures (15-55˚C). All these measured stability constants complied with the theoretical expression. Ten additional data sets from the literature comprising eight different drug molecules and three different cyclodextrins confirmed the ability of the theoretical expression to account for the observed pH-dependence of stability constants.

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“…In contrast, pyrid‐4‐yl complexes with the same chirality exhibited higher K eq values for derivatives bearing the 1,12‐ closo ‐carborane cage (e.g., ( R )‐ 2⋅ 2 NO 3 versus ( R )‐ 4⋅ 2 NO 3 ). A positive correlation between lipophilicity and β‐CD binding affinity has been previously demonstrated,25 and it is also known that the 1,12‐ closo ‐carborane cage is less polar than the 1,7‐ closo ‐carborane 26. Therefore, it is likely that the higher affinity for β‐CD observed for the 1,12‐ closo ‐carboranyl derivatives is largely due to the differences in carborane cage polarity.…”

Section: Resultsmentioning

confidence: 81%

Synthesis and Supramolecular Studies of Chiral Boronated Platinum(II) Complexes: Insights into the Molecular Recognition of Carboranes by β‐Cyclodextrin

Ching

Clifford

Bhadbhade

et al. 2012

Chemistry A European J

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The synthesis and characterisation of a novel isomeric family of closo-carborane-containing Pt(II) complexes ((R/S)-(1-4)⋅2 NO(3)) are reported. Related complexes (5⋅NO(3) and 6⋅NO(3)) that contain the 7,8-nido-carborane cluster were obtained from the selective deboronation of the 1,2-closo-carborane analogues. The corresponding water-soluble supramolecular 1:1 host-guest β-cyclodextrin (β-CD) adducts ((R/S)-(1-4)⋅β-CD⋅2 NO(3)) were also prepared and fully characterised. HR-ESI-MS experiments confirmed the presence of the host-guest adducts, and 2D-(1) H{(11)B} ROESY NMR studies showed that the boron clusters enter the β-CD from the side of the wider annulus. Isothermal titration calorimetry (ITC) experiments revealed enthalpically driven 1:1 and higher-order supramolecular interactions between β-CD and (R/S)-(1-4)⋅2 NO(3) in aqueous solution. A comparison of the predominate 1:1 binding mode established that the affinity of β-CD for the guest molecule is mainly influenced by the pyridyl ring substitution pattern and chirality of the host, whilst the nature of the closo-carborane isomer also plays some role, with the most favourable structural features for β-CD binding being the presence of the 4-pyridyl ring, 1,12-closo-carborane, and an S configuration. The results reported here represent the first comprehensive calorimetric study of the supramolecular interactions between closo-carborane compounds and β-CD, and it provides fascinating insights into the structural features influencing the thermodynamics of this phenomenon.

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Influence of lipophilicity on drug–cyclodextrin interactions: A calorimetric study

Cited by 30 publications

References 42 publications

Complexation of oxethazaine with 2-hydroxypropyl-β-cyclodextrin: increased drug solubility, decreased cytotoxicity and analgesia at inflamed tissues

Complexation of oxethazaine with 2-hydroxypropyl-β-cyclodextrin: increased drug solubility, decreased cytotoxicity and analgesia at inflamed tissues

Correlation between the stability constant and pH for β-cyclodextrin complexes

Synthesis and Supramolecular Studies of Chiral Boronated Platinum(II) Complexes: Insights into the Molecular Recognition of Carboranes by β‐Cyclodextrin

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