Micellar thin-layer chromatography in angiotensin-converting enzyme inhibitors lipophilicity evaluation

Lipophilicity is one of the most significant biologically active substances properties that attract considerable interest in medicinal chemistry, pharmacokinetics and environmental science. Lipophilicity influences drugs absorption, distribution, binding to plasma proteins and elimination. Thin-layer chromatography (TLC) is known as well established method for lipophilicity evaluation. Angiotensin – converting enzyme (ACE) inhibitors represent the group of drugs widely used in treatment of hypertension. In addition to our previous chromatographic studies of ACE inhibitors [1] in this work lipophilicity of ten ACE inhibitors under conditions of micellar thin-layer chromatography has been examined. The substances investigated were: 1. Lisinopril, 2. Cilazapril, 3. Enalapril, 4. Perindopril, 5. Ramipril, 6. Moexipril, 7. Benazepril, 8. Quinapril, 9. Zofenopril, 10. Fosinopril. The experiments were performed on RP-TLC C18 plates, commercially available, (Art. 5559, E. Merck, Germany). The plates were spotted with 1μL aliquots of freshly prepared ethanolic solutions (about 2mg/mL) of investigated drugs. The mobile phase was composed of 20% tetrahydrofuran (THF) and 80% phosphate buffer (pH = 6.8) with addition of polyoxyethylene (23) lauryl ether, Brij 35, (0.01-0.06 M). After development, by ascending technique, the detection was performed under UV lump. All investigations were performed at room temperature (25 2 C). The increase of micelle concentration in mobile phase led to decrease of retention of all lipophilic investigated substances. Only lisinopril as very polar compound showed increase of retention with increase of micelle concentration. The linear dependences between Brij 35 concentrations and RM values were established for all investigated compounds. From these linear relationships, values of RM 0 (intercept) and m (slope) were obtained and C0 values for each solute were calculated (C0 = -RM 0/m). The correlations between hydrophobicity parameters RM 0 or C0 and KOWWIN logP were investigated. The very good correlation with r2 = 0.8606 was established for RM 0 and KOWWIN logP relationship, while for C0 and KOWWIN logP significantly lower correlation was obtained r2 = 0.2878 probably due to micelle’s concentration influence on solutes retention rate.Book of apstract- ICOSECS 8, 8th International Conference of the Chemical Societies of the South-East European Countrie

Evaluation of Angiotensin-Converting Enzyme Inhibitor's Absorption with Retention Data of Micellar Thin-Layer Chromatography and Suitable Molecular Descriptor

Twelve angiotensin-converting enzyme (ACE) inhibitors were studied to evaluate correlation between their absorption (ABS) data available in the literature (22-96%) and hydrophobicity parameters (k(m) and P-m/w) obtained in micellar thin-layer chromatography (MTLC) using Brij 35. The theoretical considerations showed that the geometric molecular descriptor-volume value (Vol) should be considered as an independent variable simultaneously with calculated hydrophobicity parameters in multiple linear regression analysis to obtain reliable correlation between ACE inhibitor's absorption and lipophilicity (calculated KOWWINlog P) and that captopril should be excluded from further correlations. The results of MTLC confirmed that between the two hydrophobicity parameters k(m) and P-m/w, for absorption prediction of 11 ACE inhibitors, the micelle-water partition coefficient P-m/w provided higher correlation (R-2 = 0.756), while for the k(m) parameter R-2 = 0.612 was obtained. The micelle-water partition coefficient Pm/w could be considered as analogous to hydrophobicity parameter C-0 from reversed-phase thin-layer chromatography. Dissimilar retention behavior of lisinopril indicated its lowest non-polar interaction with micelle, because of its di-acid form. The proposed model which included ACE inhibitors on the opposite site of lipophilicity-lisinopril and fosinopril (KOWWINlog P = -0.96 and KOWWINlog P = 6.61, respectively), both with similar absorption values (25 and 36%, respectively), could indicate that absorption of investigated compounds occurs via two different mechanisms: active and passive transport

Derivative spectrophotometric determination of partition coefficient of hydrochlorothiazide between cetyltrimethylammonium bromide micelles and water

The interaction of hydrochlorothiazide (HCT), benzothiadiazine diuretic, with cationic surfactant cetyltrimethylammonium bromide (CTAB) was studied as a model system for drug/membrane interactions. From the dependence of first order derivative amplitude 1 D250.1 on CTAB concentration, by using mathematical models based on the partition of the drug between micellar and aqueous pseudo-phase, CTAB/water partition coefficient Kp was calculated.Physical chemistry 2004 : 7th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 21-23 September 200

Development of the second-order derivative UV spectrophotometric method for direct determination of paracetamol in urine intended for biopharmaceutical characterisation of drug products

