阅读说明：本技术 一种盐酸艾司洛尔的新晶型及制备方法 (Novel crystal form of esmolol hydrochloride and preparation method thereof ) 是由 姚红 罗瑾 吴晓峰 李珲 王佳 谭艳红 万兴隆 于 2020-07-22 设计创作，主要内容包括：本发明涉及盐酸艾司洛尔一种新晶型及其制备方法,其粉末X-射线衍射图谱在2θ＝5.787±0.2°、11.495±0.2°、12.903±0.2°、13.499±0.2°、15.219±0.2°、16.012±0.2°、17.219±0.2°、18.238±0.2°、18.924±0.2°、20.535±0.2°、22.159±0.2°、23.014±0.2°、23.745±0.2°、24.316±0.2°、26.311±0.2°、27.675±0.2°、28.887±0.2°、29.93±0.2°、30.973±0.2°处有特征峰。本发明所制备的盐酸艾司洛尔晶型性质稳定、溶解性好,适合药物开发,所用制备方法安全简便、可操作性强。(The invention relates to a novel esmolol hydrochloride crystal form and a preparation method thereof, wherein a powder X-ray diffraction pattern of the novel esmolol hydrochloride crystal form has characteristic peaks at 2 theta (5.787 +/-0.2 degrees), 11.495 +/-0.2 degrees, 12.903 +/-0.2 degrees, 13.499 +/-0.2 degrees, 15.219 +/-0.2 degrees, 16.012 +/-0.2 degrees, 17.219 +/-0.2 degrees, 18.238 +/-0.2 degrees, 18.924 +/-0.2 degrees, 20.535 +/-0.2 degrees, 22.159 +/-0.2 degrees, 23.014 +/-0.2 degrees, 23.745 +/-0.2 degrees, 24.316 +/-0.2 degrees, 26.311 +/-0.2 degrees, 27.675 +/-0.2 degrees, 28.887 +/-0.2 degrees, 29.93 +/-0.2 degrees and 30.973 +/-0.2 degrees. The esmolol hydrochloride crystal form prepared by the invention has stable property and good solubility, is suitable for drug development, and has safe, simple and convenient preparation method and strong operability.)

1. An esmolol hydrochloride crystal form A, which is characterized in that: the powder X-ray diffraction pattern has characteristic peaks at 2 theta of 5.787 +/-0.2 degrees, 11.495 +/-0.2 degrees, 12.903 +/-0.2 degrees, 13.499 +/-0.2 degrees, 15.219 +/-0.2 degrees, 16.012 +/-0.2 degrees, 17.219 +/-0.2 degrees, 18.238 +/-0.2 degrees, 18.924 +/-0.2 degrees, 20.535 +/-0.2 degrees, 22.159 +/-0.2 degrees, 23.014 +/-0.2 degrees, 23.745 +/-0.2 degrees, 24.316 +/-0.2 degrees, 26.311 +/-0.2 degrees, 27.675 +/-0.2 degrees, 28.887 +/-0.2 degrees, 29.931 +/-0.2 degrees and 30.973 +/-0.2 degrees.

2. A method of preparing esmolol hydrochloride form a according to claim 1 comprising the steps of:

(1) dissolving esmolol hydrochloride in a solvent A;

(2) adding the solvent B, and stirring for 1-2 hours at the temperature of 20 +/-5 ℃;

(3) cooling to 5 +/-5 ℃ and pulping for 3-4 hours;

(4) and filtering and separating, washing the solid with a solvent B, and drying in vacuum to obtain a product, namely the esmolol hydrochloride of the crystal form A.

3. The preparation method according to claim 2, wherein in the step (1), the solvent A is selected from one of methanol, ethanol and isopropanol; the dosage is 1 to 2 times of the mass of the esmolol hydrochloride.

4. The preparation method according to claim 2, wherein in the step (2), the solvent B is one selected from ethyl acetate and isopropyl acetate; the dosage is 4 to 8 times of the mass of the esmolol hydrochloride.

Technical Field

The invention relates to the technical field of medicines, in particular to a novel crystal form of esmolol hydrochloride and a preparation method thereof.

Background

Polymorphism refers to the phenomenon of solid states with different physicochemical properties formed by solid substances in two or more different spatial arrangements. In the field of pharmaceutical research, polymorphs include multicomponent crystalline forms such as organic solvates, hydrates, and the like. The polymorphism of the drug widely exists in the process of drug development and is an inherent characteristic of organic small molecular compounds. Polymorphism is not only controlled by the intrinsic factors such as the spatial structure and functional group properties of molecules, intramolecular and intermolecular interactions, but also influenced by factors such as drug synthesis process design, crystallization and purification conditions, choice of formulation excipients, formulation process routes and granulation methods, storage conditions, packaging materials, and the like. Different crystal forms have different colors, melting points, dissolution properties, chemical stability, reactivity, mechanical stability and the like, and the physical and chemical properties or the processability sometimes directly influence the safety and the effective performance of the medicine. Therefore, the research and control of the crystal form become important research content in the process of drug research and development.

