Annals of West University of Timisoara

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1 Annals of West University of Timisoara Series Chemistry 14 (2) (2005) EXPERIMENTAL AND THEORETICAL STUDY OF THE ETHACRIDINE LACTATE AN ANTISEPTIC REMEDY I. G. Bratu a, Valentina Chiosa b, Ioana Stă nculescu b a University of Pitesti, Faculty of Sciences, Chemistry and Physics Department, 1 Târgu din Vale Str., Pitesti, ROMANIA b University of Bucharest, Faculty of Chemistry, Department of Physical Chemistry, Blvd. Regina Elisabeta, 4-12, Bucharest, , ROMANIA Received: 29 June 2005 Modified: 10 September 2005 Accepted: 20 September 2005 SUMMARY The aim of this paper is the study of a very used antiseptic remedy - ethacridine lactate (EL) - by experimental and theoretical methods in view of understanding of physiological mechanism of its action. As experimental method we used the selective FTIR spectroscopy. We made the assignment of the obtained spectra by EXP AIR program version 2.0. As theoretical methods we used the molecular mechanics (MM+) and quantum mechanics (AM1). The most stable protonated form of ethacridine lactate, which is the active principle of Rivanol an antiseptic remedy delivered as aqueous solutions was calculated. Keywords: antiseptic remedy, ethacridine lactate, FTIR spectra, molecular modeling. INTRODUCTION In recent years, a considerable scientific effort is allocated to obtain the structural and enantiomeric purity characterization and the rate of degradation specific for different pharmaceuticals, which contain a chiral component as active principle [1-3]. We have interested in the theoretical and experimental study of some organic and 173

2 B RATU I. G., C HIOSA V., S T Ă NCULESCU I. inorganic lactates with various physiological properties [4-6]. Ethacridine lactate (EL) is the active principle of Rivanol a very known antiseptic remedy for external use, delivered as aqueous solution. In this paper we report an experimental study based on FTIR spectroscopy to control the quality and the purity for named pharmaceutical product. The aim of the molecular modeling study was to calculate the most stable protonated form of the ethacridine lactate. MATERIALS AND METHODS The characteristics of EL (produced by Liadong Pharmaceutical CoLtd China) given in Table I have been selected from the certificate of analysis number no. A-29/58 M.D./ , performed by National Drug Agency, from Family and Health Ministry. Table I. Characteristics of the ethacridine lactate No Parameter Characteristics 1 Description Yellow crystalline powder 2 Appearance of aqueous solution 1.5g/75ml Clear, yellow 3 ph of aqueous solution 1.5g/75ml Chlorides (ppm) Max Sulphates (ppm) Max Heavy metals (ppm) Max Loss by dry g% 4,5-5,5 8 Sulphated residue g% Max Dosage: ethacridine lactate g% FTIR spectra of ethacridine lactate were recorded on FTIR spectrophotometer using KBr pellets technique and than we performed the interpretation of these spectra using EXP AIR (L Expert Assistant Infra-Rouge) program, version 2.0. We performed calculation using HyperChem Release 6.01 Program for Windows 2000, Hypercube Inc., installed on a PC Intel Pentium 4, CPU 2.8 GHz 512 MB of RAM and the following methods: - the molecular mechanics, force field MM+, the calculation of electrostatic term by bond dipoles approximation, geometry optimization with Polack-Ribiere algorithm. The used RMS gradient was kcal/å mol - the quantum mechanics, semi empirical method AM1, RHF, Polack-Ribiere algorithm, gradient RMS = 0.01 kcal/å mol. 174

