| Risedronate sodium is a drug currently being studied for listing in China, there is still work to be perfected in quality control. In this paper, an ion-pair RP-HPLC method was established for study on the related substances in risedronate sodium raw material. The content of the main related substance was about 0.14%both in risedronate sodium bulk material and chemical reference by checking and determination, which exceeded 0.1%of the risedronate sodium API. Therefore, the main related substance should be confirmed.Combined risedronate sodium API production process, its main related substance was analyzed and identified:(1) By optimization of preparation liquid chromatography, HPLC preparation method of the primar related substance was established. The preparation liquid was analyzed by LC-MS.(2) By ion-pair RP-HPLC, impurities (such as intermediates, etc.), which may be introduced in risedronate sodium API manufacturing process, were analyzed. The related substance in risedronate sodium API was confirmed as phosphoric acid or phosphorous acid, through retention time control and spiked control of different chromatographic behavior at different wavelengths.To simply and effectively control the quality of risedronate sodium in the specific production process, the sources of its main related substance was researched. By analysis,3-pyridine acetic acid hydrochloride, neither phosphoric acid or phosphorous acid, was confirmed as the related substance in risedronate acid. It showed that the related substance in risedronate sodium API may be introduced during the synthesis of risedronate sodium with risedronate acid and sodium hydroxide or crystallization.Risedronate sodium is often characterized by better water solubility and poor solubility in organic solvents. In order to study the dissolution characteristics of risedronate sodium and better control the formation of the related substance in the production process of risedronate sodium, research on solubility characteristics of risedronate sodium in various polar solvents was carried out, on the basis of study on the related substance. By dynamically calefactive method with laser monitoring, solubility data of risedronate sodium in water-ethanol solvent were measured. The experimental data were fitted by two-parameter and three-parameter equations.The risedronate sodium solubility increased with temperature increasing, and significantly decreased with the increase of ethanol content in the binary solvent. When the mole fraction of ethanol was greater than 0.1, the solubility of risedronate sodium was very low and had almost no change. The risedronate sodium solubility values calculated by fitting curve were in good agreement with experimental values. The measured risedronate sodium solubility data and correlation model can be used as basic data and model applied to risedronate sodium API crystallization process. |
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