CN107011262B - A method of Sorafenib Tosylate polymorphic K particle is prepared based on supercritical anti-solvent technology - Google Patents

Abstract

The invention relates to a method for preparing sorafenib tosylate polymorph K microparticles based on supercritical antisolvent technology. The method includes preparing a mixed crystal solution of sorafenib toluenesulfonate: adding polymorphic form A and polymorphic form B of sorafenib toluenesulfonate to an organic solvent according to a certain mass ratio, and obtaining toluenesulfonic acid after ultrasonic treatment Sorafenib mixed crystal solution; preheating and exhausting: set the temperature of the crystallization device, preheat for 30-50 minutes and discharge the air in the crystallization device, and then increase the pressure to stabilize to 8-14MPa; mixing preparation: mix the mixed crystal solution and CO ₂ into the crystallization device, continue to feed CO ₂ at 6-8 L/min after the reaction, release the pressure after 0.5-1.5 h, and collect the sorafenib tosylate polymorphic K particles. The preparation method of the present invention has the advantages of simple operation, mild conditions, less solvent usage, crystal form transformation and product crystal form micronization, and the obtained crystal form K particles have a particle size of 1.325 μm, and the particle size distribution is narrow, which improves the crystal form K Preparation feasibility and drug performance.

Description

A kind of sorafenib tosylate polymorph K based on supercritical antisolvent technology particle method

technical field

The invention belongs to the field of medicine and supercritical technology, and in particular relates to a method for preparing sorafenib tosylate polymorph K microparticles based on supercritical antisolvent technology.

Background technique

Sorafenib is the first bisarylurea oral multikinase, multitarget inhibitor with the chemical name 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-acyl Urea]-phenoxy group}-pyridine-2-carboxylate methylamine, clinical use is sorafenib tosylate at present, jointly developed by German Bayer company and Onyx company, trade name is Nexavar (Nexavar) , was approved by the FDA for the treatment of advanced renal cell carcinoma (RCC) on December 20, 2015, and was also the first drug approved for the treatment of advanced RCC; subsequently, CFDA approved Sorafenib on September 12, 2006 Marketed in China; on November 16, 2007, FDA approved Sorafenib for unresectable liver cancer cells; in May 2008, CFDA approved it for the treatment of advanced hepatocellular carcinoma (HCC).

WO2006034797 disclosed for the first time sorafenib tosylate polymorph I, polymorph II, polymorph III, and sorafenib p-toluenesulfonate methanol solvate and ethanol solvate. CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. discloses a preparation method of polymorph K and its crystallization by adding an inert solvent after temperature-controlled dissolution in a polar solvent (CN105439947A). This method uses a large amount of solvent and crystallization The Form K yield was not ideal.

Compared with traditional granulation technology, supercritical anti-solvent crystallization technology (supercritical anti-solvent, SAS) has the advantages of small particle size, narrow particle size distribution, and low organic solvent residue in reducing particle size and improving drug bioavailability. As the most commonly used fluid, carbon dioxide has a critical temperature of 31.1°C and a critical pressure of 7.38MPa, and the conditions are relatively mild; it has the advantages of environmental protection, non-toxicity, low viscosity, good diffusivity, and strong solubility. Based on these properties, supercritical _CO2 antisolvent crystallization technology is widely used in the preparation of drug particles.

Contents of the invention

In view of the disadvantages of the above-mentioned existing Sorafenib tosylate polymorph K preparation method, the problem to be solved by the present invention is to provide a kind of utilization supercritical CO _The method for preparing Sorafenib tosylate polymorph K microparticles .

The technical scheme provided by the present invention includes adding polymorph A and polymorph B of sorafenib tosylate to an organic solvent in a certain mass ratio, and obtaining a mixed crystal form of sorafenib tosylate after ultrasonic treatment solution; preheat exhaust, set the temperature of the crystallization device, drain the air in the crystallization device after preheating for 30-50 minutes, and then increase the pressure to stabilize to 8-14MPa; mix the crystal form solution of sorafenib tosylate with CO ₂ Pass into the crystallization device, continue to pass in CO ₂ at 6-8L/min after the reaction, release the pressure after 0.5-1.5h, and collect the sorafenib tosylate polymorphic K particles.

In order to further realize the purpose of the present invention, preferably, the mass ratio of polymorphic form A and polymorphic form B of sorafenib tosylate is: 1:10-0.1.

Preferably, the concentration of the sorafenib tosylate mixed crystal solution is 4-12 mg/ml.

Preferably, the organic solvent is a mixture of dimethyl sulfoxide and ethanol, and the volume ratio of dimethyl sulfoxide and ethanol is 1:1-10.

