Preparation method of rocuronium bromide

Abstract

The invention provides a rocuronium bromide preparation method, which comprises: dissolving a rocuronium bromide crude product in an acetic acid aqueous solution to obtain a crude product solution, drying the crude product solution through a spray dryer, and collecting through a cyclone separator to obtain rocuronium bromide. The method provided by the invention is simple and convenient in operation procedure, the problem that the residual solvent in the prior art exceeds the standard is solved, the impurity content does not exceed the standard, meanwhile, the generation of residue on ignition is avoided without using sodium acetate, and the prepared rocuronium bromide is high in purity and good in stability.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and specifically relates to a preparation method of rocuronium bromide. Background Art

[0002] Rocuronium Bromide is a steroidal non-depolarizing muscle relaxant developed by the Dutch company Organon. It has a rapid onset of action and is a promising muscle relaxant. Its structural formula is as follows:

[0003]

[0004] Rocuronium bromide is a quaternary ammonium salt, which is easy to absorb moisture. At the same time, its molecular structure contains an ester group. Therefore, if the moisture content in rocuronium bromide is too high, or the air humidity is too large, the ester group at the 17th position in its molecular structure will hydrolyze to produce impurity C.

[0005] In addition, rocuronium bromide is sensitive to heat and oxygen, and is prone to produce impurity A during post-treatment and storage under heating or light conditions. At the same time, during the conventional drying process of the material, the content of impurity A also shows a significant upward trend.

[0006] At the same time, during the preparation of rocuronium bromide, it is also easy to bond with the solvent to form a solvate, resulting in an excessive residual solvent.

[0007]

[0008] Due to the above reasons, when using the conventional drying method, it is difficult to ensure the purity and stability of rocuronium bromide while removing the residual solvent.

[0009] In patent US20060058275A1, the freeze-drying method or spray-drying method is used, and the hydrolysis of rocuronium bromide is inhibited by adding acetic acid and sodium acetate buffer salt solution.

[0010] In patent CN103435674A, the freeze-drying method is used, which can ensure the purity and stability of rocuronium bromide while removing the residual solvent. Moreover, the rocuronium bromide obtained by the freeze-drying method is not prone to deliquescence and is easy to store. However, a large amount of 3-bromopropene cannot be completely removed during the freeze-drying process. Therefore, alumina must be added to adsorb 3-bromopropene before the drying process, and the procedure is complicated.

[0011] In summary, there is an urgent need to develop a preparation method of rocuronium bromide with a simple operation procedure, which can ensure the purity and stability of rocuronium bromide while removing the residual solvent, and does not cause the ignition residue to exceed the standard. Summary of the Invention

[0012] The present invention provides a method for preparing rocuronium bromide. In this method for preparing rocuronium bromide, an aqueous acetic acid solution is used as the solvent system and sodium acetate is not added, which can not only inhibit the hydrolysis of rocuronium bromide but also avoid the generation of ignited residues. At the same time, the present invention adopts the spray drying method, and by using a specific spray rate during the drying process, the residual solvent can be fully removed, and the purity and stability of rocuronium bromide can be ensured.

[0013] The present invention provides a method for preparing rocuronium bromide, and the preparation method includes: dissolving the crude rocuronium bromide in an aqueous acetic acid solution to obtain a crude product solution, and then drying the crude product solution through a spray dryer at a certain spray rate and collecting it with a cyclone separator to obtain rocuronium bromide;

[0014] wherein, the pH range of the aqueous acetic acid solution is 3.5 - 5.0, and the spray rate is 5 - 10 mL / min.

[0015] In some embodiments, the pH of the aqueous acetic acid solution is 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.0.

[0016] In some embodiments, the pH of the aqueous acetic acid solution is 3.5, 4.0, 4.5 or 5.0.