The crystal form research comprises two stages of crystal form discovery and crystal form optimization, wherein in the crystal discovery stage, various crystallization means such as melting crystallization, solution volatilization, crystallization methods of rapid cooling and suspension methods are mainly adopted, and external factors influencing drug crystallization are changed by changing crystallization conditions, solvents, temperature, speed, suspension solvent ratio and the like. A high-throughput sample preparation platform is adopted, hundreds of crystallization tests are prepared at the same time, and a trace sample preparation technology and an analysis and test means are applied. Preparation and discovery of new crystalline forms. In the crystal form optimization stage, the process amplification and preparation conditions of the new crystal form are required to be searched, various solid characterization means such as X-ray diffraction, solid nuclear magnetic resonance, Raman spectroscopy, infrared spectroscopy and other means are adopted to characterize the crystal form, in addition, thermogravimetric analysis (TG), hygroscopicity analysis (DVS) and the like are adopted to study the physicochemical properties of the crystal form, and the hygroscopicity, chemical stability, physical state stability, processability and the like of different crystal forms are compared to study. Finally, the most preferable solid form is selected for development.

Esmolol Hydrochloride (CAS: 81161-17-3) is a beta-receptor blocker widely used for treating cardiovascular diseases clinically, and has quick response and definite curative effect. The chemical name is as follows: 4- [ 2-hydroxy-3- (isopropylamino) propoxy group]Phenylpropionic acid methyl ester hydrochloride with the molecular formula C₁₆H₂₆C_lNO₄Molecular weight 331.83. At present, only the injection preparation is used in China, the effective components of the injection can be unstable during high-temperature sterilization, so that the curative effect is reduced, and the injection preparation is inconvenient to transport and store.

Wanwena et al, ai Shi Ke Long synthetic research, used p-hydroxybenzaldehyde as the starting material, and finally recrystallized to obtain 5.5g of white crystal with yield of 78.2% and melting point of 83-85 ℃. However, this form is not described and may affect the efficacy of the final product.

Disclosure of Invention

Aiming at the problems in the prior art, the invention discovers that the esmolol hydrochloride synthesized into a certain crystal form can be more stable in a large amount of systematic experimental researches on the crystal form of the esmolol hydrochloride (4- [ 2-hydroxy-3- (isopropylamino) propoxy ] phenylpropionic acid methyl ester hydrochloride), and no research report on the esmolol hydrochloride exists in the prior art. Therefore, the invention provides a new crystal form of esmolol hydrochloride, namely the crystal form A, which has good temperature and humidity stability and good solubility.

The esmolol hydrochloride A crystal form has characteristic peaks at the following positions by using Cu-Ka radiation and expressing X-ray powder diffraction by a 2 theta angle: characteristic peaks are found at 5.787 ± 0.2 °, 11.495 ± 0.2 °, 12.903 ± 0.2 °, 13.499 ± 0.2 °, 15.219 ± 0.2 °, 16.012 ± 0.2 °, 17.219 ± 0.2 °, 18.238 ± 0.2 °, 18.924 ± 0.2 °, 20.535 ± 0.2 °, 22.159 ± 0.2 °, 23.014 ± 0.2 °, 23.745 ± 0.2 °, 24.316 ± 0.2 °, 26.311 ± 0.2 °, 27.675 ± 0.2 °, 28.887 ± 0.2 °, 29.93 ± 0.2 °, and 30.973 ± 0.2 °, as shown in fig. 1 (where "± 0.2 ° is an allowable measurement error range).

The X-ray powder diffraction test of the esmolol hydrochloride A crystal form is completed under the measurement of the ambient temperature and the ambient humidity. "ambient temperature" is generally 0-40 ℃; "ambient humidity" is typically 30% to 80% relative humidity.

By thermogravimetric analysis, the decomposition temperature of the thermal weight loss analysis of the esmolol hydrochloride A crystal form is 93.32 ℃, and no weight loss exists before the decomposition temperature, which is shown in figure 2.

The esmolol hydrochloride A has small hygroscopicity, is stable under high humidity, and keeps X-ray powder diffraction unchanged under the humidity condition of 0-95%.