Preferably, in the preheating exhaust gas, the set temperature of the crystallization device is 32-38°C.

Preferably, the preheated exhaust gas, wherein the ultrasonic treatment is ultrasonic treatment at 50-70 Hz for 15-20 minutes.

Preferably, in the mixed preparation, the CO ₂ is fed into the crystallization device at a flow rate of 3-5 L/min.

Sorafenib tosylate polymorph K of the present invention has X-ray powder diffraction (XPRD) spectrogram as shown in Figure 1.

Sorafenib tosylate polymorph K according to the present invention has a scanning electron microscope (SEM) figure as shown in accompanying drawing 2, and the result shows that crystal form K is flaky crystal.

Sorafenib tosylate polymorph K of the present invention has the particle size distribution as shown in accompanying drawing 3, and the result shows, compares with bulk drug polymorph A and polymorph B, the particle size of crystal form K The diameter is smaller and the particle size distribution is narrower.

The principle of the supercritical _CO2 anti-solvent technology adopted in the present invention is: the solution containing the raw material medicine is transported to the high-pressure reaction kettle by the liquid pump through the nozzle, and the solution quickly forms tiny liquid droplets or mist droplets in the kettle, and the solvent and the The mass transfer between supercritical CO ₂ is enhanced, and the solution is rapidly dissolved in CO ₂ , causing the solution to quickly reach a supersaturated state, and the solute nucleates and crystallizes. Due to the high-pressure state of the preparation process, supercritical CO ₂ anti-solvent technology is easier to operate than traditional methods, and it is easier to prepare new crystal forms of drugs, and the product particle size is greatly reduced, which is conducive to improving the preparation feasibility and drug performance of crystal form K.

Compared with the prior art, the present invention has the following advantages:

1. The technical scheme of the present invention prepares sorafenib tosylate polymorph K simply, easy to operate, does not need to add an inert solvent, uses less solvent, and is easy to industrialized production.

2. The polymorphic form K of sorafenib tosylate prepared by adopting the technical scheme of the present invention has high purity and a yield of not less than 90%.

3. The particle size of the crystal form K product obtained by adopting the technical solution of the present invention is significantly lower than that of the original crystal form A and crystal form B. The particle size of crystal form A is 86.254 μm, the particle size of crystal form B is 56.983 μm, and the particle size of crystal form K is It is 1.325 μm, which improves the preparation feasibility and drug performance of crystal form K.

Description of drawings

Fig. 1 is the XPRD diagram of sorafenib tosylate crystal form A, crystal form B and embodiment 1 crystal form K.

Fig. 2 is the SEM image of sorafenib tosylate crystal form A, crystal form B and Example 2 crystal form K.

Fig. 3 is a particle size distribution diagram of sorafenib tosylate crystal form A, crystal form B and Example 2 crystal form K.

Detailed ways

In order to make the above objects, features and advantages of the present invention more comprehensible, the specific implementation of the present invention will be described in detail below in conjunction with specific examples.

In the following description, a lot of specific details are set forth in order to fully understand the present invention, but the present invention can also be implemented in other ways different from those described here, and those skilled in the art can do it without departing from the meaning of the present invention. By analogy, the present invention is therefore not limited to the specific examples disclosed below.

The completion process of laboratory stage setting of the present invention is:

1. Prepare the mixed crystal form solution of sorafenib tosylate, weigh polymorphic form A and polymorphic form B of sorafenib tosylate according to a certain mass ratio, and dissolve them in the two polymorphic forms by ultrasonication at 50-70Hz for 5-10min at room temperature. in a mixed solvent.

2. Check the airtightness of the entire experimental system, open the low-temperature constant temperature tank, start the heating controller of the _CO2 storage tank and the crystallization kettle, and set the temperature for preheating.

3. After the preheating is completed, open the CO ₂ steel gas cylinder and the CO ₂ intake valve on the top of the crystallization tank. The CO ₂ is cooled by the low-temperature constant temperature tank, and at the same time compressed into the air storage tank by the air compressor pump, and the CO ₂ is in the air storage tank. After preheating, enter the crystallization kettle from the top of the kettle, open the _CO2 outlet valve at the same time, adjust the fine-tuning valve, and discharge the air in the kettle for 8-15 minutes at the bottle pressure.

4. Close the CO ₂ outlet valve, set the pressure in the CO ₂ storage tank and the crystallization tank, CO ₂ enters the crystallization tank through the nozzle, and the pressure in the tank continues to rise to the preset pressure.

