RU2193191C2 - Method for detection of nicotinic acid and xanthinol nicotinate - Google Patents

Abstract

FIELD: medicine, control-analytical laboratory tests. SUBSTANCE: method could be applied in control-analytical laboratories for standardization and quality control of medicinal preparations. One should prepare a solution of standard sample of potassium dichromate properties to analyze nicotinic acid and xanthinol nicotinate. Quantitative detection is conducted, optical density is spectrophotometrically measured. Results are calculated by the formula by introducing a scaling coefficient. The method provides higher sensitivity of the assay and reproducibility of results, lower toxicity, labor intensity and error of the assay suggested. EFFECT: higher efficiency of detection. 1 cl

Description

 The 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.

 Visible and UV spectrophotometry is one of the most widely used methods in drug analysis. The objects of this study are nicotinic acid and xanthinol nicotinate, used to treat cardiovascular diseases.

 Known methods for alkalimetric determination of nicotinic acid and acidimetric determination of xanthinol nicotinate, which consist of preparing an aqueous solution of nicotinic acid and a solution of xanthinol nicotinate in glacial acetic acid with the addition of acetic anhydride, respectively, followed by titration with a 0.1 M sodium hydroxide solution in the case of phenolphthalene analysis indicator in case of nicolphtalene and 0.1 M perchloric acid using a potentiometric method for determining the point of con and in the case of titration analysis xantinol nicotinate (FS 42-2357-94 "nicotinic acid" FS 42-2596-94 "xantinol nicotinate").

 There is also known a method for the cuprimetric determination of nicotinic acid tablets, which consists in preparing an aqueous solution of the analyte, followed by precipitation of copper nicotinate and titration of 0.1 N. sodium thiosulfate solution, released in an equivalent amount of iodine as a result of interaction with potassium iodide, using starch as an indicator (FS 42-2664-89 "0.05 g nicotinic acid tablets").

 The closest and accepted as a prototype is a method for determining xanthinol nicotinate tablets by preparing solutions of the test substance and a working standard sample (PCO) of xanthinol nicotinate using a 0.1 M hydrochloric acid solution followed by spectrophotometry at a wavelength of 263 nm and calculating the results by PCR xantinol nicotinate (FS 42-2697-95 "0.15 g xanthinol nicotinate tablets"). The titrimetric methods for the quantitative determination of nicotinic acid and xanthinol nicotinate recommended by normative and technical documentation are highly toxic, insensitive, time-consuming, ununified. Using the spectrophotometric method to analyze the substances of nicotinic acid and xanthinol nicotinate is difficult due to the lack of state standard samples for these drugs. 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 be inaccessible to many laboratories.

 The technical result of the proposed method is to increase the sensitivity of the analysis and reproducibility of the results of the determination, reducing toxicity, complexity and error analysis.

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

 New in achieving the technical result is that potassium dichromate is used as a standard sample by introducing a conversion factor in the formula for calculating the results.

 The studied substances change the absorption spectrum depending on the pH of the medium. Based on the values of the ionization constants and properties of the nicotinic acid and xanthinol nicotinate, the authors proved that both a 0.1 M solution of hydrochloric acid and a 0.1 M solution of sodium hydroxide are the optimal solvent for their spectrophotometric determination. Optimum solvents provide stabilization of the tested solutions, which increases the reproducibility of the determination results and reduces the analysis errors. In these solvents, the UV absorption spectrum of nicotinic acid is characterized by three absorption bands with absorption maxima at 260, 264 and 270 nm and a minimum absorption at 240 nm, and the UV absorption spectrum of xanthine nicotinate is characterized by one absorption band with a maximum absorption at 268 nm and a minimum absorption at 240 nm in a solution of 0.1 M sodium hydroxide and 246 nm in a solution of 0.1 M hydrochloric acid. In addition, the absorption bands of xanthinol nicotinate are characterized by the presence of shoulders: in a 0.1 M sodium hydroxide solution in the region from 263 to 267 nm, and in a 0.1 M solution of hydrochloric acid, from 261 to 264 nm. As the analytical wavelength, the authors chose a wavelength of 260 nm for nicotinic acid and 263 nm for nicotinate xantinol. At given wavelengths, a minimum error in the measurement of the optical density is observed.

