Esmolol hydrochloride freeze-dried powder, preparation method and application thereof

Abstract

The present invention discloses a lyophilized powder of esmolol hydrochloride, a preparation method and application thereof, and the preparation method of the lyophilized powder of esmolol hydrochloride comprises the following steps: (1) preparing a liquid, adding sodium chloride and esmolol hydrochloride in a weight ratio of 50-70:90-110 to a preparation amount of 60%-90% water for injection, then adding hydrochloric acid or sodium hydroxide to adjust the pH value to 4.5-5.0, and adding water for injection to the preparation amount; (2) filtering and filling; (3) freeze-drying, wherein the freeze-drying comprises annealing, wherein the annealing temperature is ‑10°C-0°C; the annealing time is 1h-3h; the number of annealing is 1-3 times; (4) filling with inert gas, unpacking, and rolling the cover to obtain. The preparation method of the lyophilized powder of esmolol hydrochloride according to the present invention has simple process, low cost and high safety. And the obtained lyophilized powder of esmolol hydrochloride has high bioavailability, high stability and convenient storage.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to esmolol hydrochloride freeze-dried powder, a preparation method and application thereof. Background Art

[0002] Esmolol hydrochloride is a cardioselective, ultra-short-acting β-antagonist that acts on β-receptors of vascular and bronchial smooth muscle. It is used to control ventricular rate in atrial fibrillation and atrial flutter, perioperative hypertension, and sinus tachycardia. It was first synthesized by Zaroslinski and his colleagues in 1982. In December 1986, Du Pont Critical Care's esmolol hydrochloride injection was first launched in the United States with the approval of the US FDA. Since the ester structure of commercially available preparations is usually easily hydrolyzed during long-term storage, the content is reduced and the impurities increase significantly. Summary of the invention

[0003] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, one object of the present invention is to provide a method for preparing esmolol hydrochloride lyophilized powder, which can effectively inhibit the growth of impurities by controlling the stability of esmolol hydrochloride lyophilized powder during storage through an annealing process.

[0004] Another object of the present invention is to provide a lyophilized powder of esmolol hydrochloride.

[0005] Another object of the present invention is to provide an application of esmolol hydrochloride freeze-dried powder.

[0006] According to an embodiment of the first aspect of the present invention, the present invention provides a method for preparing esmolol hydrochloride freeze-dried powder, comprising the following steps: (1) liquid preparation: adding sodium chloride and esmolol hydrochloride in a weight ratio of 50-70:90-110 to a preparation amount of 60%-90% water for injection, then adding hydrochloric acid or sodium hydroxide to adjust the pH value to 4.5-5.0, and adding water for injection to the preparation amount; (2) filtering and filling; (3) freeze drying, wherein the freeze drying includes annealing, the annealing temperature is -10°C to 0°C; the annealing time is 1h to 3h; the number of annealing is 1 to 3 times; (4) filling with inert gas, unpacking, and capping to obtain.

[0007] According to the preparation method of the esmolol hydrochloride freeze-dried powder of the present invention, the stability of the esmolol hydrochloride freeze-dried powder during storage is controlled by an annealing process, and the growth of impurities can be effectively inhibited. The obtained esmolol hydrochloride freeze-dried powder has high stability and is convenient for storage.

[0008] According to some embodiments of the present invention, the freeze-drying further comprises: a first pre-freezing and a second pre-freezing, wherein the first pre-freezing and the second pre-freezing are respectively arranged before the annealing step and after the annealing step; and / or, The set temperatures of the first pre-freezing and the second pre-freezing are independently -35°C to -45°C; the set duration is 55min to 65min; and the duration is 1h to 2h.

[0009] According to some embodiments of the present invention, the annealing comprises a temperature reduction step, a temperature holding step and a temperature increase step. Among them, the set duration of the cooling step is 55min to 65min, the set duration of the heating step is 55min to 65min, and the duration of the heat preservation step is 1h to 3h.

[0010] According to some embodiments of the present invention, the hydrochloric acid is a 0.05 mol / L to 0.15 mol / L hydrochloric acid aqueous solution; and / or, The sodium hydroxide is a 0.05 mol / L to 0.15 mol / L sodium hydroxide aqueous solution.