[0017] In some embodiments, the spraying rate is 5.0 ml / min, 5.1 ml / min, 5.2 ml / min, 5.3 ml / min, 5.4 ml / min, 5.5 ml / min, 5.6 ml / min, 5.7 ml / min, 5.8 ml / min, 5.9 ml / min, 6.0 ml / min, 6.1 ml / min, 6.2 ml / min, 6.3 ml / min, 6.4 ml / min, 6.5 ml / min, 6.6 ml / min, 6.7 ml / min, 6.8 ml / min, 6.9 ml / min, 7.0 ml / min, 7.1 ml / min, 7.2 ml / min, 7.3 ml / min, 7.4 ml / min, 7.5 ml / min, 7.6 ml / min, 7.7 ml / min, 7.8 ml / min, 7.9 ml / min, 8.0 ml / min, 8.1 ml / min, 8.2 ml / min, 8.3 ml / min, 8.4 ml / min, 8.5 ml / min, 8.6 ml / min, 8.7 ml / min, 8.8 ml / min, 8.9 ml / min, 9.0 ml / min, 9.1 ml / min, 9.2 ml / min, 9.3 ml / min, 9.4 ml / min, 9.5 ml / min, 9.6 ml / min, 9.7 ml / min, 9.8 ml / min, 9.9 ml / min or 10.0 ml / min.

[0018] In some embodiments, the spraying rate is 5.0 ml / min, 8.3 ml / min, 8.8 ml / min or 10.0 ml / min.

[0019] In some embodiments, the inlet air temperature of the spray dryer is 100°C to 160°C, and the outlet air temperature is 60°C to 100°C; in an exemplary embodiment, the inlet air temperature is 150°C and the outlet air temperature is 65°C.

[0020] In some embodiments, the pipeline pressure of the spray dryer is 1 KPa to 5 KPa; in an exemplary embodiment, the pipeline pressure of the spray dryer is 3 KPa.

[0021] In some embodiments, the fan power of the spray dryer is 10 Hz to 50 Hz; in an exemplary embodiment, the fan power of the spray dryer is 20 Hz.

[0022] In some embodiments, the weight ratio of the crude rocuronium bromide to the acetic acid aqueous solution is <1 / 5; in an exemplary embodiment, the weight ratio of the crude rocuronium bromide to the acetic acid aqueous solution is 1 / 6.

[0023] In some embodiments, the preparation method includes: dissolving crude rocuronium bromide in an aqueous acetic acid solution to obtain a crude solution, and then drying the crude solution in a spray dryer at a certain spray rate and collecting it through a cyclone separator to obtain rocuronium bromide;

[0024] Wherein, the pH of the aqueous acetic acid solution is 3.5 - 5.0, and the spray rate is 5 - 10 mL / min;

[0025] The inlet temperature of the spray dryer is 100°C - 160°C, and the outlet temperature is 60°C - 100°C;

[0026] The pipeline pressure of the spray dryer is 1 KPa - 5 KPa;

[0027] The fan power of the spray dryer is 10 Hz - 50 Hz; and

[0028] The weight ratio of the crude rocuronium bromide to the aqueous acetic acid solution is < 1 / 5.

[0029] In the embodiments of the present invention, for the rocuronium bromide obtained by the preparation method, wherein, impurity A ≤ 0.2%, impurity G ≤ 0.1%, impurity F ≤ 0.11%, impurity B ≤ 0.3%, impurity C ≤ 0.3%, other single impurities ≤ 0.2% and total impurities ≤ 1.5%.

[0030] In the embodiments of the present invention, for the rocuronium bromide obtained by the preparation method, wherein, impurity A ≤ 0.08%, impurity G ≤ 0.1%, impurity F ≤ 0.11%, impurity B ≤ 0.04%, impurity C ≤ 0.08%, other single impurities ≤ 0.07% and total impurities ≤ 0.45%.

[0031] In the embodiments of the present invention, for the rocuronium bromide obtained by the preparation method, wherein, the residual solvent is ≤ 0.5%.