 Based on the dependence established by the authors, according to which substances can be used as standard property samples for which the interval between the analytical wavelength and the maximum (or minimum absorption) of this standard sample does not exceed half the half width of its absorption band, as a standard property sample in the proposed method the authors use potassium dichromate, since the optimal absorption region in which it can be used as a standard sample of properties of 248.5-265.5 nm; 340-359 nm; 231-243 nm; 307-323 nm. Potassium dichromate is commercially available as a chemically pure substance, there is GOST (GOST 4220-75) that regulates its quality, and the potassium dichromate solution is stable in a 0.1 M hydrochloric acid solution for a long time. The use of potassium dichromate in the proposed method leads to a decrease in the analysis error.

 Comparative analysis shows that the claimed technical solution is characterized in that potassium dichromate is used as a standard sample by introducing a conversion factor in the formula for calculating the results, which meets the criteria of the invention of "novelty."

 A new set of features provides an increase in the sensitivity of the analysis and reproducibility of the determination results, a decrease in the analysis error, and also allows to reduce the cost of analysis and exclude the possibility of using toxic reagents, which meets the criterion of "industrial applicability".

 The method is as follows. A solution of a standard sample of potassium dichromate is prepared for analysis of nicotinic acid and xanthinol nicotinate. For this, the exact mass of potassium dichromate (0.1500 g) is placed in a volumetric flask with a capacity of 100 ml, dissolved in a 0.1 M solution of hydrochloric acid and the solution is adjusted to the mark with the same solvent, mixed. 1 ml of the prepared solution of potassium dichromate is placed in a volumetric flask with a capacity of 50 ml and adjusted with a 0.1 M solution of hydrochloric acid to the mark, stirred. Then a quantitative determination of nicotinic acid and xanthinol nicotinate in the substance is carried out. To do this, the exact mass of the drug (0.0500 g) is placed in a 100 ml volumetric flask, dissolved in hot water (in the case of analysis of nicotinic acid) and in water (in the case of analysis of xanthinol nicotinate), adjusted to the mark with this water, respectively, and mixed. The nicotinic acid solution is cooled. 1 ml of the prepared solution of nicotinic acid and 2 ml of the prepared solution of xanthinol nicotinate are transferred respectively to 50 ml volumetric flasks and adjusted to the mark with a 0.1 M solution of hydrochloric acid, stirred. The optical density of the test solution is measured at a wavelength of 260 nm (for nicotinic acid) and at 263 nm (for xanthinol nicotinate) with respect to a 0.1 M solution of hydrochloric acid on a spectrophotometer in cuvettes with a working layer length of 10 mm. In parallel, the optical density of a solution of a standard sample of potassium dichromate is measured at a wavelength of 260 nm (when analyzing nicotinic acid) and at a wavelength of 263 nm (when analyzing nicotinate xanthinol) relative to a 0.1 M hydrochloric acid solution on a spectrophotometer in a cell with a working layer 10 10 mm

где D_Х и D_ст - оптические плотности определяемого вещества и стандартного образца соответственно;
a_х и a_ст - точные навески определяемого вещества и стандартного образца соответственно;
V₁ и V₂ - объемы приготовленного раствора определяемого вещества;
V₃ - объем аликвоты определяемого вещества;
V'₁ и V'₂ - объемы приготовленного раствора стандартного образца;
V'₃ - объем аликвоты стандартного образца;
100 - коэффициент для пересчета в проценты;
К_пер - коэффициент пересчета, который рассчитывают следующим образом:

где Е^1% _1стс. с - удельный показатель поглощения стандартного образца дихромата калия при аналитической длине волны препарата;
Е^1% _1стс. в - удельный показатель поглощения стандартного образца лекарственного вещества при аналитической длине волны (определяется при разработке методики);
К_пер для кислоты никотиновой - 0,340;
К_пер для ксантинола никотината - 0,515.The calculation of the results of the quantitative determination is carried out according to the formula

where D _X and D _article - the optical density of the analyte and the standard sample, respectively;
a _x and a _st - exact weights of the analyte and the standard sample, respectively;
V ₁ and V ₂ - the volumes of the prepared solution of the analyte;
V ₃ is the aliquot volume of the analyte;
V ' ₁ and V' ₂ - volumes of the prepared solution of a standard sample;
V ' ₃ is the volume of an aliquot of the standard sample;
100 - coefficient for conversion to percent;
To _lane is the conversion factor, which is calculated as follows:

where E ^1% _1CT s. C is the specific absorption rate of the standard sample of potassium dichromate at the analytical wavelength of the drug;
E ^1% _1st s. c - specific absorption rate of a standard sample of a drug substance at an analytical wavelength (determined during the development of the methodology);
To _per for nicotinic acid - 0.340;
The _lane for xanthinol nicotinate is 0.515.

 The content of nicotinic acid should be at least 99.5% in terms of dry matter, xanthinol nicotinate in terms of dry matter should be at least 98.5%.

 The proposed method is illustrated by the following examples.

 Prepare solutions of the test sample and standard sample as described above. The optical densities of the prepared solutions are measured on a spectrophotometer. Next, the results are calculated according to the formula using the conversion factor.

When determining nicotinic acid, the following results were obtained:
D _X = 0.3809, D _article = 0.3872, a _x = 0.0503, a _article = 0.1501, humidity 0.39%, x = 100.2%.

=100,0%; S=0,64;

E_α=0,67 (Р=95%), А%=0,67.For n = 6,

= 100.0%; S = 0.64;

E _α = 0.67 (P = 95%), A% = 0.67.

When determining xanthinol nicotinate, the following results were obtained:
D _X = 0.541, D _article = 0.418, a _x = 0.0505, a _article = 0.1508, humidity 0.11%, x = 99.63%.

=99,72%; S=0,408;

E_α=0,378 (Р=95%), A%=0,38.For n = 7,

= 99.72%; S = 0.408;

E _α = 0.378 (P = 95%), A% = 0.38.

 These examples confirm that the content of nicotinic acid and xanthinol nicotinate meets the requirements of the regulatory document.

 The proposed method using a standard sample of potassium dichromate was also optimal for the quantitative determination of nicotinic acid and xanthinol nicotinate in tablets and solution for injection, and also made it possible to establish with sufficient accuracy the dosage uniformity of the nicotinic acid tablets and to control the dissolution test of the nicotinic acid and xanthinol tablets nicotinate.

 Methods for the quantitative determination of nicotinic acid and xanthinol nicotinate in dosage forms differ from the methods for the quantitative determination of nicotinic acid and xanthinol nicotinate in a substance only by preparation of the test solution.

 For the quantitative determination of nicotinic acid in tablets of 0.05 g and xanthinol of nicotinate in tablets of 0.15 g, take the exact mass of powder (0.2000 g) of crushed tablets of nicotinic acid or xanthinol nicotinate and quantitatively transfer with hot water into volumetric flasks with a capacity of 100 ml, respectively, is shaken for 15 minutes, cooled, the volume is adjusted to the mark with water, stirred and filtered through a paper filter, discarding the first 15-20 ml of the filtrate. 1 ml of the obtained filtrate is transferred into volumetric flasks with a capacity of 50 ml and 100 ml, respectively, and the solution volume is adjusted with a 0.1 M hydrochloric acid solution to the mark, mixed.

 The content of nicotinic acid in tablets of 0.05 g should be 0.045-0.055 g, xanthinol nicotinate in tablets of 0.15 g should be 0.142-0.158 g, based on the average weight of one tablet.

 The quantitative determination of nicotinic acid and xanthinol nicotinate in tablets is illustrated by the following examples.