[0011] According to some embodiments of the present invention, step (1) is performed at 25°C to 35°C.

[0012] According to some embodiments of the present invention, the freeze-drying further comprises: a drying step.

[0013] According to some embodiments of the present invention, the drying step comprises: Primary drying: drying temperature: -2.5℃~2.5℃; drying time: 800min~1000min; vacuum degree: 0.2000±0.0100mbar; And analytical drying: drying temperature: 35℃~45℃; drying time: 250min~350min; vacuum degree: 0mbar.

[0014] According to an embodiment of the second aspect of the present invention, the present invention provides an esmolol hydrochloride lyophilized powder injection, and the esmolol hydrochloride lyophilized powder is prepared according to the preparation method of esmolol hydrochloride lyophilized powder described in the embodiment of the first aspect of the present invention.

[0015] According to some embodiments of the present invention, the esmolol hydrochloride lyophilized powder is a mixture of a crystalline structure and an amorphous structure.

[0016] According to an embodiment of the third aspect of the present invention, the present invention provides an application of the esmolol hydrochloride lyophilized powder described in the embodiment of the first aspect of the present invention, or the esmolol hydrochloride lyophilized powder prepared according to the preparation method described in the embodiment of the first aspect of the present invention, wherein the esmolol hydrochloride lyophilized powder is used to prepare esmolol hydrochloride lyophilized powder injection.

[0017] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is a picture of the esmolol hydrochloride lyophilized powder injection obtained according to the specific example 1 of the present invention; Figure 2 This is a picture of the esmolol hydrochloride lyophilized powder injection obtained according to Comparative Example 4 of the present invention; Figure 3 This is an example of the decomposition process of esmolol hydrochloride lyophilized powder injection according to a specific embodiment of the present invention; Figure 4 It is the structure of common impurity I in esmolol hydrochloride lyophilized powder injection according to a specific embodiment of the present invention. DETAILED DESCRIPTION

[0019] The preparation method of the esmolol hydrochloride lyophilized powder according to the embodiment of the present invention is described in detail below.

[0020] The method for preparing esmolol hydrochloride lyophilized powder according to the first aspect of the present invention comprises the following steps: (1) Preparation: Add sodium chloride and esmolol hydrochloride in a weight ratio of 50-70:90-110 to 60%-90% water for injection, then add hydrochloric acid or sodium hydroxide to adjust the pH value to 4.5-5.0, and add water for injection to the prepared amount; (2) Filtration and filling; (3) Freeze drying, which includes annealing. The annealing temperature is -10°C to 0°C. The duration of the annealing step is 1h to 3h. The number of annealing steps is 1 to 3 times. (4) Fill with inert gas, take out of the box, and roll the cap to complete.

[0021] According to the preparation method of esmolol hydrochloride freeze-dried powder according to a specific embodiment of the present invention, the stability of the product during storage is significantly improved by controlling the pH value of the intermediate product to 4.5-5.0, and the annealing temperature is -10°C-0°C, the duration is 1h-3h, and the number of times is 1-3 times. For example, the total amount of impurities can be controlled within 1.0%. Among them, annealing, also known as repeated pre-freezing, refers to the process of heating the frozen product from the cooling end temperature to a certain temperature below its melting point at a certain heating rate, and keeping it for a period of time, and then cooling the product to the cooling end temperature at a certain cooling rate. Through the annealing process research, it was found that after the frozen material was annealed, the amorphous material gradually transformed into a crystalline material, the crystal structure in the product increased, the stability of the system was destroyed, and higher energy was required to destroy the lattice energy, which was the fundamental reason for the increase in the stability of the system after annealing. After the dry layer is annealed, the product will relax, the overall surface energy will be reduced, the porosity will become smaller, the pores between molecules will become smaller, the molecular activity will be restricted, and the stability of the system can also be increased. Annealing temperature that is too low or too high, such as -20°C or +5°C, will not achieve the effect of crystal rearrangement. Annealing time that is too long or annealing times that are too many, such as annealing for more than 4 hours or annealing for more than 3 times, will not be significantly different from annealing for 1 hour to 3 hours or annealing once to 3 times, resulting in an increase in the freeze-drying cycle and energy waste. The optimal annealing temperature is -10°C to 0°C, the annealing time is 1 hour to 3 hours, and the number of annealing times is 1 to 3 times. Among them, the decomposition reaction of esmolol hydrochloride lyophilized powder during storage can be referred to Figure 3 The common impurity structures after deterioration of esmolol hydrochloride can be found in Figure 4 .

