CN111302977B - Purification method of pharmaceutical grade guanidine hydrochloride - Google Patents

Abstract

The invention discloses a method for purifying pharmaceutical grade guanidine hydrochloride, which comprises the following steps: (a) adding crude guanidine hydrochloride into water for stirring and mixing, and then pumping it into a coarse filter to remove impurities to obtain an aqueous solution of crude guanidine hydrochloride; The mass ratio of the crude guanidine hydrochloride to the water is 1.5 to 3:1; (b) the crude guanidine hydrochloride aqueous solution is pumped into the ultrasonic crystallization system, and the guanidine hydrochloride clear liquid is obtained by continuous and cyclic processing, and is induced to precipitate Fine impurities; the control parameters of the ultrasonic crystallization system are: temperature 0 ℃ ~ 120 ℃, hydraulic retention time 0.5h ~ 2h and frequency of ultrasonic power source 10KHz ~ 20KHz; (c) the guanidine hydrochloride clear liquid is pumped into the filter Then, it is pumped into the decolorizer to remove the trace amount of cyanamide impurities dissolved in the guanidine hydrochloride clear liquid to obtain a refined guanidine hydrochloride solution; (d) the purified guanidine hydrochloride solution is pumped into the Crystallizer, crystallization and purification; separation of crystals, drying to obtain pharmaceutical grade guanidine hydrochloride. Greatly improve production efficiency and reduce production cycle.

Description

A kind of purification method of pharmaceutical grade guanidine hydrochloride

technical field

The invention belongs to the technical field of purification of organic matter, relates to a purification method of pharmaceutical grade guanidine hydrochloride, and in particular relates to a method for ultrasonically induced purification of pharmaceutical grade guanidine hydrochloride.

Background technique

Pharmaceutical grade guanidine hydrochloride has a wide range of applications mainly in the fields of protein and cell biology; due to the special requirements of its application field, the product has very high requirements for impurities, in addition to conventional technologies such as content, melting point, PH, insoluble matter, and moisture content In addition to the parameters, the most demanding technical indicators are also reflected in the UV absorbance: UV absorbance 260μm≤0.04, 280μm≤0.02.

At present, the purification of guanidine hydrochloride mainly adopts the process of dissolving solid guanidine hydrochloride crude guanidine hydrochloride into an aqueous solution, utilizing the solubility difference between impurities and products in the aqueous solution, crystallization and precipitation of solid impurities, and separating guanidine hydrochloride. Since there are many types of impurities in this process, there are mainly unreacted raw materials and cyanamide polymers generated by side reactions. The content of various impurities is different, and the solubility gap is large. In order to ensure the maximum amount of various impurities The possible removal of impurities with low concentration requires a long crystallization nucleation time, which leads to a long purification cycle of guanidine hydrochloride and a serious limitation of production capacity. Therefore, it is of great significance to develop a high-throughput impurity removal process for pharmaceutical grade guanidine hydrochloride.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a purification method of pharmaceutical grade guanidine hydrochloride in order to overcome the deficiencies of the prior art.

In order to achieve the above object, the technical scheme adopted in the present invention is: a purification method of pharmaceutical grade guanidine hydrochloride, which comprises the following steps:

(a) adding crude guanidine hydrochloride to water for stirring and mixing, then pumping into a coarse filter to remove impurities to obtain an aqueous solution of crude guanidine hydrochloride; the mass ratio of crude guanidine hydrochloride to the water is 1.5 to 3:1;

(b) pumping the crude guanidine hydrochloride aqueous solution into an ultrasonic crystallization system, performing continuous and cyclic processing to obtain clear guanidine hydrochloride liquid, and inducing the precipitation of fine impurities; the control parameters of the ultrasonic crystallization system are: temperature 0 ℃～120 ℃ , hydraulic retention time 0.5h ~ 2h and frequency of ultrasonic power source 10KHz ~ 20KHz;

(c) pumping the guanidine hydrochloride clear liquid into a filter to remove the fine impurity crystal grains; then pumping into a decolorizer to remove the trace cyanamide impurities dissolved in the guanidine hydrochloride clear liquid to obtain a refined guanidine hydrochloride solution ;

(d) pumping the purified guanidine hydrochloride solution into a crystallizer for crystallization and purification; separating crystals and drying to obtain pharmaceutical grade guanidine hydrochloride.