[0032] In the embodiments of the present invention, for the rocuronium bromide obtained by the preparation method, wherein, the residual solvent is methyl tert-butyl ether, and the residual amount of methyl tert-butyl ether is ≤ 0.05%.

[0033] In the embodiments of the present invention, for the rocuronium bromide obtained by the preparation method, wherein, the residual solvent is dichloromethane, and the residual amount of dichloromethane is ≤ 0.06%.

[0034] In the embodiments of the present invention, for the rocuronium bromide obtained by the preparation method, wherein, it does not contain incineration residue.

[0035] In the embodiments of the present invention, the detection method for the residual solvent is the corresponding method of Method 2 in General Chapter 0861, Volume IV of the Chinese Pharmacopoeia 2020 Edition.

[0036] In an embodiment of the present invention, impurity A is 3α,17β-(dihydroxy)-2β-(morpholin-1-yl)-16-(pyrrolidin-1-yl)-5α-androstane-17-acetate;

[0037] Impurity G is 3α,17β-(dihydroxy)-2β-(morpholin-1-yl)-16-(pyrrolidin-1-yl)-5α-androstane;

[0038] Impurity F is 1-allyl-1-[3α,17β-(dihydroxy)-2β-(pyrrolidinyl)-5β-androst-16β-yl]pyrrolidinium-3,17-diacetate bromide;

[0039] Impurity B is 1-allyl-1-[3α,17β-(dihydroxy)-2β-(morpholin-1-yl)-5α-androst-16β-yl]pyrrolidinium-3,17-diacetate bromide;

[0040] Impurity C is 1-allyl-1-[3β,17β-(dihydroxy)-2β-(morpholin-1-yl)-5α-androst-16β-yl]pyrrolidinium bromide.

[0041] Compared with the prior art, the beneficial effects achieved by the present invention include: using an aqueous acetic acid solution as the solvent system, without adding sodium acetate to avoid the generation of incineration residues. At the same time, the spray drying method is adopted and a specific spray drying rate is used during the drying process, which can not only fully remove the residual solvent but also ensure the purity and stability of rocuronium bromide.

[0042] Other features and advantages of the present application will be described in the subsequent specification, and part of them will become obvious from the specification or be understood by implementing the present application. Other advantages of the present application can be achieved and obtained through the solutions described in the specification and the drawings. Description of the Drawings

[0043] The drawings are used to provide an understanding of the technical solutions of the present application, and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solutions of the present application and do not constitute a limitation to the technical solutions of the present application.

[0044] Figure 1 It is the HPLC chromatogram of the system suitability for the detection of related substances by high performance liquid chromatography in Example 1;

[0045] Figure 2 It is the HPLC chromatogram of the detection of related substances of I-2 by high performance liquid chromatography in Example 1;

[0046] Figure 3 It is the GC chromatogram of the detection of residual solvents of I-2 by gas chromatography in Example 1. Detailed Embodiments

[0047] The present invention will be further described in detail below in conjunction with embodiments, but it is not a limitation of the present invention. Any equivalent substitution in the technical field of the present invention made in accordance with the disclosed content of the present invention belongs to the protection scope of the present invention.

[0048] The detection of residual solvents in the present invention uses gas chromatography. The specific gas chromatography conditions are as follows:

[0049] Chromatographic column: A capillary column with 6% cyanopropylphenyl - 94% dimethylpolysiloxane as the stationary liquid;

[0050] Temperature programming: The initial temperature is 40°C, maintained for 10 minutes, heated at a rate of 4°C per minute to 100°C, and then heated at a rate of 25°C per minute to 220°C, maintained for 4 minutes;

[0051] Detector: FID detector;

[0052] Carrier gas: N2;

[0053] Injector temperature: 200°C;

[0054] Detector temperature: 250°C;

[0055] Headspace vial equilibration temperature: 90°C;

[0056] Quantitative loop temperature: 100°C;

[0057] Transfer line temperature: 110°C;

[0058] Equilibration time: 30 minutes;

[0059] Flow rate: 1.2 ml / min;

[0060] Split ratio: 10∶1.