[0022] According to some embodiments of the present invention, prefreezing further includes: a first prefreeze and a second prefreeze, the first prefreeze and the second prefreeze are respectively set before and after annealing; the set temperature of the first prefreeze and the second prefreeze is independently -35°C to -45°C; the set duration is 55min to 65min; the duration is 1h to 2h. In this way, on the one hand, by setting the first prefreeze and the second prefreeze respectively before and after annealing, the process of prefreezing the product at a low temperature for the first time, then heating up for annealing, and then prefreezing at a low temperature for the second time is realized. That is, repeated prefreezing of the product is achieved. In this way, combined with the crystal growth surface energy theory of Gibbs-Curie-Wulff, it is pointed out that the equilibrium state of the crystal should make the crystal unit volume have the minimum total surface area free energy, that is, the ratio of surface area to volume is the minimum. The transformation of the lamellar or layered structure with a large surface area free energy to the columnar or spherical structure with a small surface area free energy is the most fundamental driving force for the change of the frozen drug structure. The theoretical basis of annealing is that ice crystals with larger or negative curvature radii have lower chemical potential and slower melting speed, which is conducive to the recrystallization of the molten liquid on them. Recrystallization refers to the process in which the distribution of crystal size in the solid phase system gradually changes due to the migration of small ice crystal molecules to large ice crystals during heating. Usually, the introduction of annealing can achieve the effects of changing the shape and size of ice crystals, increasing the glass transition temperature, and shortening the drying time (reducing mass transfer resistance). The kinetic formula for ice crystal morphology change is: , μ, μ0: chemical potential, r1, r2: principal radii of curvature, ρ: density, M: relative molecular mass, γ: isotropic interface energy.

[0023] On the other hand, by setting the temperature of the first pre-freezing and the second pre-freezing, it is ensured that the product is dried at a lower temperature. By setting the time, the product is slowly cooled down at the beginning of freeze-drying, which is conducive to forming a stable product state. By setting the duration, it is conducive to removing moisture from the product and obtaining a dry product.

[0024] According to some embodiments of the present invention, annealing includes a cooling step, a heat preservation step and a heating step. Such a setting facilitates the process of first freeze-drying the product at low temperature, then heating and annealing, and then freeze-drying. That is, repeated pre-freezing of the product is achieved. Among them, the set duration of the cooling step is 55min to 65min, the set duration of the heating step is 55min to 65min, and the duration of the heat preservation step is 1h to 3h. By setting the set duration of the heating step and the cooling step, the heating and cooling speeds of the annealing can be controlled. By setting the duration of the annealing, the duration of the annealing step can be controlled, thereby controlling the morphology of the product and further controlling the stability of the product.

[0025] According to some embodiments of the present invention, annealing and the first pre-freezing and the second pre-freezing may be combined and referred to as refrigeration control.

[0026] According to some embodiments of the present invention, the hydrochloric acid is a 0.05 mol / L to 0.15 mol / L hydrochloric acid aqueous solution. In this way, the pH value of the intermediate product can be adjusted by adding a 0.05 mol / L to 0.15 mol / L hydrochloric acid aqueous solution, with an appropriate concentration and convenient use.

[0027] According to other embodiments of the present invention, the sodium hydroxide is a 0.05 mol / L to 0.15 mol / L sodium hydroxide aqueous solution. In this way, the pH value of the intermediate product can be adjusted by adding 0.05 mol / L to 0.15 mol / L sodium hydroxide aqueous solution, with an appropriate concentration and convenient use.

[0028] According to some embodiments of the present invention, step (1) is performed at 25° C. to 35° C. In this way, step (1) is performed at room temperature, the conditions are mild, and the operation is convenient.