Preferably, in step (a), the crude guanidine hydrochloride and water are stirred and mixed at a temperature of 20°C to 120°C, and the stirring time is 0.5h to 1h.

Optimally, in step (b), the ultrasonic crystallization system has an internal circulation system for circulating the crude guanidine hydrochloride aqueous solution.

Optimally, in step (c), the filter is a precision filter.

Further, in step (c), the control parameters of the decolorizer are: temperature of 50°C to 90°C, normal pressure to 0.2MPa, and hydraulic residence time of 0.5h to 1h.

Due to the application of the above-mentioned technical solutions, the present invention has the following advantages compared with the prior art: the purification method of pharmaceutical grade guanidine hydrochloride of the present invention, by controlling the mixing ratio of crude guanidine hydrochloride and water, and accurately controlling the process parameters of the ultrasonic crystallization system, In this way, the production capacity of pharmaceutical grade guanidine hydrochloride can be increased by 7 to 10 times, and the production cycle can be reduced from 20 to 30 days to about 3 days, which greatly improves the production efficiency and reduces the production cycle.

Description of drawings

Fig. 1 is the process flow diagram of the purification method of pharmaceutical grade guanidine hydrochloride of the present invention;

Fig. 2 is the purification equipment diagram of pharmaceutical grade guanidine hydrochloride of the present invention.

Detailed ways

The purification method of pharmaceutical grade guanidine hydrochloride of the present invention, as shown in Figure 1, comprises the following steps: (a) adding crude guanidine hydrochloride into water for stirring and mixing, then pumping into a coarse filter to remove impurities to obtain an aqueous solution of crude guanidine hydrochloride The mass ratio of the crude guanidine hydrochloride to the water is 1.5 to 3:1; (b) the crude guanidine hydrochloride aqueous solution is pumped into the ultrasonic crystallization system, and continuous and cyclic processing are carried out to obtain the guanidine hydrochloride clear liquid, and Induce the precipitation of fine impurities; the control parameters of the ultrasonic crystallization system are: temperature 0 ℃ ~ 120 ℃, hydraulic retention time 0.5h ~ 2h and frequency of ultrasonic power source 10KHz ~ 20KHz; (c) the guanidine hydrochloride clear liquid pump into a filter to remove fine impurity crystal grains; then pump into a decolorizer to remove trace cyanamide impurities dissolved in the guanidine hydrochloride clear liquid to obtain a refined guanidine hydrochloride solution; (d) the refined guanidine hydrochloride solution Pump into a crystallizer for crystallization and purification; separate crystals and dry to obtain pharmaceutical grade guanidine hydrochloride. By controlling the mixing ratio of crude guanidine hydrochloride and water, and accurately controlling the process parameters of the ultrasonic crystallization system, the production capacity of pharmaceutical grade guanidine hydrochloride can be increased by 7 to 10 times, and the production cycle can be reduced from 20 to 30 days to about 3 days. Greatly improve production efficiency and reduce production cycle.

In step (a), the crude guanidine hydrochloride and water are preferably stirred and mixed at a temperature of 20°C to 120°C, and the stirring time is 0.5 h to 1 h. In step (b), the ultrasonic crystallization system has an internal circulation system for circulating the crude guanidine hydrochloride aqueous solution, which is beneficial to improve the precipitation effect of fine impurity crystal grains. In step (c), the filter is a precision filter, which improves the filtering effect of fine impurity grains. In step (c), the control parameters of the decolorizer are: temperature of 50°C to 90°C, normal pressure to 0.2MPa, and hydraulic residence time of 0.5h to 1h, so as to improve the decolorization effect.