5. After the pressure and temperature are stabilized, turn on the liquid pump, and transport the sorafenib tosylate mixed crystal solution prepared in 1 to the crystallization kettle through the nozzle at the set flow rate. After the solution injection is completed, stop the liquid pump, maintain the pressure in the kettle for 30-90 minutes, and further remove the residual organic solvent in the crystallization kettle. Close the CO2 inlet valve, reduce the pressure, and wait until the pressure drops to atmospheric pressure, take out the sample in the crystallization kettle for the next step of detection and clean the entire system.

Example 1

Accurately weigh 100 mg each of sorafenib tosylate crystal form A and crystal form B, and dissolve them completely in 20 mL of mixed solvent (dimethyl sulfoxide: ethanol volume = 1: 4 (V/V) under ultrasonication at 70 Hz for 15 min. ); check the airtightness of the supercritical crystallization device, open the low-temperature constant temperature tank, start the heating controller of the _CO2 storage tank and the crystallization kettle, set the crystallization temperature at 35°C for 40 minutes of preheating; after the preheating is completed, open the _CO2 steel cylinder And the _CO2 inlet valve on the top of the crystallization kettle, _CO2 enters the crystallization kettle from the top of the kettle, and simultaneously opens the _CO2 outlet valve, adjusts the fine-tuning valve, and removes the air in the kettle for 15 minutes at bottle pressure; closes the _CO2 outlet valve, and boosts the pressure to The set crystallization pressure is 12MPa; after the temperature and pressure are stabilized, CO ₂ is passed into the crystallization kettle at a rate of 3L/min, and the liquid pump sprays the prepared mixed crystal solution into the crystallization kettle through the nozzle at 0.6mL/min, and the CO ₂ is turned on to vent Valve and fine-tuning valve, maintain the pressure in the crystallization tank at 12MPa; stop the liquid pump after the solution is injected, maintain the CO ₂ flow rate at 5L/min, keep the pressure for 40min, and remove the residual solvent; close the CO ₂ inlet valve and start depressurization , when the pressure in the crystallization kettle drops to zero, open the crystallization kettle to collect samples.

Carry out X-ray powder diffraction (XPRD) detection to the sorafenib tosylate crystal that embodiment 1 obtains, radiation source is a copper target, and XPRD collection of illustrative plates is as shown in accompanying drawing 1, and the result shows that this microcrystal is crystal form K, There are characteristic diffraction peaks at 2θ angles of 4.34, 11.01, 13.13, 14.70, 16.59, 17.79, 19.33, 20.39, 20.75, 21.43, and 22.81.

Example 2

Accurately weigh 100 mg each of sorafenib tosylate crystal form A and crystal form B respectively, and dissolve them completely in 20 ml of mixed solvent (dimethyl sulfoxide: ethanol volume = 1: 9 (V/V) under ultrasonication at 70 Hz for 20 min. ); check the airtightness of the supercritical crystallization device, open the low-temperature constant temperature tank, start the heating controller of the _CO2 storage tank and the crystallization kettle, set the crystallization temperature at 37°C to preheat for 40 minutes; after the preheating is completed, open the _CO2 steel cylinder And the _CO2 inlet valve on the top of the crystallization kettle, _CO2 enters the crystallization kettle from the top of the kettle, and simultaneously opens the _CO2 outlet valve, adjusts the fine-tuning valve, and removes the air in the kettle for 15 minutes at bottle pressure; closes the _CO2 outlet valve, and boosts the pressure to The set crystallization pressure is 10MPa; after the temperature and pressure are stabilized, CO ₂ is passed into the crystallization kettle at a rate of 3L/min, and the liquid pump sprays the prepared mixed crystal solution into the crystallization kettle through the nozzle at 0.6mL/min, and the CO ₂ is turned on to vent Valve and fine-tuning valve, maintain the pressure in the crystallization tank at 10MPa; stop the liquid pump after the solution is injected, maintain the _CO2 flow rate at 5L/min, keep the pressure for 40min, and remove the residual solvent; close the _CO2 inlet valve and start to reduce the pressure , when the pressure in the crystallization kettle drops to zero, open the crystallization kettle to collect samples.

The sorafenib tosylate crystals obtained in Example 2 were characterized by scanning electron microscopy (SEM), and the results are shown in Figure 2. The results show that the crystal form K is in the form of flakes. The sorafenib tosylate crystal obtained in Example 2 is analyzed by a Malvern particle size analyzer, and the results are shown in accompanying drawing 3, the particle diameter D (50) is shown as 1.865 μm, and the particle diameter is larger than that of the original crystal form A and The crystal form B is significantly reduced, which is conducive to improving the preparation feasibility and drug performance of the crystal form K.