[0029] According to some embodiments of the present invention, the freeze-drying further comprises: a drying step. In this way, the moisture in the product can be fully removed through the drying step, which is conducive to maintaining the stability of the product.

[0030] According to some embodiments of the present invention, the drying step includes: primary drying and analytical drying. In this way, through primary drying and analytical drying, the product can be dried step by step at different temperatures, and the moisture in the product can be fully removed. Among them, primary drying: drying temperature: -2.5℃~2.5℃; drying time: 800min~1000min; vacuum degree: 0.2000±0.0100mbar. In this way, under the conditions of -2.5℃~2.5℃; higher vacuum degree, most of the moisture can be removed. Further, analytical drying: drying temperature: 35℃~45℃; drying time: 250min~350min; vacuum degree: 0mbar. In this way, at a higher temperature, after a longer drying time and a relatively high vacuum degree, the moisture that cannot be removed by primary drying can be removed.

[0031] According to an embodiment of the second aspect of the present invention, the present invention provides a lyophilized esmolol hydrochloride powder, which is prepared according to the preparation method of lyophilized esmolol hydrochloride powder according to an embodiment of the first aspect of the present invention.

[0032] The esmolol hydrochloride freeze-dried powder according to the specific embodiment of the present invention has high stability and less impurities generated by decomposition.

[0033] According to some embodiments of the present invention, the esmolol hydrochloride lyophilized powder is a mixture of a crystalline structure and an amorphous structure. The specific product morphology is a white loose block. In this way, when the esmolol hydrochloride lyophilized powder obtained by the present invention is mixed with a crystalline structure and an amorphous structure, the stability is high.

[0034] According to an embodiment of the third aspect of the present invention, the present invention provides an esmolol hydrochloride freeze-dried powder according to an embodiment of the second aspect of the present invention, or an application of the esmolol hydrochloride freeze-dried powder prepared by the preparation method of an embodiment of the first aspect of the present invention, and the esmolol hydrochloride freeze-dried powder is used to prepare esmolol hydrochloride freeze-dried powder injection.

[0035] According to a specific embodiment of the present invention, when esmolol hydrochloride lyophilized powder is used for injection, the product is stable, the impurity content is low, and the drug effect is outstanding.

[0036] The preparation method of the esmolol hydrochloride lyophilized powder of the present invention is described below through specific exemplary embodiments and comparative examples. Example

[0037] A method for preparing esmolol hydrochloride lyophilized powder injection for injection, the prescription composition of which is shown in Table 1 below: Table 1. Formula of esmolol hydrochloride lyophilized powder injection Prescription ingredients Unit dosage form 1000 tubes of prescription <![CDATA[Esmolol Hydrochloride (C 16 H 25 NO4·HCl)]]> 100mg 100g Sodium chloride (NaCl) 59mg 59g Hydrochloric acid (HCl) Moderate Moderate Sodium hydroxide (NaOH) Moderate Moderate Water for injection Add to 10ml Add to 10L

[0038] (1) Prepare the solution. Add 80% of the prepared volume of room temperature water for injection into the preparation container. Weigh the prescribed amount of sodium chloride and esmolol hydrochloride, add them to the preparation container, stir to dissolve (solution pH 4.9), adjust the pH of the solution to 5.0 with 0.1 mol / L sodium hydroxide solution, and add water for injection to the full volume. (2) Filtration and filling: Use 0.22 μm polyethersulfone microporous filter membrane to filter and sterilize, test the properties, pH value, content, related substances, insoluble particles, and visible foreign matter of the intermediate product, and fill it after it passes the test; (3) Freeze-drying: Fill the drug solution into 30 ml borosilicate glass tube injection bottles, 10 ml / vial, half-stopper, transfer the sample to the partition, close the chamber door, set the process parameters as shown in Table 2 below, and start the equipment.

[0039] Table 2. Freeze-drying process parameters of Example 1

[0040] (4) After the freeze-drying is completed, nitrogen is backfilled, the plug is pressed, the box is taken out, and the cap is rolled to obtain the obtained esmolol hydrochloride freeze-dried powder injection. Figure 1 As shown, the product is a white loose mass.

