1. INTRODUCTION:
Cetirizine dihydrochloride (syn. Zyrtek, Zodak, Сetrine, etc.) is a derivative of piperazine and belongs to the second generation antihistamines for oral use. Cetirizine is a chiral molecule that exists as a racemic mixture of two stereoisomers (1:1), namely levocetirizine (L-CET) and dextrocetirizine (D-CET) (Fig 1).
L-stereoisomer (Levocetirizine) D-stereoisomer (Cetirizine)
Figure 1: Cetirizine structure racemic: L-and D-stereoisomers of Cetirizine.
As a metabolite of hydroxyzine formed in the human body, it is a potent selective peripheral H1 receptor antagonist used in the treatment of allergic rhinitis, perennial allergic rhinitis, chronic urticaria, and atopic dermatitis1. Levocetirizine (L-Cet) is a second generation antihistamine indicated for for rhinitis, hay fever and chronic idiopathic uticaria. As the eutomer of cetrizine, though rapidly and extensively absorbed, its volume of distribution and non-renal clearance are significantly lower than that of dextrocetirizine2. In normal adults, experiments show that L-Cet attenuate histamine-induced sneezing and increase nasal airway resistance3. Therefore, administration of L-CET alone may provide a better therapeutic benefit compared to its racemic form.
The British Pharmacopoeia has proposed a potentiometric titration method for the determination of CTZ substance; although it recommended an HPLC method for the analysis of CTZ oral solution and tablets 4. The United States Pharmacopoeia has proposed a non-aqueous titration method in glacial acetic acid CTZ. The pharmacopoeial method for the determination of CTZ as the main substance in the substance of CTZ dihydrochloride involves dissolving 0.100g of the test sample in 70ml of a mixture of water R and acetone R (30:70, v/v), followed by potentiometric titration with 0.1 M sodium hydroxide solution until the second titration jump5.
Scientists have developed different approaches to the determination of CTZ such as a titrimetric assay based on the measurement of chloride from hydrochlorides using diphenylcarbazone-bromothymol blue as an indicator6; drug precipitation using cadmium nitrate for subsequent evaluation of residual cadmium using EDTA after separation of the complex7; potentiometrically where the ion pair was preliminary prepared by precipitation of cetirizinium ion with tetraphenylborate 8; spectrophotometric methods9-19; using High Performance Liquid Chromatography20-41; High Performance Thin Layer Chromatography42-43 and conductometry44.
These methods use complex derivatizations, expensive instruments or toxic reagents for quantitative analysis. Although El-Kommos et. al. opine that titrimetric procedures, with the exception of Hg(II), are indirect, lengthy, and laborious45, we believe redox titrimetry can serve as a useful alternative to many of the earlier listed methods due to its cost effectiveness, simplicity, sensitivity, exceptional accuracy and wide applicability.
The purpose of our work is to develop an oxidimetric method for assay of CTZ and L-Cet using a green (biodegradable) reagent – potassium hydrogen peroxomonosulfate in the form of Oxone.
2.1. Objects of analysis:
a. Cetirizine dihydrochloride, 98.5% (HPLC) (Sigma-Aldrich). Empirical Formula: C21H25ClN2O3 · 2HCl CAS Number: 83881-52-1 Molecular Weight: 461.81
b. Levocetirizine dihydrochloride, (-)-Cetirizine dihydrochloride; CAS Number 130018-87-0. Empirical Formula C21H25ClN2O3·2HCl Molar mass: 461.8 g/mol; Purity ≥ 98% (Sigma- Aldrich).
c. Cetirizine tablets (Astrapharm): coated tablets, 10 mg, no. 20 in blisters; Serial No. 011020
Characteristics:
Release form, packaging and composition of the drug Cetirizine
Tablets, film-coated white or almost white, round, biconvex; on a cross section - a kernel of white or almost white color.1 tab. cetirizine dihydrochloride 10 mg
Excipients: microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate, colloidal silicon dioxide.
