RU2514002C2 - Method of drotaverine determination - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and can be applied in control-analytic laboratories for standardisation and control over medication quality. Method deals with determination of drotaverine hydrochloride by spectrophotometry of determined substance and standard sample of comparison, as solvent for preparation solution to be determined applied is 0.1 M solution of hydrochloric acid, concentration of analysed solution constitutes 0.000017 g/ml, as comparison, sample potassium dichromate is applied, value of conversion rate 0.434 is introduced into formula for calculation of results and calculation is performed by formula.

EFFECT: method makes it possible to increase reproducibility of determination results, reduce cost, labour consumption, analysis error, to unify analysis methodology.

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Description

The present invention relates to medicine and can be used in control and analytical laboratories for standardization and quality control of medicines.

The current drug quality control system requires pharmaceutical science to continuously improve the effectiveness of existing methods of analysis.

Among modern methods of pharmaceutical analysis, optical control methods occupy an important place, which are widely used both for the purposes of quantitative determination and for the control of purity and identification of drugs.

Various methods are known for determining drotaverine [1 (3,4-diethoxybenzylidene) -6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline

hydrochloride] used as an antispasmodic.

A known method for the acidimetric determination of drotaverine, which consists in preparing a solution of drotaverine in glacial acetic acid, adding a solution of mercury oxide acetate followed by titration with a 0.1 M perchloric acid solution to a green color with a crystal violet indicator (FS 42-0097022600 “Drotaverina hydrochloride”, C. 12). The titrimetric method for the quantitative determination of drotaverine hydrochloride recommended by regulatory documents is highly toxic, insensitive, and time-consuming.

The closest is a method for determining drotaverine hydrochloride solution in ampoules by preparing solutions of the test substance, followed by reaction with phenol red using an ammonia-acetate buffer solution with pH 9 as a solvent, followed by spectrophotometry at a wavelength of 560 nm and calculating calibration results schedule (Karibyants M.A., Mazhitova M.V., Ryzhkova A.V., Bisenova A.B.Determination of drotaverine by reaction with phenol red // Natural Sciences. - 2010. - No. 3 (3 2). - S.161-166.). In this work, a spectrophotometric method for determining drotaverine according to a calibration graph is proposed, therefore, the analysis and calibration in this method are carried out in different experiments, which leads to an increase in the analysis error. The paper shows the possibility of quantitative determination of drotaverine with phenol red in the concentration range of drotaverine from 0.498 mg / ml to 2.49 mg / ml. This method leads to both an increase in time (construction of a calibration graph) and an increased consumption of reagents and solvents.

Using the spectrophotometric method to analyze the substance of drotaverine hydrochloride is difficult due to the lack of state standard samples for this drug. The production of such reference materials is expensive, as they find application only in pharmaceutical analysis. Therefore, the method of determination using state standard samples will not be available for many laboratories.

In the proposed method, the authors use a 0.1 M solution of hydrochloric acid as a solvent, the detection sensitivity is 50 times higher than in the prototype, the possibility of quantitative determination of drotaverine at a concentration of 0.017 mg / ml (0.000017 g / ml) is shown as an analytical use a wavelength of 353 nm. The use of a 0.1 M solution of hydrochloric acid and 353 nm as an analytical length as a solvent allows one to reduce the analysis error, which confirms the comparison of the errors in determining E = 0.28% for the proposed method and E = 4.78% for a close analogue, therefore, the proposed The method allows to reduce the analysis error in comparison with the prototype. In addition, the reproducibility of the determination results is increased, which confirms the comparison of the variances of two sample sets using the F - distribution at f ₁ = f ₂ = 10, p = 99% for the proposed method and a close analogue. It was established F _ex = 15.4 at F _table. = 8.47, therefore, the proposed method has higher reproducibility.

The use of potassium dichromate as a standard sample in the proposed method reduces the error and cost of analysis. An important role in the analysis of external comparison samples is played by the specific value of the conversion factor, which allows conversion to the test substance. The accuracy of determining the conversion factor significantly affects the achievement of a technical result. The experimental studies conducted by the authors proved that the value of the conversion factor of 0.434 leads to reproducible and accurate results, which leads to a determination error of 0.28%. The value of the conversion factor must be indicated in the calculation formula.