[0041] Example 2 Example 2 is basically the same as Example 1, except that the pH is adjusted to 4.5 in step (1), and the freeze-drying process is specifically shown in Table 3 below.

[0042] Table 3. Process parameters of freeze drying in Example 2

[0043] Example 3 Example 3 is basically the same as Example 1, except that the pH is adjusted to 5.0 in step (1), and the freeze-drying process is specifically shown in Table 4 below.

[0044] Table 4. Process parameters for freeze drying of Example 3.

[0045]

[0046] Example 4 (1) Prepare the solution. Add 60% of the prepared volume of room temperature water for injection into the preparation container. Weigh the prescribed amount of sodium chloride and esmolol hydrochloride, add them into the preparation container, and stir to dissolve (solution pH 4.9). Adjust the pH of the solution to 5.0 with 0.1 mol / L sodium hydroxide solution, and add water for injection to the full amount. (2) Filtration and filling: Use 0.22 μm polyethersulfone microporous filter membrane to filter and sterilize, test the properties, pH value, content, related substances, insoluble particles, and visible foreign matter of the intermediate product, and fill it after it passes the test; (3) Freeze-drying: Fill the drug solution into 30 ml borosilicate glass tube injection bottles, 10 ml / vial, half-stopper, transfer the sample to the partition, close the box door, set the process parameters as shown in Table 5 below, and start the equipment.

[0047] Table 5. Process parameters of freeze drying in Example 4

[0048] (4) After freeze-drying, backfill with nitrogen, press the stopper, take the product out of the box, and roll the cap to obtain the product.

[0049] Example 5 (1) Prepare the solution. Add 60% of the prepared volume of room temperature water for injection into the preparation container. Weigh the prescribed amount of sodium chloride and esmolol hydrochloride, add them into the preparation container, and stir to dissolve (solution pH 4.9). Adjust the pH of the solution to 5.0 with 0.1 mol / L sodium hydroxide solution, and add water for injection to the full amount. (2) Filtration and filling: Use 0.22 μm polyethersulfone microporous filter membrane to filter and sterilize, test the properties, pH value, content, related substances, insoluble particles, and visible foreign matter of the intermediate product, and fill it after it passes the test; (3) Freeze-drying: Fill the drug solution into 30 ml borosilicate glass tube injection bottles, 10 ml / vial, half-stopper, transfer the sample to the partition, close the box door, set the process parameters as shown in Table 6 below, and start the equipment.

[0050] Table 6. Process parameters of freeze drying in Example 5 .

[0051] Example 6 Example 6 is basically the same as Example 5, except that the temperature in step (3) freeze-drying-refrigeration control step 2 is set to 0°C.

[0052] (1) Prepare the solution. Add 80% of the prepared volume of room temperature water for injection into the preparation container. Weigh the prescribed amount of sodium chloride and esmolol hydrochloride, add them to the preparation container, stir to dissolve (solution pH 4.9), adjust the pH of the solution to 5.0 with 0.15 mol / L sodium hydroxide solution, and add water for injection to the full volume. (2) Filtration and filling: Use 0.22 μm polyethersulfone microporous filter membrane to filter and sterilize, test the properties, pH value, content, related substances, insoluble particles, and visible foreign matter of the intermediate product, and fill it after it passes the test; (3) Freeze-drying: Fill the drug solution into 30 ml borosilicate glass tube injection bottles, 10 ml / vial, half-stopper, transfer the sample to the partition, close the box door, set the process parameters as shown in Table 7 below, and start the equipment.

[0053] Table 7. Process parameters of freeze drying in Example 7

[0054] (4) After freeze-drying, backfill with nitrogen, press the stopper, take the product out of the box, and cap it.

