Preparation method of fine-particle budesonide crystal

Abstract

The invention relates to the technical field of medicines, in particular to a preparation method of fine-particle budesonide crystals, which comprises the following steps: (1) mixing budesonide with ethanol, heating and stirring until budesonide is completely dissolved to obtain a dissolved clear solution; (2) adding the dissolved clear liquid into rapidly stirred purified water, and rapidly stirring at 0-20 DEG C for 10-60 minutes; and (3) stopping stirring, filtering, and drying to obtain a budesonide product with the granularity D95 being less than or equal to 5 microns. The invention aims to provide a method for directly obtaining a budesonide raw material with a small particle size through recrystallization without crushing. Meanwhile, the budesonide raw material prepared by the method is not easy to coat a solvent, and the solvent residue meets the standard.

Description

Technical Field

[0001] The invention relates to the field of medical technology, and in particular to a method for preparing fine particle budesonide crystals. Background Art

[0002] Budesonide is a highly selective inhaled glucocorticoid with anti-inflammatory, antispasmodic and antiasthmatic effects. It is the first choice for the clinical treatment of bronchial asthma due to its high efficiency and safety. The structural formula is:

[0003]

[0004] Currently, the best way to treat asthma is pulmonary administration, and particle size is a key factor affecting the deposition effect of pulmonary administration. Drugs with particle sizes between 0.5μm and 5μm mainly settle in the bronchi and bronchioles of the lungs, particles larger than 10μm mainly deposit in the oropharynx, and particles of 0.5μm are easily exhaled with the airflow. Therefore, drugs with particle sizes between 0.5μm and 5μm are most suitable for pulmonary administration.

[0005] At present, the most widely used budesonide micronization process is the pulverization method, among which the airflow pulverization method is the most commonly used, which can produce particles as low as 1μm in size by causing collisions between particles at a high rate. However, the pulverization method has many disadvantages such as high energy consumption, low efficiency, and large material loss.

[0006] my country's "Technical Guidelines for the Study of Residual Organic Solvents in Chemical Drugs" stipulates that the ethanol residue limit is 0.5%. When ethanol is used as the recrystallization solvent in the production of budesonide raw materials, the crystals are easily coated with the solvent, and the solvent needs to be effectively removed by extending the vacuum drying time, which increases the production cost. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the defects of the prior art and provide a method for preparing fine particle budesonide crystals.

[0008] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0009] The present invention provides a method for preparing fine particle budesonide crystals, comprising the following steps:

[0010] (1) mixing budesonide and ethanol, heating and stirring until completely dissolved to obtain a clear solution;

[0011] (2) Add the clear solution into rapidly stirred purified water and stir rapidly at 0-20°C for 10-60 minutes;

[0012] (3) stopping stirring, filtering, and drying to obtain a budesonide product with a particle size of D95≤5 μm.

[0013] As a preferred technical solution of the present invention, in step (1), the mass ratio of ethanol to budesonide is 8-12:1; the heating temperature is 50-90°C; and the weight ratio of purified water to the ethanol in step (1) is 4-10:1.

[0014] As a preferred technical solution of the present invention, in step (2), the rotation speed of the rapid stirring is 1500-10000 rpm; and the temperature of the purified water is 0-20°C.

[0015] As a preferred technical solution of the present invention, in step (3), the drying method is vacuum drying, with a drying temperature of 50-80°C and a negative pressure of 0.07-0.1 MPa.

[0016] As a preferred technical solution of the present invention, in step (1), the heating and stirring temperature is 65-75°C; in step (2), rapid stirring is performed at 0-20°C for 30-50 minutes; in step (3), the filtered filter cake temperature is 55-70°C, and the filter cake is dried at a negative pressure of 0.090-0.100 MPa for 7-10 hours.

[0017] As a preferred technical solution of the present invention, the ratio of budesonide to ethanol is 1:10, the heating and stirring temperature is 70-75°C, the rapid stirring speed is 2500 rpm, the purified water is 350 g at 10°C, the rapid stirring time is 30 minutes; and the filter cake temperature is 60-65°C.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The present invention aims to provide a method for obtaining a budesonide raw material with a smaller particle size directly through recrystallization without pulverization. Meanwhile, the budesonide raw material prepared by the method is not easy to be coated with solvent, and the solvent residue meets the standard.

[0020] The invention provides a method for preparing budesonide with a particle size D95≤5μm, the process has strong controllability, low cost, high yield, and is suitable for industrial production. The product obtained by the process has complete crystal form, good dispersibility, stable quality, and solvent residue that meets the standard, and can be directly used for the preparation of budesonide inhalation preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation of the present invention. In the accompanying drawings:

[0022] Figure 1 This is a particle size distribution diagram of the product obtained in Example 1 of the present invention;

[0023] Figure 2This is a particle size distribution diagram of the product obtained in Example 2 of the present invention;

[0024] Figure 3 This is a particle size distribution diagram of the product obtained in Example 3 of the present invention;

[0025] Figure 4 This is the particle size distribution diagram of the product obtained in Comparative Example 1;