[0061] Example 1 Screening test for the pH value range of acetic acid aqueous solution

[0062] Technical parameter settings of the spray dryer: The inlet temperature of the temperature control tank is 150°C, the outlet temperature is 65°C, the fan power is 20 Hz, and the pipeline nitrogen pressure is 3 KPa.

[0063] Preparation of acetic acid aqueous solution: Weigh 6 appropriate amounts of acetic acid and dissolve them in water respectively to prepare 6 acetic acid aqueous solutions with different pH values, which are successively: pH = 3.0, pH = 3.5, pH = 4.0, pH = 4.5, pH = 5.0, pH = 5.5.

[0064] Preparation of crude rocuronium bromide:

[0065] The preparation method of crude rocuronium bromide generally includes the following steps: Using rocuronium bromide ester (2β, 3α, 5α, 16β, 17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-3-hydroxy-17-acetoxy-5-androstan) and allyl bromide as raw materials, in the presence of an inorganic base, and using dichloromethane as the reaction solvent. After the reaction is complete, the reaction solution is subjected to ether pulping and solid precipitation, and then filtered to obtain a filter cake. The filter cake is dried in vacuo to obtain the product.

[0066] Add 24.4 kg of rocuronium bromide ester and 122.0 kg of dichloromethane to the reaction kettle. After purging with nitrogen and protecting with nitrogen, stir and cool down to 0 - 10 °C. Then add 21.2 kg of anhydrous sodium carbonate and 24.2 kg of 3-bromopropene in sequence, and keep the temperature at 0 - 10 °C for reaction. When the conversion rate ≥ 99.7%, the reaction ends. Centrifuge, and filter the filtrate through a titanium rod filter, then dropwise add it to a reaction kettle containing 366.0 kg of methyl tert-butyl ether at 0 - 10 °C with vigorous stirring (30 - 50 Hz). After dropping, control the temperature at 0 - 10 °C and stir for 30 min, then centrifuge. Wash the filter cake with 48.8 kg of methyl tert-butyl ether. The filter cake is dried in vacuo at -0.09 - -0.10 MPa and below 35 °C for more than 12 h to obtain crude rocuronium bromide, and the yield is 119.04%.

[0067] Preparation of crude rocuronium bromide solution: Weigh 6 equal amounts of crude rocuronium bromide, each with a mass of 5.00 g, and dissolve them in the above 6 acetic acid aqueous solutions with different pH values respectively to obtain 6 corresponding crude rocuronium bromide solutions (numbered I-1 - I-6 in sequence), where the mass of each acetic acid aqueous solution is 30 g.

[0068] Spray drying process: After the technical parameters of the spray dryer are stable, spray the above-prepared 6 crude rocuronium bromide solutions I-1 - I-6 through the spray dryer at a spray rate of 5 mL / min, and finally collect them through a cyclone separator to obtain rocuronium bromide.

[0069] Use high performance liquid chromatography to detect the related substances of the 6 rocuronium bromide samples obtained by the above preparation method respectively, and the detection results are shown in Table 1.

[0070] Use gas chromatography to detect the residual solvents of the 6 rocuronium bromide samples obtained by the above preparation method respectively, and the detection results are shown in Table 2.

[0071] Conclusion: Comprehensive analysis of the data of I-1 to I-6 in Table 1 and Table 2 shows that: under the pH range conditions of the aqueous acetic acid solution in Example 1, after the crude rocuronium bromide is spray-dried, the residual solvent results of the 6 samples of rocuronium bromide obtained all meet the relevant regulations under rocuronium bromide in Part II of the Chinese Pharmacopoeia 2020 Edition. However, under the condition of pH = 3.0 of the aqueous acetic acid solution, not only the contents of other single impurities and total impurities exceed the standards, but also the content of impurity F has a risk of exceeding the standard. Similarly, under the condition of pH = 5.5 of the aqueous acetic acid solution, the content of impurity F also has a risk of exceeding the standard. In view of this, the pH range of the aqueous acetic acid solution is finally determined to be pH = 3.5 - 5.0 in the present invention.

