Validation of the Method of Standardization of Concomitant impurities in "Carbatryl" Tablets

Abstract

The discovery of recent decades has established that the majority of widespread human diseases that reduce life expectancy and reduce social activity, especially pathology of the cardiovascular system, respiratory tract, neurodegenerative diseases, and malignant neoplasms have a clearly expressed free-radical phase in their pathogenesis. It is important to create medicines based on fixed combinations containing compatible physico-chemical and pharmacological characteristics of an antioxidant and a drug of basic therapy, which determines their higher therapeutic efficiency and safety compared to the use of individual components of complex treatment. The most promising antioxidant component of fixed combinations is thiotriazoline. The creation of highly effective medicinal products based on fixed combinations with antioxidant, thiotriazoline allows not only to enhance the main properties of the basic component (nootropic, neuroprotective, anticonvulsant, anti-inflammatory, antiarrhythmic, antianginal, etc.), but also to significantly reduce the severity of their side effects2. Carbamazepine is currently the main drug in the treatment of focal epilepsies. However, the proven effectiveness of carbamazepine is only for large convulsive attacks, and the side effects that limit its use in the clinic are clearly evident. The solution to this problem is the creation of a new, more effective antiepileptic drug that exhibits pronounced antidepressant, nootropic, neuroprotective and antioxidant properties based on a fixed combination of carbamazepine and thiotriazoline, which will also significantly reduce the amount of side effects. All medicinal products must meet quality standards. And the developed analytical methods included in the regulatory documentation for a pharmaceutical substance or a finished dosage form must be validated3. The purpose of our work is to validate the methodology for quantitative determination of accompanying impurities in "Carbatryl" tablets. Materials and methods: The following analytical equipment was used during the validation study: Chromatograph: LC-20 Prominence Shimadzu models in the following configuration: two LC-20AD pumps, SIL-20A autosampler, SPD-20AV detector, CTO-20A thermostat, CBM-20 ALITE system controller. Column: polymer column (Peek), size 100mm x 4.6mm, "Chromolith Speed RODRP-18e" cat. No. 1.02129.0001 production of the firm "MerkKGaA", Germany; Analytical balance model AUW 220D, manufactured by Shimadzu, Germany, uncertainty of weighing results 0.033 mg. Samples for studying the characteristics of correctness, convergence (precision) and range of application were prepared similarly to comparison solution B, only 0.25ml, 0.50ml, 0.75ml, 1.00ml and 1.25ml of the original solution of 3-methyl-1,2,4-triazolyl-5-thione and impurity A of carbamazepine. These amounts correspond to impurity concentrations equal to 50%, 75%, 100%, 125% and 150% of the maximum permissible amount7-9. In this case, the number of model solutions was reduced to 5, due to the high cost of the standard sample of impurity A. Results and discussion: The method is characterized by sufficient convergence, since the found value of the relative confidence interval of the value ΔΖ for the impurities of thiotriazoline and carbamazepine does not exceed the critical value for the convergence of the results. The method is characterized by sufficient accuracy, since the criterion of insignificance of the systematic error of the method is fulfilled. The systematic error of the method meets the requirements of statistical (for the admixture of thiotriazoline) and practical (for the admixture of carbamazepine) insignificance: The high value of the correlation coefficient r = 0.99994 and 0.9998 satisfies the requirements of the acceptance criterion (r = 0.9998) and confirms the linear relationship between the taken and the amount of thiotriazoline and carbamazepine impurities found in the range from 50% to 150% relative to its nominal content in the preparation. Conclusions: the method of standardization of accompanying impurities in "Carbatryl" tablets was validated according to the following indicators: specificity, range of application, correctness and precision (convergence).