The conversion factor is found from the expression

$$K_{PeR}=\frac{E_{\mathrm{at}\mathrm{about}\mathrm{from}}}{E{}_{\mathrm{about}\mathrm{from}}}$$

wherein E _Sun - specific absorption coefficient of the sample when comparing potassium dichromate analytical wavelength;

E _OS - the specific absorption rate of the working sample comparing the determined (investigated) substance at the analytical wavelength (determined during the development of the methodology).

The method proposed by the authors allows the analysis both in tablets and in substance, i.e. is unified.

The technical result of the proposed method is to increase the reproducibility of the determination results, reducing the analysis error, unifying the analysis methodology, reducing the cost of analysis.

The technical result is achieved by preparing a solution of the analyte and a standard reference sample, followed by spectrophotometry and calculation of the results.

New in achieving the technical result is that a 0.1 M hydrochloric acid solution is used as a solvent for the preparation of the test solution, the concentration of the test solution is 0.000017 g / ml, potassium dichromate is used as a standard reference sample, and the optical density of the solutions is measured at a wavelength of 353 nm, a conversion factor of 0.434 is entered into the formula for calculating the results.

The studied substance changes the absorption spectrum depending on the pH of the medium. Based on the experimental data and the properties of drotaverine hydrochloride, the authors proved that the 0.1 M solution of hydrochloric acid is the optimal solvent for their spectrophotometric determination. The optimal solvent provides stabilization of the test solution, which increases the reproducibility of the determination results and reduces the error of analysis.

The absorption spectrum of drotaverine hydrochloride in a 0.1 M solution of hydrochloric acid is characterized by one absorption band with absorption maxima at wavelengths of 241 ± 2 nm, 302 ± 2 nm and 353 ± 2 nm and three minima at 223 ± 2 nm, 262 ± 2 and 322 ± 2 nm. A study of the stability of solutions during the day showed that at all pH values, the optical properties of drotaverine do not change. We chose a 0.1 M solution of hydrochloric acid as the optimal solvent, since the acid properties of the drug substance are suppressed in this solvent, and it is in the form of a salt constructed by the type of ammonium.

Based on the dependence established by the authors, according to which, substances for which the interval between the analytical wavelength and the maximum (or minimum absorption) of this comparison sample does not exceed half the half-width of its absorption band can be used as a standard comparison sample in the proposed method, the authors use potassium dichromate. The optimal absorption region of potassium dichromate in a 0.1 M solution of hydrochloric acid, in which it can be used as a reference sample, is 340.5-359.5 nm. Potassium dichromate is produced commercially by the xc category industry, it has GOST 4220-75 regulating its quality.

A solution of potassium dichromate in a 0.1 M solution of hydrochloric acid is stable during storage for a long time. The use of potassium dichromate, which is a less expensive reference sample (10 times less cost) compared to the working standard sample of drotaverine, reduces the cost of analysis. The use of potassium dichromate in the proposed method leads to a decrease in the analysis error.

Comparative analysis with the prototype shows that the claimed technical solution is characterized in that a 0.1 M solution of hydrochloric acid is used as a solvent for the preparation of the test solution, the concentration of the test solution is 0.000017 g / ml, potassium dichromate is used as a standard reference sample, the optical density of the solutions is measured at a wavelength of 353 nm, a conversion factor of 0.434 is entered into the formula for calculating the results, which corresponds to the “novelty” criterion of the invention.

A new set of features provides an increase in the reproducibility of the determination results, a decrease in the analysis error, allows to reduce the cost of analysis, to unify the analysis methods, which meets the criterion of "industrial applicability".

In the analysis of known solutions, it was revealed that they lack information on the influence of distinguishing features on the achievement of the technical solution, therefore, the invention meets the criterion of "inventive step".

The method is as follows. Prepare a solution of a comparison sample of potassium dichromate for the analysis of drotaverine. For this, the exact mass of potassium dichromate (0.1 g) is placed in a 50 ml volumetric flask, dissolved in 20 ml of water, the solution volume is adjusted to the mark with the same solvent and stirred. 1 ml of the resulting solution is placed in a 50 ml volumetric flask, adjusted the volume of the solution with a 0.1 M hydrochloric acid solution to the mark and mix.