[0072] Table 1. Detection Results of Related Substances in the pH Screening Test of Aqueous Acetic Acid Solution

[0073]

[0074]

[0075] Table 2. Detection Results of Residual Solvents in the pH Screening Test of Aqueous Acetic Acid Solution

[0076]

[0077] Example 2 Spray Rate Screening Test

[0078] The spray-drying process and the technical parameter settings of the spray dryer are the same as those in Example 1.

[0079] Preparation of the crude rocuronium bromide solution: The preparation process is the same as that in Example 1. The pH of the aqueous acetic acid solution used is 4.0, and the 6 samples of the crude rocuronium bromide solution obtained are numbered II-1 to II-6 in sequence.

[0080] The spray rates of the crude rocuronium bromide solutions II-1 to II-6 through the spray dryer are 3.7 mL / min, 5 mL / min, 8.3 mL / min, 8.8 mL / min, 10 mL / min, and 15 mL / min respectively.

[0081] The related substances of the rocuronium bromide obtained by the above preparation method are detected by high performance liquid chromatography respectively, and the detection results are shown in Table 3.

[0082] The residual solvents of the rocuronium bromide obtained by the above preparation method are detected by gas chromatography respectively, and the detection results are shown in Table 4.

[0083] Conclusion: Comprehensive analysis of the data of II-1 to II-6 in Table 3 and Table 4 shows that when the spray rate is too low (<5 mL / min), the growth of impurity C is obvious, and there is also a risk of exceeding the total impurity content; when the spray rate is too high (>10 mL / min), the sample is blown and adsorbed on the tank wall and continuously heated, resulting in a significant increase in impurity C, exceeding the total impurity content, and a significant decrease in the yield. Finally, the spray rate during the spray drying process is determined to be 5-10 mL / min.

[0084] Table 3. Detection Results of Related Substances in Spray Rate Screening Test

[0085]

[0086]

[0087] Table 4. Detection Results of Residual Solvents in Spray Rate Screening Test

[0088]

[0089] Example 3. Inlet Air Temperature Screening Test of Spray Dryer

[0090] The spray drying process and other technical parameters are set the same as in Example 1, and the inlet air temperature of the temperature control tank is set to 95 °C.

[0091] The preparation process of rocuronium bromide crude product solution is the same as in Example 1.

[0092] The results show that for the atomized droplets formed after the rocuronium bromide crude product solution is atomized by the atomizer, when the inlet air temperature is lower than 100 °C, the water in the droplets cannot be removed by gasification. Therefore, it is finally determined that the inlet air temperature of the spray dryer should be set to >100 °C.

[0093] Example 4. Three-Batch Verification Test

[0094] Three-batch verification tests (LK220914, LK220915, LK220916) are carried out. Among them, the spray drying process and the technical parameters of the spray dryer are set with reference to Example 1; the preparation process of the rocuronium bromide crude product solution is set with reference to Example 1, in which the rocuronium bromide crude product is dissolved in acetic acid aqueous solution with pH = 4.0.

[0095] Take the rocuronium bromide of the three batches shown in the following table, and detect the related substances by high performance liquid chromatography, and the detection results are shown in Table 5. Detect the residual solvents by gas chromatography, and the detection results are shown in Table 6. Sodium acetate is not used during the preparation process, and the above three batches of rocuronium bromide do not contain incineration residues.