Shell composition: [hypromellose, talc, titanium dioxide, macrogol 4000] or [dry white film shell containing hypromellose, talc, titanium dioxide, macrogol 4000].
d. Levocetirizine tablets (Astrapharm): coated tablets, 5 mg, No. 20 in blisters; Series No. 020917 GMP Certificate of Compliance No. 041/2016/SAUMP/GMP. Water 5.68%
In this study, pure substances of CTZ and L-Cet were used, as well as Oxone as an oxidizing agent.
e. The ternary salt 2KHSO5 ·KHSO4 ·K2SO4 known under the trade name Oxone: Potassium peroxomonosulfate, extra pure, min. 4.5% active oxygen (Acros Organics).
2.1.1 Preparation of Oxone Solution preparation:
To avoid repetition of this information, find the information in our recent work “Blazheyevskiy et. al 2022”46.
2.1.2 The preparation of pH buffer solutions:
For pH = 7.00: Dissolve 90.715 g of dipotassium hydrogen phosphate (K2HPO4) and 37.996 g of potassium dihydrogen phosphate (KH2PO4) in 1liter volume double distilled water.
2.1.3 0.2 M solution potassium pyrophosphate:
Dissolve 66.067g potassium pyrophosphate (potassium diphosphate) in 1liter volume double distilled water.
2.1.4 Preparation method of рН buffers:
Add diluted hydrochloric acid by drops into an aqueous solution of 0.2M solution potassium pyrophosphate while measuring the pH with a pH meter to achieve pH 8.0 and pH 9.0 values.
2.1.5 Preparation method of рН buffers with pH 10.0 values:
50ml of 25mM borax was mixed with 18.3ml of 0.1M NaOH. Final buffer volume completed to 100mL with double distilled water.
2.1.6 The preparation a diluted sodium hydroxide solutions:
Add to two weeks old prepared saturated (50% w/v) solution of sodium hydroxide calculated volume of freshly boiled and cooled double distilled water. Other concentrations were prepared by dilution.
2.1.7 Sodium thiosulphate standard solution:
c (Na2S2O3∙5H2O) = 0.1mol/L), was prepared with 0.1 M Normadose® (standard titre) in freshly boiled and cooled distilled water with addition of 0.5g sodium carbonate in a 1L volumetric ask. It is then filled with the same solvent to the mark at 293K
2.1.8 Potassium iodide 5 % solution
5.0 g of potassium iodide was dissolved in 50ml of freshly boiled andcooled water. It is then filled with the same solvent to 100 ml. The solution should be colourless.:
2.1.9 Preparation of 0.2mol L-1 phosphate buffer solution (pH 8.3)
Disodium hydrogen phosphate dodecahydrate (35.75 g) was dissolved in 500 mL flask using double-distilled water. Then 19 mL of 0.1 mol L-1 solution of the hydrochloric acid solution was added. The pH of the final solution was controlled by potentiometry.
Other chemicals and reagents such as hydrochloric acid and potassium iodide used were of analytical grade from Qualigens. All reagents and solutions were prepared using this double distilled water. All the reactions were carried out in a thermostat and the temperature was controlled to ±0.10°C Hydrochloric acid diluted: was prepared with 0.1 M Normadose® (standard titre).
2.2.1 Method for the quantitative determination of L-Cet in model (standard) solutions:
An aliquot of 10.00ml of a solution containing 2–10mg of L - CET was placed with a pipette into a 100-ml Erlenmeyer flask; after that, 5.0ml of 0.2 M buffer solution (It should be taken into account that pH 8.3), 1 ml of NaOH (0.02 M ) and 5.00ml of KHSO5 (0.008 M) were successively added and left for a certain time (1.5 min) at room temperature to complete the oxidation of the drug. To lower the pH, 1.0ml of a 1.0 M H2SO4 solution was added, followed by 1ml of 10% potassium iodide while stirring the contents of the flask. The mixture was again left for about 10 seconds, and the liberated iodine was titrated with 0.01M thiosulfate, while 1ml of 1% starch solution was added near the end point. The whole procedure was also applied in a blank determination on water.
