CN111196835B

CN111196835B - Rocuronium bromide crystal form

Info

Publication number: CN111196835B
Application number: CN201911372921.XA
Authority: CN
Inventors: 匡建明; 王成刚; 刘力超; 高建; 李有章; 伍伟
Original assignee: Chengdu Sino Strong Pharmaceutical Co ltd
Current assignee: Chengdu Sino Strong Pharmaceutical Co ltd
Priority date: 2019-12-27
Filing date: 2019-12-27
Publication date: 2021-10-26
Anticipated expiration: 2039-12-27
Also published as: CN111196835A

Abstract

The invention discloses a rocuronium bromide crystal form A, which uses Cu-Kalpha radiation, and an X-ray powder diffraction pattern expressed by a 2 theta angle has characteristic diffraction peaks at the positions of 8.0 +/-0.2 degrees, 11.1 +/-0.2 degrees, 15.4 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.2 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.8 +/-0.2 degrees and 25.4 +/-0.2 degrees. The rocuronium bromide crystal form is simple in preparation method, good in stability and more beneficial to production, storage and transportation.

Description

Rocuronium bromide crystal form

Technical Field

The invention relates to the field of medicines, and particularly relates to a rocuronium bromide crystal form.

Background

Muscle relaxants are necessary anesthetic aids for surgical operations, are used in large amounts, and currently, rocuronium bromide, vecuronium bromide, succinylcholine, atracurium and the like are common. RocuroniumBromide (the name of Chinese: rocuronium bromide), chemically 1- [ (2 β,3 α,5 α,16 β,17 β) -17- (acetoxy) -3-hydroxy-2- (4-morpholinyl) androstan-16-yl ] -1- (2-propenyl) pyrrolidine bromide, is a steroid non-depolarizing muscle relaxant developed by Organon, the Netherlands. The rocuronium bromide has the fastest effect and no side effects of histamine release and the like, so the rocuronium bromide becomes the most promising medicine in the similar medicines. Since the development of the Ougan company in the Netherlands, more than forty countries and regions such as the Netherlands, Belgium, Germany, the United states, the United kingdom, Japan, hong Kong of China, etc., were sold in the market and were widely recognized and commented on, and 500 prescription drug sales were leading in the world in 1998. The structural formula is shown as formula I:

in the last step of rocuronium bromide synthesis, as reported in patents US2006/0058275, WO2007/03348 and the like, in general, an intermediate (2 β,3 α,5 α,16 β,17 β) -17-acetoxy-3-hydroxy-2- (4-morpholinyl) -16- (1-pyrrolidinyl) androstane, 3-bromopropene, a reaction solvent (such as dichloromethane, acetonitrile, acetone), a catalyst and the like are reacted, and then the reaction mixture is filtered, decompressed to remove the solvent, redissolved and mixed with an anti-solvent to precipitate rocuronium bromide, and a product is filtered out and dried. The organic solvent generally used herein includes ethyl acetate, ethyl formate, ethyl isobutyrate, ethyl isopropoxide, diethyl ether, isopropyl ether, t-butyl methyl ether, pentane, hexane, heptane, petroleum ether, or a mixed solvent thereof. The preparation of rocuronium bromide according to the above process has the following disadvantages:

1. the prepared rocuronium bromide is easy to form a solvate with a solvent. Because rocuronium bromide is poor in thermal stability, the residual solvent in the rocuronium bromide product can only meet the pharmacopeia standard through freeze-drying, spray-drying, long-time drying and other treatment modes in the prior art, and the complexity and the production cost of the rocuronium bromide production process are greatly increased.

2. Rocuronium bromide has hygroscopicity, and is easy to hydrolyze after moisture absorption to generate a compound shown as a formula II; meanwhile, rocuronium bromide is easy to degrade to generate a compound of a formula III under the condition of heating or illumination in the post-treatment and storage processes, and the compounds of the formula II and the formula III are shown as the following figures:

3. the produced rocuronium bromide has strong static property, is not beneficial to crushing, packaging and subpackaging, and is not beneficial to the production operation of raw material medicines and preparations.