The preferred embodiments of the present invention will be described in detail below.

Example 1

The present embodiment provides a purification method of pharmaceutical grade guanidine hydrochloride, which comprises the following steps:

(a) under normal pressure, add 500 g of water into the mixer, then add 1200 g of crude guanidine hydrochloride, stir at 60 ° C for 30 min, stir evenly and then pump into a coarse filter to remove mechanical impurities and incompletely dissolved solid particles to obtain Guanidine hydrochloride crude guanidine aqueous solution;

(b) The crude guanidine hydrochloride aqueous solution obtained by removing mechanical impurities and incompletely dissolved solid particle impurities through a coarse filter is pumped into an ultrasonic crystallization system for continuous and cyclic treatment to obtain guanidine hydrochloride clear liquid to induce the precipitation of fine impurities (the ultrasonic crystallization system adopts Continuous treatment type, which has an internal circulation system to recycle the crude guanidine hydrochloride aqueous solution) to obtain guanidine hydrochloride clear liquid; the operation control parameters of the ultrasonic crystallization system are: temperature 60 ° C, pressure and normal pressure, hydraulic residence time 60min and The frequency of the ultrasonic power source is 20KHz; the above-mentioned ultrasonic crystallization system adopts self-developed equipment, as shown in Figure 2, including a static component 1, an ultrasonic-induced crystallization component 2 and a filter press 3. The ultrasonic-induced crystallization assembly 2 includes a liquid inlet pipe 22 for feeding the crude guanidine hydrochloride aqueous solution, and a plurality of ultrasonic crystallizers 21 (three in this embodiment, three in this embodiment, one end of the liquid inlet pipe 22 and a plurality of ultrasonic crystallizers 21 connected in series through the pipes. The specific number can be selected according to actual needs) and a liquid outlet pipe 23 with one end connected to the ultrasonic crystallizer 21 (the most downstream one, which is defined according to the flow direction of the crude guanidine hydrochloride aqueous solution); the static component 1 includes a static tank 10. The clear liquid outlet pipe 11 whose one end communicates with the upper end of the stationary tank 10, and the impurity enrichment liquid outlet pipe 12 whose one end is communicated with the lower end of the stationary tank 10, is installed in the stationary tank 10 and has one end connected to the lower end of the stationary tank 10. The liquid conduit 13 connected to the other end of the liquid outlet pipe 23 and the conical separator assembly 14 installed in the static tank 10 and matched with the liquid conduit 13 (the conical separator assembly 14 is arranged in the liquid conduit). The bottom of the other end of the tube 13 communicates with it, including a central tube and a conical baffle installed on the side wall of the central tube and communicated with it. The effluent of the component is buffered and then introduced into the stationary tank 10, so that impurities can be gradually enriched to the bottom of the stationary tank 10; at this time, the level of the guanidine hydrochloride clear liquid in the stationary tank 10 rises and passes The liquid outlet pipe 11 overflows or discharges); the filter press 3 is respectively connected with the other end of the impurity-enriched liquid outlet pipe 12 and the middle of the liquid inlet pipe 22 through the pipeline, and is used to filter the impurity-enriched liquid after pressure filtration. The filtrate is re-introduced into the liquid inlet pipeline 22 for recycling, and the filter cake produced by the pressure filtration can be outsourced;

(c) Pump the guanidine hydrochloride clear liquid that has been induced to remove impurities by the ultrasonic crystallization system into the precision filter to remove the fine impurity grains not completely removed by the ultrasonic crystallization system; then pump the guanidine hydrochloride solution that has passed through the precision filter into the decolorizer , in order to remove the trace amount of cyanamide impurities dissolved in the solution to obtain a refined guanidine hydrochloride solution, the process conditions of the decolorizer are: temperature 60 ℃, pressure 0.15MPa (G) and hydraulic residence time 30min;

(d) pumping the purified guanidine hydrochloride solution into the finished product crystallizer for crystallization and purification; separating the crystals and drying to obtain pharmaceutical grade guanidine hydrochloride; the yield is 85% (calculated as crude guanidine) and the purity is 99.7%.

