-
[show abstract]
[hide abstract]
ABSTRACT: Tolfenamic acid is a non-steroidal inflammatory drug with associated gastrointestinal sideeffects and problems with bioavailability. Furthermore, it is extremely insoluble in water. Tolfenamic acid was complexed with various cyclodextrins (β-CyD, HP-β-CyD, methyl-β-CyD) in order to circumvent some of these problems.During the characterization of the inclusion complexes with spectroscopic methods, significant variations in the UV and NMR spectra were observed and attributed to the supramolecular interactions between the guest and host molecules. A validated HPLC method was applied to obtain accurate measurements. The complexation process was further examined; the time needed for the completion of the complexation was determined, the binding constants of the complexes were calculated and the energetics of the system were evaluated.The solubility of tolfenamic acid was 30-fold in the presence of HP-β-CyD and twofold in the presence of methyl-β-CyD.
Pharmacy and Pharmacology Communications. 02/2010; 5(2):79 - 84.
-
[show abstract]
[hide abstract]
ABSTRACT: Quantitative NMR spectroscopy is always an attractive goal as the identity and quantity could be simultaneously determined. Although significant advancements have been achieved in this field it is common that all reported quantitative NMR methods perform the analysis by utilizing the average integral intensities of selected signals. During the calculation of the area under NMR peaks several response problems can occur which should always be treated carefully to overcome inaccuracies. In the method proposed in this work the quantitative information is obtained utilizing the measurement of selected protons chemical shift displacements which is a quite straightforward and highly reproducible process. The (1)H NMR spectra of multiple fluoroquinolone (FQ) solutions revealed that the chemical shifts of protons, especially the aromatic ones, were concentration dependent for all tested compounds, as a result of extensive self-association phenomena. In the present work a novel methodology is described for the quantitation of several FQs based on this dependence. The proposed method was applied to Ciprofloxacin solutions over a wide range of concentrations. Evaluation of the obtained data presented acceptable characteristics regarding accuracy, precision, and robustness. The applicability limitations of this method were found to be posed by current instrumentation, mainly by the magnetic field frequency e.g. the slope of the response function achieved with a 400MHz instrument was twice the one achieved at 200MHz. The pH effect was negligible from pD 2.5 to 5.5. The phenomenon appeared in a pattern that can be applied for a plethora of drug categories revealing self-association phenomena in a range of concentration determined by the magnet strength of the instrument.
Journal of Pharmaceutical and Biomedical Analysis 11/2006; 42(4):405-10. · 2.97 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The chromatographic behaviour of host-guest inclusion complexes was studied, in order to predict the optimal conditions for their accurate analysis and overcome the significant analytical errors generated by the presence of cyclodextrins. Complexes of tolfenamic acid and ketoprofen with beta-cyclodextrtin (betaCD), 2-hydroxypropyl-betaCD (HPbetaCD) and methyl-betaCD (MebetaCD) prepared in different molar ratios, were studied. Since the drug release from cyclodextrins' complexes is a prerequisite for its accurate quantitation, several parameters affecting the dissociation during the analysis were evaluated. In an attempt to explain the drug release mechanism from cyclodextrins, during HPLC analysis, the possible correlation of the NMR structural findings with the binding constants and the thermodynamic quantities of complexation were examined, in relation to their chromatographic behaviour. Finally, the presence of the solvation spheres around the supramolecules, which affect the complex stability, is suggested to be crucial for our chromatographic findings. Particularly, entropy change in the system is considered the most critical factor, determining the time required for dissociation of drug-cyclodextrin complexes, during drug quantitation.
Journal of Chromatography 10/2005; 1087(1-2):86-94. · 4.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cyclodextrins are known to alter the absorptivity of the guest molecules, therefore, analytical methods that are based on the spectrophotometric data present accuracy problems. In this work, using RP-HPLC methods for naproxen-cyclodextrins quantitation, extensive analytical inaccuracies are detected. Competitive complexation technique is utilised in an attempt to develop an analytical method enabling the determination of naproxen as a free drug. For this reason, stationary phases with silica ligands that can function as competing agents were used, thus contributing to the drug release. The release of the drug from cyclodextrins complexes is achieved by modification of the thermodynamic parameters that determine the stability constant, by changing: the interactions with the mobile phase components (e.g. pH, organic modifier, competitive agents) and the interactions with the stationary phase ligands (C8). After studying the parameters affecting the interaction between the alkyl-chain C8 and naproxen:cyclodextrin complexes, we developed and validated a new specific method for the accurate determination of the drug. Consecutive accumulation of the cyclodextrins molecules on the stationary phase was studied.