Example 3

Accurately weigh 140 mg of sorafenib tosylate crystal form A and 60 mg of crystal form B respectively, and dissolve them completely in 20 mL of mixed solvent (dimethyl sulfoxide: ethanol volume = 1:9 (V/V) under ultrasonication at 70 Hz for 20 min. ); check the airtightness of the supercritical crystallization device, open the low-temperature constant temperature tank, start the heating controller of the _CO2 storage tank and the crystallization kettle, set the crystallization temperature to 33°C and preheat for 40 minutes; after the preheating is completed, open the _CO2 steel cylinder And the _CO2 inlet valve on the top of the crystallization kettle, _CO2 enters the crystallization kettle from the top of the kettle, and simultaneously opens the _CO2 outlet valve, adjusts the fine-tuning valve, and removes the air in the kettle for 15 minutes at bottle pressure; closes the _CO2 outlet valve, and boosts the pressure to The set crystallization pressure is 10MPa; after the temperature and pressure are stabilized, CO ₂ is passed into the crystallization kettle at a rate of 3L/min, and the liquid pump sprays the prepared mixed crystal solution into the crystallization kettle through the nozzle at 0.8mL/min, and the CO ₂ is turned on to vent Valve and fine-tuning valve, maintain the pressure in the crystallization tank at 10MPa; stop the liquid pump after the solution is injected, maintain the _CO2 flow rate at 5L/min, keep the pressure for 40min, and remove the residual solvent; close the _CO2 inlet valve and start to reduce the pressure , when the pressure in the crystallization kettle drops to zero, open the crystallization kettle to collect samples.

Figure 2 and Figure 3 show that the particle size of sorafenib tosylate polymorph K particles prepared based on supercritical antisolvent technology is greatly reduced. Compared with the original polymorph K preparation method, the supercritical antisolvent technology of the present invention can further realize the process of crystal transformation and micronization, greatly simplify the production process, simple operation, mild conditions, and less solvent usage, especially The particle size of crystal form K is greatly reduced, which increases the feasibility of sorafenib tosylate crystal form K in the formulation, and reducing the particle size can improve the water solubility of the drug. It has a good application prospect in terms of diameter and so on.

Claims (5)

1. a kind of method for preparing Sorafenib Tosylate polymorphic K particle based on supercritical anti-solvent technology, the toluene X-ray powder diffraction (XPRD) map of sulfonic acid Sorafenib polymorphic K, which is shown, has following 2 θ value diffraction maximum: 4.34 °, 11.01 °, 13.13 °, 14.70 °, 16.59 °, 17.79 °, 19.33 °, 20.39 °, 20.75 °, 21.43 °, 22.81 °, feature It is, the preparation method includes the following steps:

Prepare Sorafenib Tosylate mixing crystal form solution: by Sorafenib Tosylate polymorphic A and polymorph b by certain Mass ratio is added in organic solvent, Sorafenib Tosylate mixing crystal form solution is obtained after ultrasonic treatment, described is organic Solvent is the mixture of dimethyl sulfoxide and ethyl alcohol, and the volume ratio of dimethyl sulfoxide and ethyl alcohol is 1: 1~10；

Pre- thermal exhaust: setting crystallization apparatus temperature empties air in crystallization apparatus after preheating 30~50min, and then boosting is stablized To 8~14MPa, described sets crystallization apparatus temperature as 32~38 DEG C；

It is mixed with: by Sorafenib Tosylate mixing crystal form solution and CO₂Be passed through crystallization apparatus, after reaction with 6~ 8L/min continues to be passed through CO₂, release after 0.5~1.5h collects Sorafenib Tosylate polymorphic K particle；

The XPRD figure of the Sorafenib Tosylate polymorphic A, polymorph b are substantially as shown in Fig. 1.

2. the side of Sorafenib Tosylate polymorphic K particle is prepared based on supercritical anti-solvent technology as described in claim 1 Method, it is characterised in that: the mass ratio of the Sorafenib Tosylate polymorphic A and polymorph b are as follows: 1: 10~0.1.

3. the side of Sorafenib Tosylate polymorphic K particle is prepared based on supercritical anti-solvent technology as described in claim 1 Method, it is characterised in that: the Sorafenib Tosylate mixed crystal solution concentration is 4~12mg/mL.

4. the side of Sorafenib Tosylate polymorphic K particle is prepared based on supercritical anti-solvent technology as described in claim 1 Method, it is characterised in that: the ultrasonic treatment is 15~20min of ultrasonic treatment at 50~70Hz.

5. the side of Sorafenib Tosylate polymorphic K particle is prepared based on supercritical anti-solvent technology as described in claim 1 Method, it is characterised in that: described to be mixed with, wherein the CO₂It is passed through crystallization apparatus, being passed through flow velocity is 3~5L/min.