Then, drotaverine hydrochloride in a substance is quantified. For this, the exact mass of the drug (0.17 g) is placed in a 100 ml volumetric flask, dissolved in 20 ml of water, the solution volume is adjusted to the mark with the same solvent and stirred. 1 ml of the resulting solution is placed in a 100 ml volumetric flask, the volume is adjusted solution to the mark with a 0.1 M hydrochloric acid solution and mix. The optical density of the test solution is measured on a spectrophotometer at a wavelength of 353 nm in a cuvette with a working layer length of 10 mm. As a comparison solution, a 0.1 M solution of hydrochloric acid is used. In parallel, the optical density of a solution of a comparison sample of potassium dichromate is measured on a spectrophotometer at a wavelength of 353 nm in a cuvette with a working layer length of 10 mm relative to a 0.1 M solution of hydrochloric acid.

The calculation of the results of the quantitative determination of drotaverine is carried out according to the formula

, $$X\%=\frac{D_x\cdot a_{\mathrm{at}\mathrm{about}\mathrm{from}}\cdot V_{\mathrm{one}}\cdot V_2\cdot V_3^{/}\cdot 0.434\cdot \mathrm{one\; hundred}\cdot \mathrm{one\; hundred}}{D_{\mathrm{at}\mathrm{about}\mathrm{from}}\cdot a_x\cdot V3\cdot V_{\mathrm{one}}^{/}\cdot V_2^{/}(\mathrm{one\; hundred}-W)}$$

,

where D _x and D _VOS are the optical densities of the analyte and the reference sample, respectively;

a _x and a _boc are the exact weights of the analyte and the reference sample, respectively;

V ₁ and V ₂ - the volumes of the prepared solution of the analyte;

V ₃ - the volume of an aliquot of the analyte;

и $$V_2^{/}$$

- объемы приготовленного раствора образца сравнения; $$V_{\mathrm{one}}^{/}$$

and $$V_2^{/}$$

- volumes of the prepared solution of the reference sample;

- объем аликвоты образца сравнения; $$V_3^{/}$$

- the volume of an aliquot of the reference sample;

100 - coefficient for conversion to percent;

W - humidity,%;

0.434 is the conversion factor for potassium dichromate in a 0.1 M solution of hydrochloric acid.

The content of drotaverine hydrochloride should be at least 98.0% and not more than 101% in terms of dry matter, according to the regulatory document.

The proposed method is illustrated by the following examples.

Example 1. Prepare solutions of the analyte and the reference sample as described above. Optical densities of the prepared solutions are measured on a spectrophotometer. Next, they calculate the results according to the formula using the conversion factor.

When determining drotaverine hydrochloride by potassium dichromate, the following results were obtained:

D _x = 0.4299; _Sun D = 0.4378; and _x = 0.1747; and _Boc = 0.1022; humidity = 0.05%; X = 99.77%. The results of the experiments are statistically processed:

; S²=0,1519; S=0,3898; $$S_{\overline{x}}=\mathrm{0,1233}$$

; ΔX=0,2786; E%=0,279; S_r=0,004.When n = 10; $$\overline{X}=99.97$$

; S ² = 0.1519; S = 0.3898; $$S_{\overline{x}}=\mathrm{0,1233}$$

; ΔX = 0.2786; E% = 0.279; S _r = 0.004.

These examples confirm that the content of drotaverine hydrochloride meets the requirements of the regulatory document.

The proposed method using a comparison sample of potassium dichromate is optimal for the quantitative determination of drotaverine hydrochloride in tablets.

The method for the quantitative determination of drotaverine hydrochloride in a dosage form differs from the method for the quantitative determination of drotaverine hydrochloride in a substance only by preparing the test solution.

Example 2. For the quantitative determination of drotaverine hydrochloride in tablets of 0.04 g, take the exact mass of powder of ground tablets (0.15 g), place in a volumetric flask with a capacity of 200 ml, dissolve in 20 ml of water, bring the solution volume to the mark with the same solvent and mix. The solution is filtered, the first 10-15 ml of the filtrate is discarded and 5 ml of the resulting solution is placed in a 50 ml volumetric flask, the solution volume is adjusted to the mark with a 0.1 M hydrochloric acid solution and stirred.