2.2.2 Method for assay of L – CETsubstance:
Accurate weight of 0.230905g of L - CET drug powder was dissolved in 70ml of twice distilled water in a 100 ml volumetric flask, diluted with water to the mark and mixed well. A 20.00ml aliquot of the drug solution was transferred to a 100ml calibrated flask, 60ml of pH 8.3 buffer solution and 5.00ml of KHSO5 (0.04 M) were added, the volume was finally diluted with water to 100 ml and mixed well. After 1.5 min, an aliquot of the reaction mixture (10.00ml) was quickly added to the Erlenmeyer flask, which already contained 1 ml of 1 M H2SO4 solution and immediately after that, 1 ml of 5% potassium iodide solution was added with shaking. The mixture was left again for about 10 seconds and the liberated iodine was titrated with 0.01 M thiosulfate with the addition of 1 ml of 1% starch solution near the end point. Similarly, a blank determination was performed with water instead of a solution of the analyzed substance.
The content of the main substance in the substance L - CET ( w , %) was found by the formula:
1.00ml of standard 0.0100mol/l sodium thiosulfate solution corresponds to 0.00230905 g mL -1 Levoceterizine hydrochloride (C21H25ClN2O3·2HCl), which should be 98-102% in the preparation in terms of anhydrous substance.
Where the volume of standard 0.0100mol/l sodium thiosulfate used for titration in the control experiment, ml;
V is the volume of standard 0.0100mol/l sodium thiosulfate used for titration in the working experiment, ml;
100 and 100 is volumes of volumetric flasks, ml;
20 is taken for the analysis of the volume of the solution of the dosage form, ml;
a is the mass of the sample of the substance, g
w (H2O) is moisture content in the substance (weight loss upon drying),%;
10 is the volume of the reaction mixture taken for titration, ml.
T is the amount of L-Cet hydrochloride, which corresponds to 1ml of a standard 0.0100mol/l thiosulfate solution, g/ml;
1.00ml of a standard 0.0100mol/l sodium thiosulfate solution corresponds to 0.00230905g mL -1 L-Cet hydrochloride (C21H25ClN2 O3·2HCl), which should be 98-102% in the preparation in terms of anhydrous substance.
2.2.3 Method for quantitative determination of L-Cet in tablets:
Twenty tablets were accurately weighed and ground into a fine powder. An accurately weighed amount of ground powder, equivalent to 100mg of L - CET, was transferred into a 100ml volumetric flask. 60ml of water was added and the contents were thoroughly shaken for 15-20 minutes to extract the drug into the liquid phase, the volume was finally adjusted to the mark with water, mixed well and filtered using Whatman No. 42 filter paper. An aliquot of the filtrate (10 mg/ml) was used for the method described above (see : "Method for the determination of L-cet in model ( standard ) solutions" ).
3. RESULTS AND DISCUSSION:
Kinetic study of the reaction of N - oxidation of Cetirizine and Levocetirizine using potassium hydrogenperoxo- monosulfate in buffer solution:
In this study, peroxomonosulfate was found to quantitatively react with CTZ and L-Cet in an alkaline medium to form its N-oxides. The stoichiometry of the reaction of potassium caroate with CTZ showed that 1 mole of potassium caroate was required to oxidize 1 mole of CTZ; same for L-Cet.
The results from the study of the kinetics of N-oxidation of L-Cet by potassium hydrogenperoxomonosulfate during iodometric titration (according to the consumption of the oxidizing agent) are shown in Fig. 2-4 and Table 1. As can be seen in figure 2, at pH 8.0-9.0 (after 1-1.5 minutes), stoichiometric consumption of the oxidizing agent is achieved.