Rocuronium bromide prepared by the technical scheme reported in the literature is amorphous and has poor stability, and the stability of rocuronium bromide is improved to a certain extent by generally freezing, sealing and shading below-20 ℃ for storage or introducing acetic acid in the refining process, but the problem is not fundamentally solved. The prior art scheme can greatly increase the storage and transportation cost.

Therefore, the development of a preparation method of rocuronium bromide with higher stability is of great significance.

Disclosure of Invention

Based on the above problems, on one hand, the invention provides a rocuronium bromide crystal form, wherein rocuronium bromide with the characteristics of the crystal form has significant advantages in stability, and solves the problems that rocuronium bromide is easy to degrade and difficult to store and transport, and the rocuronium bromide crystal form is defined as an A crystal form in the invention.

The technical scheme is as follows: an X-ray powder diffraction pattern of the rocuronium bromide crystal form, which is expressed by a 2 theta angle, has characteristic diffraction peaks at the positions of 8.0 +/-0.2 degrees, 11.1 +/-0.2 degrees, 15.4 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.2 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.8 +/-0.2 degrees and 25.4 +/-0.2 degrees.

Preferably, the infrared spectrum of the crystal form is near 3354 +/-5 cm^-1、2919±5cm^-1、2850 ±5cm^-1、1751±2cm^-1、1646±2cm^-1、1448±2cm^-1、1374±2cm^-1、1213±2cm^-1、 1122±2cm^-1Has obvious characteristic absorption peaks.

Preferably, the HPLC purity of the crystal form A is greater than or equal to 99.8%, and the single impurity content is less than 0.10%.

Preferably, the HPLC purity of the crystal form A is greater than or equal to 99.95 percent, and the monohetero is greater than or equal to 0.02 percent.

In one aspect, the invention also provides a method for preparing the rocuronium bromide crystal form.

The technical scheme is as follows: a process for preparing the above crystalline form of rocuronium bromide comprising the steps of:

adding rocuronium bromide into an organic solvent, and stirring to dissolve a solid;

crystallization and filtration;

drying to obtain rocuronium bromide crystal; .

The preparation method meets the GMP production requirements of factories, is suitable for industrial production, has simple process and low cost, and the prepared crystalline rocuronium bromide has better stability, can solve the risk of degradation under the heating condition, and can be applied to the storage and transportation of rocuronium bromide.

Preferably, the drying is air-blast drying or drying under reduced pressure.

Preferably, the organic solvent is organic solvent A or a mixture of organic solvent A and organic solvent B;

the organic solvent A is selected from one or more of methyl ketone, butanone, acetone, butanone and methyl isopropyl methyl ketone, and the organic solvent B is selected from one or more of methanol, ethanol, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, N-dimethylformamide and N, N-dimethylacetamide.

Preferably, the organic solvent A is selected from one or two of butanone and acetone, and the organic solvent B is selected from one or more of acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol, methyl tert-butyl ether and diethyl ether.

Preferably, the weight of the organic mixed solvent is 0.5-50 times of the weight of the rocuronium bromide.

Preferably, the weight of the organic mixed solvent is 2-10 times of that of rocuronium bromide.

The crystallization temperature needs to be lower, the lower the temperature is, the higher the yield is, so the crystallization temperature is-80-30 ℃, the convenience is brought to production amplification, and the crystallization temperature is-30-10 ℃.

The longer the crystallization time, the higher the yield, so the crystallization time is 3-100 hours, and for convenience of production amplification, the crystallization time is 10-72 hours.

Because rocuronium bromide is poor in thermal stability and poor in solubility at low temperature, the dissolving temperature of the rocuronium bromide is 0-80 ℃, and a good effect can be achieved when the dissolving temperature of the rocuronium bromide is 20-60 ℃.

In one aspect, the invention also provides a pharmaceutical composition.

The technical scheme is as follows: a pharmaceutical composition comprising the crystalline form of rocuronium bromide described above and any one or more pharmaceutically acceptable excipients.

In one aspect, the invention also provides a use of the pharmaceutical composition.