The content of drotaverine hydrochloride in tablets of 0.04 g should be 0.038-0.042 g, based on the average weight of one tablet.

When analyzing tablets of drotaverine hydrochloride at 0.04 g for potassium dichromate, the results are obtained

D _x = 0.5036; _Sun D = 0.3872; and _x = 0.1456; and _Boc = 0.0956; P _cf. = 0.1368; X = 0.0404 g.

Thus, the content of drotaverine in tablets meets the requirements of the regulatory document.

Example 3. To determine the uniformity of the dosage of drotaverine tablets in 0.04 g tablets, one tablet is placed in a 200 ml volumetric flask and dissolved in a 0.1 M hydrochloric acid solution, adjusted to the mark with this acid, stirred and filtered. 5 ml of the filtrate is placed in a volumetric flask with a capacity of 50 ml and the solution volume is adjusted with a 0.1 M hydrochloric acid solution to the mark. The optical density of the resulting solution is measured on a spectrophotometer at a wavelength of 353 nm in a cuvette with a working layer length of 10 mm. As a comparison solution, a 0.1 M hydrochloric acid solution is used. In parallel, the optical density of the solution of an external comparison sample of potassium dichromate is measured.

The permissible deviation from the nominal value is not more than 15% for ten analyzed tablets.

When analyzing ten tablets of drotaverine, 0.04 g each received a maximum deviation from the nominal content of + 6.35 and -8.49%.

Example 4. To control the test of "dissolution" of drotaverin tablets, a unified methodology was taken as the basis (GFH ed., P.159-160). A 0.1 M hydrochloric acid solution was used as the dissolution medium, the dissolution time was 30 minutes, the volume of the dissolution medium was 1000 ml, the rotation speed was 100 rpm, and the temperature was (37 ± 1) ° С.

When analyzing drotaverine tablets of 0.04 g, one tablet is placed in a basket, after 30 minutes of rotation a sample is taken. The solution is filtered, 20 ml of the filtrate is placed in a 50 ml volumetric flask, the solution volume is adjusted to the mark with a 0.1 M hydrochloric acid solution and stirred. The optical density of the test solution is measured on a spectrophotometer at a wavelength of 353 nm in cuvettes with a working layer length of 10 mm. As a comparison solution, a 0.1 M solution of hydrochloric acid is used. In parallel, the optical density of the solution of the comparison sample of potassium dichromate is measured.

According to (GFH1 ed, p.159-160), at least 75% of the active substance from the content in the dosage form should go into the dissolution medium.

When analyzing drotaverine tablets of 0.04 g each, the release of the substance was: 91.17%, 93.14%, 92.11%, 93.09%, 93.16%, 91.35%, 91.18%, 91, 73%, 92.25%, 92.23% for ten tablets, respectively.

The proposed method for determining drotaverine hydrochloride using a comparison sample of potassium dichromate can increase the reproducibility of the analysis, reduce the error of the analysis, reduce its cost, unify the analysis methods.

Claims (1)

A method for determining drotaverine hydrochloride by spectrophotometry of an analyte and a standard reference sample, characterized in that a 0.1 M hydrochloric acid solution is used as a solvent for the preparation of a determined solution, the concentration of the test solution is 0.000017 g / ml, and potassium is used as a comparison sample dichromate, a conversion factor of 0.434 is entered into the formula for calculating the results and the calculation is carried out according to the following formula:

,
where D _x and D _VOS are the optical densities of the analyte and the reference sample, respectively;
a _x and a are the _eastern weights of the analyte and the reference sample, respectively;
V ₁ and V _{2 are the} volumes of the prepared solution of the analyte;
V ₃ - the volume of an aliquot of the analyte;
$$V_{\mathrm{one}}^{\text{'}\text{'}}$$

and $$V_2^{\text{'}\text{'}}$$

- volumes of the prepared solution of the reference sample;
$$V_3^{\text{'}\text{'}}$$

- the volume of an aliquot of the reference sample;
100 - coefficient for conversion to percent;
W - humidity,%;
0.434 is the conversion factor for potassium dichromate in a 0.1 M solution of hydrochloric acid.