[0055] Example 8 (1) Prepare the solution. Add 80% of the prepared volume of room temperature water for injection into the preparation container. Weigh the prescribed amount of sodium chloride and esmolol hydrochloride, add them to the preparation container, stir to dissolve (solution pH 4.9), adjust the pH of the solution to 5.0 with 0.05 mol / L sodium hydroxide solution, and add water for injection to the full volume. (2) Filtration and filling: Use 0.22 μm polyethersulfone microporous filter membrane to filter and sterilize, test the properties, pH value, content, related substances, insoluble particles, and visible foreign matter of the intermediate product, and fill it after it passes the test; (3) Freeze-drying: Fill the drug solution into 30 ml borosilicate glass tube injection bottles, 10 ml / vial, half-stopper, transfer the sample to the partition, close the box door, set the process parameters as shown in Table 8 below, and start the equipment.

[0056] Table 8. Process parameters of freeze drying in Example 8

[0057] (4) After freeze-drying, backfill with nitrogen, press the stopper, take the product out of the box, and cap it.

[0058] Example 9 Example 9 is substantially the same as Example 1, except that the formulation composition is shown in Table 9 below: Table 9. Formula of esmolol hydrochloride lyophilized powder injection for injection in Example 9 Prescription ingredients Unit dosage form 1000 tubes of prescription <![CDATA[Esmolol Hydrochloride (C 16 H 25 NO4·HCl)]]> 90mg 90g Sodium chloride (NaCl) 70mg 70g Hydrochloric acid (HCl) Moderate Moderate Sodium hydroxide (NaOH) Moderate Moderate Water for injection Add to 10ml Add to 10L

[0059] Example 10 Example 10 is substantially the same as Example 1, except that the formulation composition is shown in Table 10 below: Table 10. Formula of esmolol hydrochloride lyophilized powder injection for injection in Example 10 Prescription ingredients Unit dosage form 1000 tubes of prescription <![CDATA[Esmolol Hydrochloride (C 16 H 25 NO4·HCl)]]> 110mg 110g Sodium chloride (NaCl) 50mg 50g Hydrochloric acid (HCl) Moderate Moderate Sodium hydroxide (NaOH) Moderate Moderate Water for injection Add to 10ml Add to 10L

[0060] Comparative Example 1 (1) Prepare the solution. Add 80% of the prepared volume of room temperature water for injection into the preparation container. Weigh the prescribed amount of sodium chloride and esmolol hydrochloride, add them into the preparation container, stir to dissolve (solution pH 4.9), adjust the pH of the solution to 7.0 with 0.1 mol / L sodium hydroxide solution, and add water for injection to the full volume. (2) Filtration and filling: Use 0.22 μm polyethersulfone microporous filter membrane to filter and sterilize, test the properties, pH value, content, related substances, insoluble particles, and visible foreign matter of the intermediate product, and fill it after it passes the test; (3) Freeze-drying: Fill the drug solution into 30 ml borosilicate glass tube injection bottles, 10 ml / vial, half-stopper, transfer the sample to the partition, close the box door, set the process parameters as shown in Table 11 below, and start the equipment.

[0061] Table 11. Process parameters of freeze drying of comparative example 1

[0062] (4) After freeze-drying, backfill with nitrogen, press the stopper, take the product out of the box, and cap it.

[0063] Comparative Example 2 Comparative Example 2 is basically the same as Example 4, except that the duration in step (3) freeze-drying-refrigeration control-step 2 is 240 minutes.

[0064] Comparative Example 3

[0065] Comparative Example 3 is basically the same as Example 4, except that the duration in step (3) freeze-drying-refrigeration control-step 2 is 10 minutes.

[0066] Comparative Example 4

[0067] Comparative Example 4 is basically the same as Example 4, except that the duration in step (3) freeze drying - refrigeration control - step 2 is 0 min, and the resulting esmolol hydrochloride lyophilized powder for injection is shown in the figure. Figure 2 shown.

[0068] Comparative Example 5

[0069] (1) Prepare the solution. Add 90% of the prepared volume of room temperature water for injection into the preparation container. Weigh the prescribed amount of sodium chloride and esmolol hydrochloride, add them to the preparation container, stir to dissolve (solution pH 4.9), adjust the pH of the solution to 5.0 with 0.1 mol / L sodium hydroxide solution, and add water for injection to the full amount. (2) Filtration and filling: Use 0.22 μm polyethersulfone microporous filter membrane to filter and sterilize, test the properties, pH value, content, related substances, insoluble particles, and visible foreign matter of the intermediate product, and fill it after it passes the test; (3) Freeze-drying: Fill the drug solution into 30 ml borosilicate glass tube injection bottles, 10 ml / vial, half-stopper, transfer the sample to the partition, close the box door, set the process parameters as shown in Table 12 below, and start the equipment.

