Study On Impurities And Stability In Preparation Of Tetracaine Hydrochloride

Tetracaine hydrochloride is a kind of long-acting local esters anesthetics with widely used. This thesis studied on the impurities of tetracaine hydrochloride series pharmaceutics:the determination methods of related substances in tetracaine hydrochloride for injection and tetracaine hydrochloride injection were established. A process to determine the related substances and preservative chlorhexidine acetate in tetracaine hydrochloride jelly was established. The structure of the unknown impurities with content greater than 0.1% in tetracaine hydrochloride jelly and injection were identified. The possible degradation pathways of the impurities were analyzed, and further optimize the related substances by increasing the control of the impurity, and provided a direction for drug production process improvement and quality control. Meanwhile the stability test of tetracaine hydrochloride jelly was discussed, so the holding conditions and validity of tetracaine hydrochloride jelly were formulated on these bases.The first part of this thesis:a determination method of related substances in tetracaine hydrochloride for injection and tetracaine hydrochloride injection was established and verified. The method was: chromatography was carried on a Kromasil C18 column (150 mm×4.6mm,5μm), the phosphate buffer (KH2PO4 1.36g and phosphate 0.5mL, add water to 1000mL)-acetonitrile were adopted as the mobile phase with gradient elution, the column temperature was 35℃, the flow rate was 1.0 mL·min-1, the detection wavelength was 300 nm. The method above was effective for determination of related substances in tetracaine hydrochloride for injection and tetracaine hydrochloride injection. On this basis, through adjust the conditions of gradient elution, High Performance Liquid Chromatography (HPLC) used to determine the contents of related substances and chlorhexidine acetate (the detection wavelength was 258 nm) in tetracaine hydrochloride jelly was established and verified.The second part of this thesis:the preparation and identification of the major unknown impurity and its source analysis were examined. The related substances of tetracaine hydrochloride jelly were analyzed by HPLC, and a impurity with greater content (we called it impurity A) was found. HPLC-QTOF-MS was adopted to study the mass spectroscopy (MS) fragmentation pathways of tetracaine hydrochloride and impurity A. Based on the testing results, the impurity A was inferred as 2-(Dimethylamino)ethyl -4-aminobenzoate. The degradation pathway of impurity A was explored. The impurity A was extracted from tetracaine hydrochloride acid degradation solution by Pre-HPLC and confirmed its structure by nuclear magnetic resonance (NMR) By control the impurity A, the determination methods of related substances was optimized. This research provided a technical support for drug production process improvement and product quality control.The third part of this thesis:the stability test of tetracaine hydrochloride jelly, which included influence factors test, accelerated test and long-term stability test, were discussed respectively. Finally, used appearance, related substances and their contents as control indexes. The results showed that tetracaine hydrochloride jelly was not stable in heat and light,provided theoretical basis for the holding conditions and validity of tetracaine hydrochloride jelly.