Semilogarithmic anamorphoses of the kinetic curves of the oxidation reaction of L-Cet with potassium hydrogenperoxomosulfate, depending on the pH of the medium, are linear (see Figue 3) which indicates the second order of the reaction. The tangents of the angles of these dependences are the observed reaction rate constants. As can be seen from the data in Table 1, the highest reaction rate is observed at pH 9.0. At the same pH of the medium, the maximum product of the molar fractions of the base of L-Cet and the monoanion HSO5 - is observed.
Figure 2: Kinetic curves of the reaction of N - oxidation of L-cet by potassium hydrogen peroxomonosulfate depending on the pH of the medium. pH: 1 - 7.0 ; 2 - 8,0 and 10,0; 3 - 9.0. c ( L - Сet) = 0.001 mol/l; c (KHSO5 ) = 0.00205 mol/l;
Table 1: Influence of medium pH on the rate of N -oxidation of L-Cet with potassium hydrogen peroxomonosulfate. с(L-Cet) = 0,001 mol/l; с(КНSО5) =0,002 mol/l
|
Medium pH |
Second-order reaction rate constant, kobs, mol -1 l min -1 |
|
7,0 |
0,404 |
|
7,5 |
0,591 |
|
8,0 |
0,904 |
|
9,0 |
1,030 |
|
10,0 |
0,904 |
Figure 3: Semilogarithmic anamorphoses of the kinetic curves of the oxidation reaction of L-Cet with potassium hydrogenperoxomosulfate depending on the pH of the medium. pH: 1 - 7.0; 2 - 7.5; 3 - 8.0; 4 - 10.0; 5 - 9.0. с (L-cet) = 0,001 mol/l; с0 =0,002 mol/l;
Based on the assumption that the unprotonated form of the base of the tertiary nitrogen levocetirizine ( L - СET 0 ) and the hydrogen peroxymonosulfate monoanion (НSO5-) take part in the reaction, we derived the kinetic equation of the reaction :
Rate = kobs · c ( L - cet) · с(КНSО5)
kobs = k α(L-СET0) · α (НSO5–)
where, α (L-СET0) is the molar fraction of the base of Levocetiricine;
α (НSO5–) is the molar fraction of hydrogen peroxymonosulfate monoanion;
which are respectively equal to: α (СET0) = Ka / (Ka + [H+]) = α (L-СET0) = 10–8,25 / (10–8,25 + 10–рН);
α (HSO5–) = (10–0,4 · 10–рН) / [(10–рН)2 + (10–0,4 · 10–рН) + (10–0,4 ·10–9,4);
Ka is dissociation constant of the acid form of L-Cet;
It should be taken into account that pH = - lg [ H + ], and [ H + ] = 10 - pH .
pKa = - lg Ka , and Ka=10-pKa . pKa of L-Cet = 8.25.
The Caro acid has two dissociation constants, which are expressed as
the following indicators pKa: p Ka1 =0.4 and p Ka2 = 9.4.
Linear dependence with k observed on the product of the mole fractions of L-Cet base and monoanion HSO5 - (Fig.4) confirm the correct assumption that it is the base of L-Cet and mainly the monoanion of hydrogen peroxomonosulfate acid that takes part in the reaction (correlation coefficient R = 0.9, which is close to 1).
Figure 4: Dependence of the observed rate constant of the N -oxidation reaction of levocetirizine by potassium hydrogenperoxomonosulfate from the product of the mole fractions of the base of L-Cet and the mole fraction of the monoanion hydrogenperoxomonosulfate.
The rate constants of the second order reaction k (Lmol-1min-1) for CTZ and L-Cet are 1.051 and 1.225 respectively.
Thus, the oxidation of Levocetirizine potassium hydrogen peroxomonosulfate can be represented by the scheme (Fig.5).