[0070] Table 12. Process parameters of freeze drying of comparative example 5

[0071] (4) After freeze-drying, backfill with nitrogen, press the stopper, take the product out of the box, and roll the cap to obtain the product.

[0072] Comparative Example 6 Comparative Example 6 is basically the same as Example 5, except that the temperature in step (3) freeze-drying-refrigeration control-step 2 is set to 5°C.

[0073] Comparative Example 7

[0074] Comparative Example 7 is substantially the same as Example 1, except that the pH is adjusted to 3.0 in step (1).

[0075] The properties of the esmolol hydrochloride lyophilized powder injection obtained in Examples 1 to 10, Comparative Examples 1-7, and Comparative Product 1 and Comparative Product 2 were specifically compared in combination with the processes and parameters in the production process, and the content of relevant impurities in the products was detected when stored at 60°C. The results are shown in Table 14 below.

[0076] Among them, the detection method of impurity content can refer to the high performance liquid chromatography (General Rule 0512) test.

[0077] The test includes the following steps: for the test solution, take an appropriate amount of the product, add mobile phase A to dissolve and dilute to make a solution containing about 1.0 mg of esmolol hydrochloride per 1 ml; For the control solution, accurately measure an appropriate amount of the test solution and quantitatively dilute it with mobile phase A to produce a solution containing approximately 2 µg of esmolol hydrochloride per 1 ml; System suitability solution: take about 10 mg of esmolol hydrochloride, place in a 10 ml volumetric flask, add 1 ml of 1 mol / L hydrochloric acid solution, let stand for 30 minutes, add 1 ml of 1 mol / L sodium hydroxide solution to neutralize, dilute to scale with mobile phase A, and shake well; Chromatographic conditions: octadecylsilane bonded silica gel as filler (CAPCELL PAK C18 MG Ⅲ column, 4.6mm×250mm, 5µm or chromatographic column with equivalent performance); acetonitrile-methanol-phosphate buffer (3.0g of potassium dihydrogen phosphate, dissolved in water and diluted to 650ml) (15:20:65) as mobile phase A, methanol as mobile phase B, gradient elution according to the table below; flow rate of 1.0ml per minute; detection wavelength of 222nm; injection volume of 20µl.

[0078] Table 13. Chromatographic conditions of the test method Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 15 100 0 30 65 35 50 65 35 51 100 0 58 100 0 Limit: if there are impurity peaks in the chromatogram of the test solution, the peak area of ​​impurity I shall not be larger than the main peak area of ​​the control solution (0.2%), the peak area of ​​other individual impurity peaks shall not be larger than 1.5 times the main peak area of ​​the control solution (0.3%), the sum of the peak areas of all impurities shall not be larger than 5 times the main peak area of ​​the control solution (1.0%), and the chromatographic peaks less than 0.1 times the main peak area of ​​the control solution shall be ignored (0.02%).

[0079] Table 14. Properties of Examples, Comparative Examples and Reference Products and Impurities after Storage .