Paracetamol is a widely used nonsalicylate analgesic and antipyretic drug. The existing methods for the determination of paracetamol in biological fluids are mainly HPLC techniques, although there are some reported methods based on spectrophotometric determinations. However, all these methods involve some extraction or derivatisation procedures. In the present study the UV spectra of investigated samples were recorded over the wavelength range 220-400 nm (lambda step 0.21 nm; scan speed 60 nm/min) and second-order derivative spectra were calculated. Second-order derivative spectra of different blank urine samples displayed the presence of a zero-crossing point at 245-247 nm defined as lambda(zc). The zero-order absorption spectra of paracetamol in water displays maximum absorbance at 243 nm, while in second derivative spectra, a minimum peak at 246 nm was observed. Therefore, the application of zero-crossing technique to the second-derivative UV absorption spectrum should be useful for the determination of paracetamol using 2D(lambdazc). The proposed method enables determination of total paracetamol in urine directly and simply by reading the D-2(lambdazc) of the diluted samples. The obtained results were in good accordance with published data on cumulative urinary excretion after per oral administration of paracetamol obtained applying different spectrophotometric methods of determination. It could be useful for biopharmaceutical characterisation of drug products (monitoring of the levels of paracetamol in urine in bioavailability testing, for the evaluation of in vitro-in vivo correlation and screening of different formulations during drug product development). Copyrigh

Evaluation of ACE inhibitors lipophilicity using in silico and chromatographically obtained hydrophobicity parameters

The aim of this study was to compare different calculation methods to determine lipophilicity, expressed as logP value, of seven ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, and benazapril) with significantly different structure. Experimentally determined n-octanol/water partition coefficients, logPO/W values, were obtained from relevant literature. The correlations between all collected logP values were studied and the best agreements between calculated logP and experimentally determined logPO/W values, were observed for KOWWINlogP or MilogP values (r = 0.999 or r = 0.974, respectively). The correlations between all collected logP values and chromatographically (reversed-phase thin-layer chromatography) obtained hydrophobicity parameters, RM0 and C0, were established. The good correlations (r > 0.90) were obtained in the majority of relationships. The KOWWINlogP was established as the most suitable hydrophobicity parameter of investigated group of ACE inhibitors with r = 0.981 for correlation with RM0 and r = 0.977 for correlation with C0 parameters (water-methanol mobile phase). Using multiple linear regressions, it was established that application of two selected logP, calculated by different mathematical approaches, led to very good correlation due to the benefits of both calculation methods. The good relationships indicate that the computed logP, with careful selection of method calculation, can be useful in ACE inhibitors lipophilicity evaluation, as high-throughput screening technique

Investigation of Solvolysis Kinetics of New Synthesized Fluocinolone Acetonide C-21 Esters-An In Vitro Model for Prodrug Activation

In this study the solvolysis of newly synthesized fluocinolone acetonide C-21 esters was analysed in comparison with fluocinonide during a 24-hour period of time. The solvolysis was performed in an ethanol-water (90:10 v/v) mixture using the excess of NaHCO(3). The solvolytic mixtures of each investigated ester have been assayed by a RP-HPLC method using isocratic elution with methanol-water (75:25 v/v); flow rate 1 mL/min; detection at 238 nm; temperature 25 degrees C. Solvolytic rate constants were calculated from the obtained data. Geometry optimizations and charges calculations were carried out by Gaussian W03 software. A good correlation (R = 0.9924) was obtained between solvolytic rate constants and the polarity of the C-O2 bond of those esters. The established relation between solvolytic rate constant (K) and lipophilicity (cLogP) with experimental anti-inflammatory activity could be indicative for topical corticosteroid prodrug activation

Use of pralidoxime-Pd(II) complex for the spectrophotometric determination of the cholinesterase reactivator (PAM-2Cl) in the urine

A simple and rapid method for the spectrophotometric determination of pralidoxime chloride in urine, based on complex formation with palladium(II) without preliminary mineralization of the sample, is described. The proposed method is shown to be reproducible and in good agreement with a reference method, which involved spectrophotometric determination of corresponding oximate ions in ammonium hydroxide solution at 336 nm. Our results indicate that the proposed method is reliable, rapid and of sufficient sensitivity for pralidoxime chloride analysis in urine

Potentiometric investigation of the stability of palladium(II) complex of pralidoxime chloride in aqueous solution

The formation of a complex between palladium(II) chloride and pralidoxime chloride (PAM-2Cl) has been studied by means of potentiometric pH measurements. The real stability constant of the complex in aqueous medium of ionic strength 0.3 M (KCl) at 25.0°C was log Ks = 7.29. This value was close to that (log Ks = 7.02) obtained previously by spectrophotometric methods after appropriate correction with respect to the corresponding value of the acidic constant of PAM-2Cl (pKca = 8.05), which was also determined under the same experimental conditions