Figure 5: Oxidation scheme of Levocetirizine by potassium hydrogen peroxomonosulfate
Table 2: Results of titrimetric assay for the pure substances of Levocetirizine and Cetirizine using Oxone ( n = 7; P = 0.95)
|
API |
Claimed content ( w , %) |
Found ( ( %) |
RSD, %
|
(%) |
|
L-СETsubst |
99.7* |
99.5 ± 0.67 |
0.75 |
- 0.20 |
|
CTZsubst |
99.6* |
99.2±0.65 |
0.74 |
- 0.40 |
* Using the British Pharmacopoeia method
The obtained results from studying the reaction kinetics were similar for CTZ. This formed the basis for the development of a new method for quantitative determination of L-Cet and CTZ by N -oxidation using potassium hydrogen peroxomonosulfate as an analytical reagent (see Tables 2-4).
Table 3: The results of the analysis of Levocetirizine and Cetirizine tablets according to the proposed method ( n = 5; P = 0.95)
|
Determined substance - analyzed drug |
Found ( mg/tabl. |
RSD, % |
Certificate data (µ*) mg per tablet |
(%) |
|
Levocetirizine - Astrafarm, coated tablets, 5 mg, No. 20 in blisters; Serial No. 020917 |
4.87 ±0.091 (Re 99.4±1.82%) |
1.50 |
4.83 |
+0.83 |
|
Сetirizine - Astrafarm, coated tablets, 10 mg, No. 20 in blisters; Serial No. 011020 |
10.10 ±0.18 (Re 101.0±1.8%) |
1.42 |
10.05 |
+0.50 |
* Using the British Pharmacopoeia method
Table 4: The results of titrimetric assay of Levocetirizine and Cetirizine pure substances in model solutions using Oxone (n = 7; P =0.95)
|
Taken (mg) |
Found х ̅±Δх ̅ (mg) |
RSD, % |
δ=( (%) |
||||
|
L-CET |
CTZ |
L-CET |
CTZ |
L-CET |
CTZ |
L-CET |
CTZ |
|
2.31 |
2.31 |
2.35± 0.06 |
2.32± 0.06 |
2.91 |
3.05 |
+1.73 |
+0,43 |
|
4.62 |
4.62 |
4.65± 0.05 |
4.65± 0.05 |
1.20 |
1.25 |
+0.65 |
+0.65 |
|
9.24 |
9,24 |
9.25± 0.058 |
9,26± 0.07 |
0.70 |
0.80 |
+0.11 |
+0.22 |
* µ - known content of analyte in the model solution (mg)
4. CONCLUSION:
Techniques have been developed and the possibility of quantitative determination of Levocetirizine and Cetirizine in the substance and tablet forms by iodometry using oxone as an analytical reagent has been shown. RSD ≤1.5%.
This developed method can serve as a useful alternative to many of the above complex methods due to its cost-effectiveness, simplicity, sensitivity, exceptional accuracy, and broad applicability. The proposed methods for the quantitative determination of Levocetirizine dihydrochloride and Cetirizine dihydrochloride in its pure and tablet forms by iodometric titration using KHSO5 as an analytical reagent can be used in the development of analytical procedures for drugs, as well as in state laboratories for quality control of medicines and central pharmaceutical factory laboratories or enterprises. The proposed methods for performing analysis do not require the use of expensive instruments, as well as toxic chemical reagents. By sensitivity, speed of execution and selectivity, the developed methods of analysis are practicable and cost-effective compared to the existing methods.
5. LIST OF ABBREVIATIONS
|
CTZ |
- Cetirizine |
|
L-CET |
- Levocetirizine |
|
PMS |
- Potassium hydrogen peroxomonosulfate |
|
RSD |
- Relative Standard Deviation |
6. CONFLICT OF INTEREST:
The authors declare no conflict of interest, financial or otherwise.
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Received on 14.06.2023 Modified on 22.10.2023
Accepted on 12.01.2024 © RJPT All right reserved
Research J. Pharm. and Tech 2024; 17(4):1805-1811.
DOI: 10.52711/0974-360X.2024.00287