The technical scheme is as follows: the use of a pharmaceutical composition for the manufacture of a medicament for general anaesthesia, skeletal muscle relaxation and/or endotracheal intubation, said pharmaceutical composition being as defined above.

In one aspect, the invention also provides the use of a crystalline form of rocuronium bromide in the manufacture of a medicament for use in general anaesthesia, relaxing skeletal muscles and/or endotracheal intubation.

The technical scheme is as follows: use of a crystalline form of rocuronium bromide in the manufacture of a medicament for use in general anaesthesia, relaxing skeletal muscles and/or endotracheal intubation, said crystalline form of rocuronium bromide being as hereinbefore described.

The principle and the beneficial effects of the invention are as follows:

the crystal form is one of important physicochemical properties of a compound, and for a polymorphic medicine, due to different crystal structures, some physicochemical properties such as melting point, solubility, stability and the like may have larger difference. These properties may have a significant impact on the production, stability, solubility and bioavailability of the drug, which in turn affects the safety and efficacy of the drug.

The crystalline rocuronium bromide prepared by the invention has obvious advantages in stability, solves the degradation risk under the heated condition, and has no change of related substances through the investigation of the high-temperature 25 ℃ harsh condition (the EP standard is required to be stored below 15 ℃ below zero; the USP standard is required to be stored in a sealed container at the temperature of 20 ℃ below zero or below zero under the condition of no acetic acid) of influencing factors. The requirements of the variety on storage and transportation conditions are reduced, and the storage and transportation cost is greatly saved.

The rocuronium bromide is prepared by a recrystallization method, the production process and the operation are simple, the conventional solvent and production equipment are used, the energy consumption is saved, and the method is green and environment-friendly and has no safety risk.

The rocuronium bromide has the characteristic of low static electricity, is beneficial to the production operation of raw material medicines and preparations, can be used in the fields of medicine research, process research, preparation research and production and medicine registration declaration, and can be used for general anesthesia, skeletal muscle relaxation and endotracheal intubation medicines.

The preparation method of the invention meets the GMP production requirements of factories and is suitable for industrial production.

Drawings

FIG. 1 is an HPLC chromatogram of form A of formula I.

FIG. 2 is an infrared spectrum of form A of formula I;

FIG. 3 is a photograph of the crystallinity of form A of formula I as observed under a microscope;

FIG. 4 is an X-ray powder diffraction pattern of form A of formula I;

Detailed Description

The invention will be further explained with reference to the drawings.

The examples provided herein are merely to further illustrate the invention and should not be construed as limiting the invention in any way.

It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified, in the following.

The infrared spectrum detection of the invention uses the following instruments: nicloet380FT-LR

The test method comprises the following steps: about 1mg of sample is taken and placed in an agate mortar, about 200mg of dried potassium bromide powder is added as a dispersing agent, the mixture is fully and uniformly ground, the mixture is moved into a pressing die and pressurized to 0.8 x 106kPa for about 0.5-2 min, and a sample tablet is prepared. And (3) subtracting the background by using a blank sheet, and then placing the sample sheet into a sample frame for scanning to obtain the absorption spectrum of the sample.

The invention relates to an X-ray powder diffraction detection instrument, which comprises the following parts: DX-2700B X-ray powder diffractometer

The test method comprises the following steps: the sample is filled in the blind hole sample plate, and the sample is lightly pressed by a glass slide, so that the surface of the sample in the window hole is completely on the same plane with the surface of the sample plate. And inserting the prepared sample plate on a sample table of a diffractometer goniometer for scanning. A copper X-ray source of 40KV and 40mA is used, the scanning angle is 3-53 degrees (2 theta), and the scanning speed is 0.05 degrees/second.