[0080] Combined with the specific embodiments, comparative examples and the test results of Table 14, it can be seen that the pH value of the intermediate product is controlled at 4.5 to 5.0, the temperature of the annealing step is -10°C to 0°C, the time of the annealing step is 1h to 3h, and the number of annealing steps is 1 to 3 times, so as to ensure that the total amount of impurities during the storage of the sample is controlled within 1.0%, and the stability of the product is significantly improved. Combined with Example 4 and Comparative Example 1 and Comparative Example 7, it can be seen that when the pH value of the intermediate product is too high or too low, even if the product properties are good, the storage process is unstable. The specific reason is that when the pH value is too high, the product is unstable and easily decomposed during storage, such as Comparative Example 1. When the pH value is too high (greater than 5.5), for example, when the pH value is 7.0, the ester bond of the esmolol hydrochloride solution is gradually hydrolyzed and degraded into impurity I. The higher the pH value, the faster the hydrolysis rate. Combined with Example 4 and Comparative Examples 2-Comparative Examples 6, it can be seen that the duration and temperature of the annealing step during annealing will affect the storage stability of the product. When the annealing step is short, the white powder has almost no rigid structure, and the product is easy to deteriorate. For details, please refer to Comparative Examples 3 and 4. When the annealing step is short, the stability of the product no longer changes, which will extend the production process and increase costs. For details, please refer to Comparative Example 2. When the annealing step temperature is high, the sample melts significantly during the annealing process, the white powder has almost no rigid structure, and the product is easy to deteriorate. For details, please refer to Comparative Example 6. When the annealing step temperature is low or no annealing is performed, the white powder has almost no rigid structure, and the product is easy to deteriorate. For details, please refer to Comparative Example 4.

[0081] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example.

[0082] Although the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

Claims

1. A method for preparing esmolol hydrochloride lyophilized powder, characterized in that: The steps include: (1) Preparation: Add sodium chloride and esmolol hydrochloride in a weight ratio of 50-70:90-110 to 60%-90% water for injection, then add hydrochloric acid or sodium hydroxide to adjust the pH value to 4.5-5.0, and add water for injection to the prepared amount; (2) Filtration and filling; (3) freeze drying, wherein the freeze drying includes annealing, wherein the annealing temperature is -10°C to 0°C, the annealing time is 1h to 3h, and the number of annealing times is 1 to 3 times; (4) Fill with inert gas, take out of the box, and roll the cap to complete.

2. The method for preparing esmolol hydrochloride lyophilized powder according to claim 1, characterized in that: The freeze-drying further comprises: a first pre-freezing and a second pre-freezing, wherein the first pre-freezing and the second pre-freezing are respectively arranged before the annealing and after the annealing; and / or, The set temperatures of the first pre-freezing and the second pre-freezing are independently -35°C to -45°C; the set duration is 55min to 65min; and the duration is 1h to 2h.

3. The method for preparing esmolol hydrochloride lyophilized powder according to claim 2, characterized in that: The annealing comprises a temperature reduction step, a temperature holding step and a temperature increase step. Among them, the set duration of the cooling step is 55min to 65min, the set duration of the heating step is 55min to 65min, and the duration of the heat preservation step is 1h to 3h.

4. The method for preparing esmolol hydrochloride lyophilized powder according to claim 3, characterized in that: The hydrochloric acid is a 0.05 mol / L to 0.15 mol / L hydrochloric acid aqueous solution; and / or, The sodium hydroxide is a 0.05 mol / L to 0.15 mol / L sodium hydroxide aqueous solution.

5. The method for preparing esmolol hydrochloride lyophilized powder according to claim 1, characterized in that: The step (1) is carried out at 25°C to 35°C.

6. The method for preparing esmolol hydrochloride lyophilized powder according to claim 1, characterized in that: The freeze-drying further comprises: a drying step.

7. The method for preparing esmolol hydrochloride lyophilized powder according to claim 6, characterized in that: The drying step comprises: Primary drying: drying temperature: -2.5℃~2.5℃; drying time: 800min~1000min; vacuum degree: 0.2000±0.0100mbar; And analytical drying: drying temperature: 35℃~45℃; drying time: 250min~350min; vacuum degree: 0mbar.

8. A lyophilized powder injection of esmolol hydrochloride, characterized in that: The esmolol hydrochloride lyophilized powder is prepared according to the preparation method of esmolol hydrochloride lyophilized powder according to any one of claims 1 to 7.

9. The esmolol hydrochloride lyophilized powder injection according to claim 8, characterized in that: The esmolol hydrochloride freeze-dried powder is a mixture of a crystalline structure and an amorphous structure.

10. The use of the esmolol hydrochloride freeze-dried powder according to claim 8 or 9, or the esmolol hydrochloride freeze-dried powder prepared by the preparation method according to any one of claims 1 to 7, characterized in that: The esmolol hydrochloride freeze-dried powder is used for preparing esmolol hydrochloride freeze-dried powder injection.

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