[0096] Table 5. Detection Results of Related Substances in Three-Batch Samples

[0097]

[0098] Table 6. Detection Results of Residual Solvents in Three Batches of Samples

[0099]

[0100] Conclusion: The data in Table 5 and Table 6 show that the impurity content and residual solvents of the three batches of rocuronium bromide do not exceed the standards and do not contain incineration residues, meeting the relevant regulations under rocuronium bromide in Part II of the Chinese Pharmacopoeia (2020 Edition).

[0101] Example 5 Stability Investigation Test

[0102] Rocuronium bromide with batch number LK220914 was stored at 2 - 8°C for 2 months. Samples at 0 month, 1 month, and 2 months were taken for testing. The content of related substances did not show significant changes. The stability test data are shown in Table 7:

[0103] Table 7. Results of Stability Investigation Test (2 - 8°C)

[0104]

[0105] In summary, the present invention adopts the spray drying method, uses an aqueous acetic acid solution with pH = 3.5 - 5.0 as the solvent system, and by controlling the spray drying rate at 5 - 10 mL / min, while removing the residual solvent, ensures the purity and stability of rocuronium bromide. At the same time, sodium acetate is not used to ensure that rocuronium bromide does not contain incineration residues.

[0106] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limitations to the present application. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present application.

Claims

1. A preparation method of rocuronium bromide, characterized in that, The preparation method includes: dissolving the crude rocuronium bromide in an acetic acid aqueous solution to obtain a crude product solution, and then drying the crude product solution through a spray dryer at a certain spraying rate and collecting it with a cyclone separator to obtain rocuronium bromide. Among them, the pH range of the acetic acid aqueous solution is 3.5 - 5.0, and the spraying rate is 5 - 10 mL / min.

2. The preparation method of rocuronium bromide according to claim 1, characterized in that, The inlet air temperature of the spray dryer is 100°C - 160°C, and the outlet air temperature is 60°C - 100°C.

3. The preparation method of rocuronium bromide according to claim 1 or 2, characterized in that, The pipeline pressure of the spray dryer is 1 KPa - 5 KPa.

4. The preparation method of rocuronium bromide according to claim 3, characterized in that, The fan power of the spray dryer is 10 Hz - 50 Hz.

5. The preparation method of rocuronium bromide according to any one of claims 1-4, characterized in that, The weight ratio of the crude rocuronium bromide to the acetic acid aqueous solution is <1 / 5.

6. The preparation method of rocuronium bromide according to any one of claims 1-5, characterized in that, The pH of the acetic acid aqueous solution is 3.5, 4.0, 4.5 or 5.0, and the spraying rate is 5.0 ml / min, 8.3 ml / min, 8.8 ml / min or 10.0 ml / min; and / or The inlet air temperature of the spray dryer is 150°C, and the outlet air temperature is 65°C; and / or The pipeline pressure of the spray dryer is 3 KPa; and / or The fan power of the spray dryer is 20 Hz; and / or The weight ratio of the crude rocuronium bromide and the acetic acid aqueous solution is 1 / 6.

7. The preparation method of rocuronium bromide according to any one of claims 1-6, characterized in that, For the rocuronium bromide obtained by the preparation method, among them, impurity A ≤ 0.2%, impurity G ≤ 0.1%, impurity F ≤ 0.11%, impurity B ≤ 0.3%, impurity C ≤ 0.3%, other single impurities ≤ 0.2% and total impurities ≤ 1.5%.

8. The preparation method of rocuronium bromide according to claim 7, characterized in that, For the rocuronium bromide obtained by the preparation method, among them, impurity A ≤ 0.08%, impurity G ≤ 0.1%, impurity F ≤ 0.11%, impurity B ≤ 0.04%, impurity C ≤ 0.08%, other single impurities ≤ 0.07% and total impurities ≤ 0.45%.

9. The preparation method of rocuronium bromide according to any one of claims 1-8, characterized in that, For the rocuronium bromide obtained by the preparation method, among them, the residual solvent is less than ≤ 0.5%; and / or It does not contain incineration residue.

Images