Example 1: preparation of rocuronium bromide

500g of dichloromethane was added to a 1000ml flask, 100g of (2 β,3 α,5 α,16 β,17 β) -17-acetoxy-3-hydroxy-2- (4-morpholinyl) -16- (1-pyrrolidinyl) androstane was added, the mixture was stirred until the solid was completely dissolved, 100g of sodium carbonate and 100g of 3-bromopropylene were added, and the mixture was reacted at 20 to 30 ℃. And after the reaction is finished, filtering to remove inorganic salt, washing a filter cake by using dichloromethane, dripping the filtrate into 4000g of diethyl ether, stirring and dispersing, filtering, washing, and drying under reduced pressure at the temperature of 45-50 ℃ to obtain 119g of rocuronium bromide, wherein the yield is 95.2%, and the purity is 98.5%.

Example 2: preparation of rocuronium bromide crystal form A

Adding 10g of low-purity rocuronium bromide prepared in example 1 into 50g of acetone, 1g of methanol and 2.5g of diethyl ether, stirring at 20-30 ℃ to dissolve the solid, stirring at-20 to-15 ℃ to crystallize for 48 hours, filtering, and drying under reduced pressure at 10-20 ℃ to obtain 6.78g of high-purity rocuronium bromide, wherein the yield is 67.8%, the maximum single impurity is 0.015% and the total impurity is 0.040%.

The HPLC detection spectrum, the infrared spectrum, the crystallinity photograph and the X-ray powder diffraction pattern are shown in the following figures 1, 2, 3 and 4, respectively.

Example 3: preparation of rocuronium bromide crystal form A

Adding 15g of rocuronium bromide prepared by the method of example 1 into 70g of acetone, 3.2g of ethanol and 2.8g of diethyl ether, stirring at 20-30 ℃ to dissolve the solid, stirring at-25 to-20 ℃ to crystallize for 48 hours, filtering, and drying by air blowing at 10-20 ℃ to obtain 7.92g of rocuronium bromide crystal form A, wherein the yield is 52.8%, the maximum single impurity is 0.014%, and the total impurity is 0.038%.

Through detection, the HPLC spectrum is basically consistent with that of figure 1, the infrared spectrum is basically consistent with that of figure 2, and the X-ray powder diffraction pattern is basically consistent with that of figure 4.

Example 4: preparation of rocuronium bromide crystal form A

Adding 5g of rocuronium bromide prepared by the method of example 1 into 20g of acetone, 0.8g of methanol and 2.5g of methyl tert-butyl ether, stirring at 20-30 ℃ to dissolve the solid, stirring at-25 to-20 ℃ to crystallize for 48 hours, filtering, and drying at 10-20 ℃ under reduced pressure to obtain 3.12g of rocuronium bromide of crystal form A, wherein the yield is 62.4%, the maximum single impurity is 0.015% and the total impurity is 0.039%.

Example 5: preparation of rocuronium bromide

Adding 12g of rocuronium bromide prepared by the method of example 1 into 53g of acetone and 0.6g of methanol, stirring at 30-35 ℃ until the solid is completely dissolved, stirring at-25 to-20 ℃ for crystallization for 60 hours, filtering, and drying at 10-20 ℃ under reduced pressure to obtain 5.74g of rocuronium bromide crystal form A, wherein the yield is 47.8%, the maximum single impurity is 0.016%, and the total impurities are 0.016%.

Example 6 stability test

The crystal form A rocuronium bromide prepared in the example 2 is taken for influence factor test, the stability is inspected, and the purity is detected by an HPLC method. The test method comprises the following steps:

the measurement is carried out by high performance liquid chromatography (0512 in the four-department general regulation of the 2015 edition in China pharmacopoeia). Chromatography column using Amino-bonded silica gel as filler (e.g., SephaxHP-Amino, 4.6X 250mm,

) (ii) a Tetramethylammonium hydroxide solution (4.53g → 1000ml water, pH adjusted to 7.4 with phosphoric acid) -acetonitrile (10:90) as mobile phase; the flow rate was 2.0ml per minute; the detection wavelength is 210 nm; the column temperature was 25 ℃ and the amount of sample was 5. mu.l.

The method is a detection method approved by the drug evaluation center of the State food and drug administration.