3 EXPERIMENTAL AND THEORETICAL STUDY OF THE ETHACRIDINE LACTATE RESULTS AND DISCUSSION The FTIR spectrum of ethacridine lactate is given in Figure 1. Figure 1 FTIR spectra of ethacridine lactate Using the correlation tables from the literature data [1, 2, 5] and the EXP AIR program we realized the interpretation of analyzed samples spectra which show the presence of the functional groups characteristic for EL (ether, alchyl appeared very significant; the secondary amide it s an impurity), as results from Table II. Table II. Assignment of functional groups in FTIR spectra of ethacridine lactate (C 15 H 15 N 3 O C 3 H 6 O 3 H 2 O) No The functional group Frequencies (cm -1 ) Pertinence 1 Aliphatic ethers Very significant 2 Nitric compounds Very significant 3 Secondary amides Very significant 4 Primary amides Very significant 5 Alchil Very significant 6 Alcohol Significant 7 Tertiary amides 1633 Significant 8 Epoxy Significant 9 Alchene Significant 10 Conjugate ether 1228 Significant 11 Aromatic nucleus Little significant 12 Carboxylic acid Little significant 13 Phenol Little significant 14 Beta-lactones 1120 Little significant 15 Primary amine Little significant 16 Anhydrides Insignificant 175

4 B RATU I. G., C HIOSA V., S T Ă NCULESCU I. We have performed the calculation for the initial ethacridine and for three protonated form and then for the anion lactate. In the Figure 2 are illustrated numbering schema for ethacridine, three protonated form of ethacridine and for anion lactate. In Table III are presented corresponding QSPR properties for these species. Figure 2. Numbering schema of the initial ethacridine, three protonated forms and anion lactate Table III. Calculated properties of initial ethacridine, Ethacridine 1, Ethacridine 2, Ethacridine 3 and Lactate anion, respectively Numeric values for N Calculated initial Ethacridine Ethacridine Ethacridine Lactate o properties Ethacridine anion 1 Surface vdw (Å 2 ) Surface acc. solv. (Å 2 ) log P Volume (Å 3 ) Refractivity (Å 3 ) Polarizability (Å 3 ) Molecular weight (uam) 176

5 EXPERIMENTAL AND THEORETICAL STUDY OF THE ETHACRIDINE LACTATE For the named species are also calculated IR spectra, dipole moments and molecular orbital energetic levels (see Figure 3 and Table IV). Figure 3. MO energetic levels for initial ethacridine LUMO: ; HOMO: ev Table IV. The principal MO energetic levels of protonated ethacridine forms Protonated etacridine forms E HOMO (ev) E LUMO (ev) Eth Eth Eth The dipole moment is a very important characteristics for the analysis of drugs transport phenomena in methabolic pathways. We can observe that the value of calculated dipole moments (expresed in Debye) of ethacridine derivated species are disposed in the next increasing order: Initial ethacridine Ethacridine 3 Ethacridine 1 Ethacridine 2 μ (D) From comparative analysis of all these calculated data it can be concluded that 177

6 B RATU I. G., C HIOSA V., S T Ă NCULESCU I. ethacridine 3 which has the protonated atom number 10 (a nitrogen atom) corresponds to the most probable ethacridine protonated form. CONCLUSION 1. A FTIR spectrum analysis of ethacridine lactate probe, produced by Liadong Pharmaceuticals CoLtd China, was effected and shows presence of some secondary amide impurity. 2. The modeling study concerning the three protonated form permit affirmations that ethacridine 3 is the most stable protonated form of ethacridine lactate, the active principle of Rivanol an antiseptic remedy. REFERENCES 1. Mandravel C., Chiosa V.,,,Metode de studiu ale structurii moleculare, E.U.B., Bucuresti, (2005), , C. Mandravel, I. Stănculescu,,,Interactions moleculaire, EUB, (2003), C. Mandravel, R. Stanescu, Chiosa V.,,,Relatii structura, proprietati si activitate biologica aplicate la poluanti industriali,, E.U.B., Bucuresti, (2003) 4. G. Bratu, Ph D Thesis, Bucuresti, (2004) 5. George, B., Mc. Yntyre, P., Infrared Spectroscopy, John Wiley & Sons, London, (1987), p Clark T., A handbook of computational chemistry, John Willey and Sons, New York, (1985),