Journal of Chromatography 08/2004; 1041(1-2):187-93. · 4.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recognition and uptake by specific cellular receptors and transport systems for cyclodextrins have been demonstrated. Based on this concept, natural and synthetically modified cyclodextrins were used as drug carriers. Several beta-lactam antibiotics were selected and their inclusion complexes with different cyclodextrins were prepared (molar ratio ranging from 1:1 to 1:3). The complex formation, in aqueous solution, was monitored and optimum complexation conditions were selected. The inclusion of the active molecules in the cyclodextrin cavity was confirmed by (1)H NMR spectroscopy. Specific HPLC methods for the quantitation of antibiotics in the presence of cyclodextrins were developed and their chemical stability under complexation conditions was confirmed. Antimicrobial activity of drug-cyclodextrin complexes, in terms of minimum inhibitory concentration (MIC), were compared with the corresponding values of uncomplexed free molecules. A wide range of clinical pathogens and known beta-lactamase-producing strains were tested. The activity of the cyclodextrin-included antibiotics was increased, particularly against Gram-negative clinical strains. The nature and degree of substitution on cyclodextrin macromolecules may be the predominant factor in the observed improvement in antimicrobial activity. We believe that the proposed methodology is a novel approach to the microbial resistance problem and will trigger research towards the development of new cyclodextrin derivatives bearing the ability to increase the uptake of included antimicrobial molecules through intensification of the corresponding molecular recognition phenomena.
Journal of Pharmacy and Pharmacology 04/2003; 55(3):291-300. · 2.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Inclusion complexes of tolfenamic acid (TA), a non-steroidal anti-inflammatory drug, with methyl-beta cyclodextrin and hydroxypropyl-beta cyclodextrin were prepared and characterised. Spectrophotometric, chromatographic (RP-HPLC) and 1H NMR studies of the complexes were conducted. It was observed that cyclodextrins influence TA's molar absorptivity leading to Beer's law deviation. Consequently, the accuracy problem arose, urged for the application of specific chromatographic conditions for the determination of TA in the presence of CDs. A new HPLC method was developed and validated. TA was analysed on a C18 column 5 microm (150 x 4.6 mm), using a column thermostat regulated at 30 degrees C. The mobile phase consisted of methanol-phosphate buffer solution (pH 3.2; 0.07 M) (90:10 v/v) and the flow rate was set at 2.0 ml min(-1). The detector was operated at 286 nm. TA was successfully determined, overcoming the problems arising from the presence of cyclodextrins.
Journal of Pharmaceutical and Biomedical Analysis 01/1999; 18(4-5):899-905. · 2.97 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A series of adamantane-containing molecules consisting of two lipophilic centers which are linked by different bridges (oxime esters, oxime ethers, amides, and symmetric alcohols), were designed and synthesized as anti-inflammatory agents. Their anti-inflammatory activity was evaluated as their ability to inhibit phlogistic-induced mouse paw edema. Some of the tested compounds exhibited activity comparable to that of diclofenac, others had a weaker activity, while some oxime esters proved to enhance the inflammatory response. In all cases, activity was dose-dependent. The deacylated compound 10 was found to be the most active of the series, inhibiting inflammation due to Baker's yeast, the mechanism of which involves mainly the activation of lipoxygenase and/or complement systems, a property which is absent from most selective cyclooxygenase only inhibiting non-steroidal anti-inflammatory drugs (NSAIDs).
Archiv der Pharmazie 03/1998; 331(2):72-8. · 1.71 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Differential Scanning Calorimetry (DSC) has been applied to study the thermal properties of the membrane perturbing antibacterial octyl- and dodecyl-bromide salts of quaternary dimethylamino adamantanol (ADM-8 and ADM-12 correspondingly) incorporated in free or complexed form with beta-cyclodextrin (beta-CD) into dipalmitoylphosphatidylcholine (DPPC) containing bilayers. The DSC results showed that the studied compounds exert pronounced thermotropic changes in DPPC bilayers when inserted as free molecules. These effects are reduced when are present in a complex form with beta-CD. Since the studied compounds exert destructive effects in membrane bilayers their insertion in membrane bilayers as complexes with cyclodextrin may result in differentiation of their activity. The obtained results suggest that their complexation with beta-CD may improve their biological profile. It also increases their aqueous solubility, a limited factor for their use as drugs.
Life Sciences 02/1998; 62(20):1901-10. · 2.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: -Cyclodextrin (CD) complexes of I1-8, I1-10, I1-12, were prepared, isolated and characterized in solid and liquid form. Their thermotropic effects were studied by inserting them in DPPC bilayers both in pure and complexed forms. The results have shown that the presence of I1-8 causes spliting, broadening and lowering of the phase transition of DPPC bilayers. Their effects are more significant when I1-0 and I1-12 are inserted. These differential effects are eliminated when the above studied three molecules are incorporated in a complex form with CD in DPPC bilayers. The obtained results suggest that the bromine salts in the bilayer are likely to remain in the complex form rather than released in the membrane.
Journal of Inclusion Phenomena 01/1996; 25(1):161-164. · 1.89 Impact Factor