After 30 days of investigation under the high temperature condition of the influencing factor test, the related substances and crystal forms of the influencing factor test are detected to be unchanged, the HPLC spectrum is basically consistent with the figure 1, the infrared spectrum is basically consistent with the figure 2, and the X-ray powder diffraction pattern is basically consistent with the figure 4. The stability data are as follows:

the data show that the quality level of the rocuronium bromide crystal form A prepared by the invention is far higher than the quality control requirements of pharmacopoeias of various countries, the rocuronium bromide crystal form A has good chemical stability, and related substances of the rocuronium bromide crystal form A are unchanged through the investigation of harsh conditions with influence factors of high temperature for 30 days, so that the quality level of the rocuronium bromide crystal form A in the long-term storage and transportation processes after production can be improved. Meanwhile, the storage and transportation are not required to be carried out under the harsh conditions specified in European and American pharmacopoeias, so that the storage and transportation cost can be greatly reduced.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A rocuronium bromide crystal form A, characterized in that: using Cu-Kα radiation, the X-ray powder diffraction pattern represented by 2θ angle is at 8.0±0.2°, 11.1±0.2°, 15.4±0.2°, 15.9 There are characteristic diffraction peaks at positions ±0.2°, 17.1±0.2°, 18.2±0.2°, 19.0±0.2°, 19.6±0.2°, 20.2±0.2°, 22.0±0.2°, 22.8±0.2°, and 25.4±0.2°.

2. rocuronium bromide crystal formation according to claim 1, is characterized in that: its infrared spectrum of described crystal formation is near 3354±5cm ^-1 , 2919±5cm ^-1 , 2850±5cm ^-1 , 1751±2cm ^-1 , 1646±2cm ^-1 , 1448±2cm ^-1 , 1374±2cm ^-1 , 1213±2cm ^-1 , 1122±2cm ^-1 have characteristic absorption peaks.

3. The crystal form of rocuronium bromide according to any one of claims 1 and 2, wherein the HPLC purity of the crystal form is greater than or equal to 99.8%, and the single impurity is less than 0.10%.

4. The crystal form of rocuronium bromide according to claim 3, characterized in that: the crystal form has a single impurity≤0.02%.

5. a method for preparing the arbitrary described rocuronium bromide crystal form of claim 1-4, the method comprises the following steps:

①Add rocuronium bromide to the organic solvent, stir to dissolve the solid;

②Crystallization and filtration;

③Dry the rocuronium bromide crystals; choose blast drying or vacuum drying;

Described organic solvent is the mixture of organic solvent A or organic solvent A and organic solvent B;

Described organic solvent A is selected from one or more in acetone, butanone, methyl isopropyl ketone,

The organic solvent B is selected from methanol, ethanol, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, ethyl acetate, isopropyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide one or more of;

The weight of the organic mixed solvent is 0.5 to 50 times the weight of rocuronium bromide; and/or the crystallization temperature is -80 to 30°C; and/or the crystallization time is 3 to 100 hours; and/or The dissolving temperature of the dissolving is 0-80°C.

6. preparation method according to claim 5 is characterized in that: described organic solvent A is selected from one or two in acetone, butanone, and described organic solvent B is selected from acetonitrile, tetrahydrofuran, methanol, ethanol, One or more of isopropanol, methyl tert-butyl ether, and diethyl ether.

7. The preparation method according to claim 6, wherein: the weight of the organic mixed solvent is 2 to 10 times the weight of rocuronium bromide; and/or the crystallization temperature is -30 to 10°C; and /or the crystallization time is 10-72 hours; and/or the dissolution temperature of the dissolution is 20-60°C.

8. A pharmaceutical composition, characterized in that: the pharmaceutical composition comprises the rocuronium bromide crystal form according to any one of claims 1-4 and any one or more pharmaceutically acceptable excipients.

9 . The application of a pharmaceutical composition in the preparation of medicines for general anesthesia, skeletal muscle relaxation and/or endotracheal intubation, wherein the pharmaceutical composition is the pharmaceutical composition of claim 8 .

10. The application of a rocuronium bromide crystal form in the preparation of medicine for general anesthesia, skeletal muscle relaxation and/or endotracheal intubation, is characterized in that: the rocuronium bromide crystal form is claim 1- 4 any of the rocuronium bromide crystal forms.