When analyzing nicotinic acid tablets of 0.05 g each, the results were obtained: D _X = 0.3675, D _article = 0.4295, and _x = 0.2020, and _article = 0.1559, P _cf = 0.2022, x = 0.0454 g.

When analyzing xanthinol nicotinate tablets of 0.15 g, the results were obtained: D _X = 0.343, D _article = 0.410, a _article = 0.1499, a _x = 0.2000, P _cf = 0.2288, x = 0.1478 g .

 These examples confirm that the content of nicotinic acid and xanthinol nicotinate in tablets meets the requirements of the regulatory document.

 To quantify nicotinic acid in a 1% solution for injection and xanthinol nicotinate in a 15% solution for injection, the volume of the dosage form 1 ml and 2 ml, respectively, is placed in volumetric flasks with a capacity of 100 ml and 250 ml, respectively, and the volume is adjusted to the mark with water are mixed. 5 ml and 2 ml of the resulting solution are transferred into volumetric flasks with a capacity of 50 ml and 100 ml, respectively, and the volume of the solution is adjusted with a 0.1 M hydrochloric acid solution to the mark, mixed.

 The content of nicotinic acid in 1 ml of the drug in grams (χ) should be 0.0097-0.0103. Xanthinol nicotinate in 1 ml of the drug in grams (x) should be 0.142-0.158.

When analyzing nicotinic acid in a 1% solution for injection, the results were obtained: D _X = 0.3925, D _article = 0.4034, a _article = 0.1500, x = 0.0099 g.

When analyzing xanthinol nicotinate in a 15% solution for injection, the results were obtained: D _X = 0.650, D _article = 0.417, and _article = 0.1504, x = 0.1509 g.

 To determine the uniformity of dosage of 0.05 g nicotinic acid tablets, one tablet is placed in a 100 ml volumetric flask and dissolved in hot water, cooled, adjusted to the mark with water, mixed, filtered. The first 15-20 ml of the filtrate is discarded. 1 ml of the filtrate is placed in a volumetric flask with a capacity of 50 ml and the volume of the solution is adjusted with a 0.1 M hydrochloric acid solution to the mark.

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

 In the analysis of ten tablets of nicotinic acid 0.05 g each received a maximum deviation from the nominal content of +10.6 and -5.3%.

To control the test for dissolving nicotinic acid and xanthinol nicotinate tablets, a unified methodology was used as the basis (GF XI ed., Pp. 159-160). As a dissolution medium, a 0.1 M solution of hydrochloric acid was used, the dissolution time was 20 minutes, the volume of the medium was 1000 ml, the rotation speed was 100 rpm, the temperature was (37 ± 1) ^o С.

 When analyzing 0.05 g nicotinic acid tablets and 0.15 g xanthinol nicotinate tablets, one tablet is placed in the basket, after 20 minutes of rotation a sample is taken. The solution is filtered, 5 ml of the filtrate (in the analysis of nicotinic acid tablets) and 10 ml of the filtrate (in the analysis of xanthinol nicotinate tablets) are placed in a 25 ml and 100 ml volumetric flask, the solution volume is adjusted with a 0.1 M hydrochloric acid solution to the mark and mix.

 According to the Global Fund XI 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 nicotinic acid tablets of 0.05 g, the release of the active substance was: 81.8%; 81.1%; 83.2%; 86.4%; 84.2% for five tablets, respectively.

 When analyzing xanthinol nicotinate tablets of 0.15 g, the release of the active substance was: 97.3%; 94.7%; 92.3%; 95.8%; 96.2% for five tablets, respectively.

 Thus, the proposed method for determining nicotinic acid and xanthinol nicotinate using a standard sample of the properties of potassium dichromate can increase the sensitivity of the analysis, reduce the error of analysis, reduce its cost, eliminate the use of toxic reagents and unify analysis methods.

Claims (1)

 A method for determining nicotinic acid and xanthinol nicotinate by preparing a solution of the analyte and a standard sample of properties, followed by spectrophotometry and calculation of the results, characterized in that potassium dichromate is used as a standard sample by introducing a conversion factor in the calculation formula.