Example 2

The present embodiment provides a purification method of pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that: in step (a), 500 g of water is added to the mixer, and then 750 g of crude guanidine hydrochloride is added; The yield was 87% (based on crude guanidine), and the purity was 99.6%.

Example 3

The present embodiment provides a purification method for pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that: in step (a), 500 g of water is added to the mixer, and then 1500 g of crude guanidine hydrochloride is added; The yield was 83.5% (calculated as crude guanidine), and the purity was 99.8%.

Example 4

This example provides a purification method of pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that: in step (a), stirring is performed at 120° C. for 45 min; the yield is 86% (calculated as crude guanidine) , the purity is 99.6%.

Example 5

This example provides a purification method for pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that: in step (a), stirring is performed at 20° C. for 1 h; the yield is 84.5% (calculated as crude guanidine) , 99.8% purity.

Example 6

This embodiment provides a purification method of pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that in step (b), the temperature is 0°C, the pressure is normal pressure, the hydraulic residence time is 2h, and the ultrasonic power source is used. The frequency is 10KHz; the yield is 83.5% (calculated as crude guanidine), and the purity is 99.7%.

Example 7

This embodiment provides a purification method of pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that: in step (b), the temperature is 120° C., the pressure is normal pressure, the hydraulic residence time is 0.5h, and the ultrasonic wave is applied. The frequency of the power source is 15KHz; the yield is 84.0% (calculated as crude guanidine), and the purity is 99.5%.

Comparative Example 1

This example provides a purification method for pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that: in step (a), 500 g of water is added to the mixer, and 2000 g of crude guanidine hydrochloride is added; The yield was 74% (calculated as crude guanidine), and the purity was 99.7%.

Comparative Example 2

This example provides a purification method of pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that: in step (b), the frequency of the ultrasonic power source is 50KHz; the yield is 80% (calculated as crude guanidine), Purity 98.5%.

Comparative Example 3

This example provides a purification method of pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that: in step (b), the frequency of the ultrasonic power source is 5KHz; the yield is 75% (calculated as crude guanidine), Purity 98.7%.

Comparative Example 4

This example provides a purification method of pharmaceutical grade guanidine hydrochloride, which is basically the same as that in Example 1, except that: in step (b), the temperature in the ultrasonic crystallization system is controlled to be 130°C; guanidine), the purity is 98.5%.

Comparative Example 5

This example provides a kind of purification method of existing conventional pharmaceutical grade guanidine hydrochloride, and the concrete steps are:

(a) under normal pressure, add 500 g of water into the mixer, then add 1200 g of crude guanidine hydrochloride, stir at 60 ° C for 30 min, stir evenly and then pump into a coarse filter to remove mechanical impurities and incompletely dissolved solid particles to obtain Guanidine hydrochloride crude guanidine aqueous solution;

(b) the crude guanidine hydrochloride aqueous solution obtained by removing mechanical impurities and incompletely dissolving solid particle impurities through the coarse filter is pumped into the impurity-removing sedimentation tank, and left standstill for 20 days at ambient temperature;

(c) pump the supernatant of the impurity-removing sedimentation tank into the decolorizer to obtain a purified guanidine hydrochloride solution, and the process conditions of the decolorizer are: temperature 60° C., pressure 0.15MPa (G) and hydraulic residence time 30min;

(d) pumping the purified guanidine hydrochloride solution into the finished product crystallizer for crystallization and purification; separating the crystals and drying to obtain pharmaceutical grade guanidine hydrochloride.