The infrared spectrum of esmolol hydrochloride A has characteristic peaks at 2933cm-, 1727.04cm-, 1512cm-, 1173cm-, 1160cm-, 846cm-, 837 cm-and the like, as shown in figure 3.

Another object of the present invention is to provide a preparation method of the form a of esmolol hydrochloride, comprising the following steps:

(1) esmolol hydrochloride is dissolved in solvent A.

(2) Adding solvent B, and stirring at 20 + -5 deg.C for 1-2 hr.

(3) Cooling to 5 + -5 deg.C, and pulping for 3-4 hr.

(4) And filtering and separating, washing the solid with a solvent B, and drying in vacuum to obtain a product, namely the esmolol hydrochloride of the crystal form A.

According to the method, the conventional esmolol hydrochloride is used as a raw material, the esmolol hydrochloride with the crystal form A is obtained through two-step solvent crystallization, the solvent adopted by the two-step crystallization does not participate in chemical reaction, and the obtained product is still the esmolol hydrochloride.

The solvent A in the step (1) of the method is selected from one of methanol, ethanol and isopropanol; the dosage of the esmolol hydrochloride is 1-2 relative to the mass of the esmolol hydrochloride.

The solvent B in the step (2) of the method is selected from one of ethyl acetate and isopropyl acetate; the dosage of the esmolol hydrochloride is 4-8 relative to the mass of the esmolol hydrochloride.

In the step (4), the vacuum drying temperature is 35-45 ℃, and the drying time is 4-6 hours.

The invention has the beneficial effects that: the esmolol hydrochloride crystal form prepared by the invention has stable property and good solubility, is suitable for drug development, and has safe, simple and convenient preparation method and strong operability.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of esmolol hydrochloride form A provided by the present invention.

Figure 2 is a DSC profile of esmolol hydrochloride form a provided by the present invention.

FIG. 3 is an infrared spectrum of esmolol hydrochloride form A provided by the present invention.

Specific experimental mode

The present invention will be described in further detail with reference to the following examples, which should not be construed as limiting the invention thereto.

Example 1:

adding 10g of esmolol hydrochloride into a 100ml reaction bottle, adding 10ml of methanol, stirring for dissolving, keeping the temperature at 15-25 ℃ after the solid is completely dissolved, adding 50ml of ethyl acetate, keeping the temperature at 15-25 ℃, stirring for crystallizing for 1-2 hours, then cooling to 0-10 ℃, stirring for 3-4 hours, filtering out the solid, washing with a small amount of ethyl acetate, and vacuum drying at 40 ℃ for 4-6 hours to obtain 8.5g of white-like powder with the yield of 85%.

The X-ray powder diffraction, expressed in terms of 2 θ angles, using Cu-Ka radiation at ambient temperature and humidity has characteristic peaks at the following positions: characteristic peaks are found at 2 θ of 5.787 °, 11.495 °, 12.903 °, 13.499 °, 15.219 °, 16.012 °, 17.219 °, 18.238 °, 18.924 °, 20.535 °, 22.159 °, 23.014 °, 23.745 °, 24.316 °, 26.311 °, 27.675 °, 28.887 °, 29.93 °, and 30.973 °, as shown in fig. 1.

Through thermogravimetric analysis, the decomposition temperature of the thermal weight loss analysis of the esmolol hydrochloride A crystal form is about 93.32 ℃, and no weight loss exists before the decomposition temperature.

A glycine-hydrochloric acid buffer solution having a pH of 2.0 containing 0.5% (w/v) Tween, a disodium hydrogen phosphate-citric acid buffer solution having a pH of 4.6 containing 0.5% (w/v) Tween, and a disodium hydrogen phosphate-citric acid buffer solution having a pH of 6.8 containing 0.5% (w/v) Tween were prepared by the method described in Cryst. growth Des.2014,14, 4562-.

Taking the esmolol hydrochloride A crystal form 3mg prepared above, dividing into three parts, adding 1mL of prepared glycine-hydrochloric acid buffer solution with pH of 2.0 of 0.5% (w/v) Tween, 1mL of disodium hydrogen phosphate-citric acid buffer solution with pH of 4.6 containing 0.5% (w/v) Tween and 1mL of disodium hydrogen phosphate-citric acid buffer solution with pH of 6.8 containing 0.5% (w/v) Tween respectively, and stirring at room temperature for 24 h.

After stirring for 24 hours, the supernatant was collected by centrifugal filtration, and the concentration was monitored by high performance liquid chromatography at each pH in the order of 0.8mol/L, 0.83mol/L, and 0.85 mol/L.