The yield of the final pharmaceutical grade guanidine hydrochloride is 83% (calculated as crude guanidine), and the purity is 99.6% (the total processing time of the whole purification method is about 23 days).

The above-mentioned embodiments are only to illustrate the technical concept and characteristics of the present invention, and its purpose is to enable those who are familiar with the technology to understand the content of the present invention and implement accordingly, and cannot limit the scope of protection of the present invention with this. Equivalent changes or modifications made in the spirit of the invention shall all be included within the protection scope of the present invention.

Claims (5)

1. a purification method of pharmaceutical grade guanidine hydrochloride, is characterized in that, it comprises the following steps: (a) adding crude guanidine hydrochloride into water for stirring and mixing, and then pumping it into a coarse filter to remove impurities to obtain an aqueous solution of crude guanidine hydrochloride; the mass ratio of crude guanidine hydrochloride to the water is 1.5 to 3:1; (b) pumping the crude guanidine hydrochloride aqueous solution into an ultrasonic crystallization system, and performing continuous and cyclic processing to obtain guanidine hydrochloride clear liquid, and inducing the precipitation of fine impurities; the control parameters of the ultrasonic crystallization system are: temperature 0 ℃ ~ 120 ℃ , the hydraulic retention time is 0.5h~2h and the frequency of the ultrasonic power source is 10KHz~20KHz; the ultrasonic crystallization system includes a static component, an ultrasonic-induced crystallization component and a filter press, and the ultrasonic-induced crystallization component includes a crude guanidine hydrochloride for guanidine hydrochloride. The liquid inlet pipeline for the aqueous solution inlet, a plurality of ultrasonic crystallizers connected with one end of the liquid inlet pipeline and connected in series through the pipelines, and the liquid outlet pipeline connected with the ultrasonic crystallizer at one end; the static component comprises a static tank, One end of the clear liquid outlet pipe connected with the upper end of the static tank body, one end of the impurity enriched liquid outlet pipe connected with the lower end of the static tank body, installed in the static tank body and one end communicated with the other end of the liquid outlet pipe A catheter and a conical baffle assembly installed in the static tank and matched with the catheter; the conical baffle assembly is arranged below the other end of the catheter and communicated with it, including a central pipe and A conical baffle installed on the side wall of the central tube and communicated with it, the conical baffles are stacked in sequence from bottom to top and extend downward to buffer the effluent of the ultrasonic-induced crystallization assembly into the static tank; The filter press is connected with the other end of the impurity-enriched liquid outlet pipe and the middle of the liquid inlet pipe respectively through pipes; (c) Pump the guanidine hydrochloride clear liquid into a filter to remove fine impurity grains; then pump it into a decolorizer to remove trace cyanamide impurities dissolved in the guanidine hydrochloride clear liquid to obtain a refined guanidine hydrochloride solution ; (d) pumping the purified guanidine hydrochloride solution into a crystallizer for crystallization and purification; separating the crystals and drying to obtain pharmaceutical grade guanidine hydrochloride. 2. The method for purifying pharmaceutical grade guanidine hydrochloride according to claim 1, characterized in that: in step (a), the crude guanidine hydrochloride and water are stirred and mixed at a temperature of 20°C to 120°C, and the stirring time is 0.5 h~1h. 3 . The method for purifying pharmaceutical grade guanidine hydrochloride according to claim 1 , wherein in step (b), the ultrasonic crystallization system has an internal circulation system for circulating the crude guanidine hydrochloride aqueous solution. 4 . 4 . The method for purifying pharmaceutical grade guanidine hydrochloride according to claim 1 , wherein in step (c), the filter is a precision filter. 5 . 5. The purification method of pharmaceutical grade guanidine hydrochloride according to claim 1 or 4, characterized in that: in step (c), the control parameters of the decolorizer are: temperature 50 ℃ ~ 90 ℃, pressure and normal pressure ~ 0.2MPa and hydraulic retention time 0.5h~1h.

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