[0026] Figure 5 The XRD powder diffraction patterns of the budesonide products obtained in Examples 1-3 and Comparative Example 1 are shown. DETAILED DESCRIPTION

[0027] The preferred embodiments of the present invention are described below in conjunction with the accompanying drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0028] Example 1

[0029] Mix 5.00g of budesonide with 50.00g of ethanol, heat and stir at 70-75°C until completely dissolved. Add the clear solution to 350g of 10°C purified water at a speed of 2500 rpm, and stir to crystallize for 30 minutes. After the crystallization is completed, stop stirring, filter, and dry the filter cake at 60-65°C and negative pressure 0.090MPa for 8h to obtain 4.92g of budesonide finished product with a yield of 98.4%. HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 99.8%, the proportion of diastereomer A was 47.6%, the unknown single impurity content was 0 (less than 0.05% was not included), the impurity A content was 0.08%, the impurity D content was 0.06%, and the impurity L content was 0.08%. The particle size D95 of the obtained budesonide was 4.025μm, and the X-ray powder diffraction data are shown in Table 1 below. The particle size distribution diagram of the product is shown in Figure 1 shown.

[0030]

[0031]

[0032]

[0033] Table 1 X-ray powder diffraction data of budesonide in Example 1

[0034] Example 2

[0035] Mix 10.00g of budesonide with 120.00g of ethanol, heat and stir at 65-70℃ until completely dissolved. Add the clear solution to 900g of 8℃ purified water at a speed of 3000 rpm, and stir to crystallize for 50 minutes. After the crystallization is completed, stop stirring, filter, and dry the filter cake at 55-60℃ and negative pressure of 0.090MPa for 10h to obtain 9.90g of budesonide finished product with a yield of 99.0%. HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 99.7%, the proportion of diastereomer A was 47.4%, the unknown single impurity content was 0 (less than 0.05% was not included), the impurity A content was 0.07%, the impurity D content was 0.06%, and the impurity L content was 0.09%. The particle size D95 of the obtained budesonide was 2.503μm, and the X-ray powder diffraction data is shown in Table 2 below. The particle size distribution diagram of the product is shown in Figure 2 shown.

[0036]

[0037]

[0038] Table 2 X-ray powder diffraction data of budesonide in Example 2

[0039] Example 3

[0040] 10.00g of budesonide was mixed with 110.00g of ethanol, and heated and stirred at 65-70°C until completely dissolved. The clear solution was added to 800g of 6°C purified water at a speed of 6000 rpm, and stirred for crystallization for 30 minutes. After the crystallization was completed, stirring was stopped, and the filter cake was dried at 65-70°C and a negative pressure of 0.100MPa for 7h to obtain 9.92g of budesonide finished product with a yield of 99.2%. HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 99.5%, the proportion of diastereomer A was 47.8%, the unknown single impurity content was 0 (less than 0.05% was not included), the impurity A content was 0.06%, the impurity D content was 0.06%, and the impurity L content was 0.08%. The particle size D95 of the obtained budesonide was 2.603μm, and the X-ray powder diffraction data were shown in Table 3 below. The particle size distribution diagram of the product is shown in Figure 3 shown.

[0041]

[0042]

[0043] Table 3 X-ray powder diffraction data of budesonide in Example 3 Comparative Example 1

[0044] According to the pulverization process of our company's budesonide raw materials, air flow pulverization was carried out, and the air flow pulverization conditions were: pulverization pressure 0.70 MPa, feed pressure 0.80 MPa, and feed speed 70 g / h. The pulverization yield of the obtained budesonide was 90.0%, the particle size D95 was 3.917 μm, and the X-ray powder diffraction data were shown in Table 4 below.

[0045]

[0046]

[0047] Table 4 X-ray powder diffraction data of budesonide in comparative example 1 The budesonide obtained in Example 1 and comparative example 1 was subjected to stability tests, and accelerated tests were carried out under the conditions of temperature 30±2°C and humidity 75±5%, respectively. The samples were tested by HPLC according to the detection method of the European Pharmacopoeia at 0 days, 20 days, 40 days and 60 days. The specific results are shown in Tables 5 and 6 below.

[0048] project Require Day 0 20 days 40 days 60 days content / % 97.5-102 99.8 99.8 99.7 99.9 Dimer A / % 40-51 47.6 47.7 47.5 47.6 Impurity A / % ≤0.2 0.08 0.08 0.07 0.08 Impurity D / % ≤0.2 0.06 0.07 0.07 0.06 Impurities L / % ≤0.2 0.08 0.09 0.08 0.08 Unknown impurities / % ≤0.1 0 0 0 0

[0049] Table 5 Example 1 Stability test of budesonide (0 days, 20 days, 40 days, 60 days)

[0050] project Require Day 0 20 days 40 days 60 days content / % 97.5-102 99.6 99.8 99.7 99.9 Dimer A / % 40-51 44.6 44.6 44.5 44.6 Impurity A / % ≤0.2 0.09 0.09 0.08 0.08 Impurity D / % ≤0.2 0.08 0.09 0.08 0.08 Impurities L / % ≤0.2 0.08 0.10 0.12 0.13 Unknown impurities / % ≤0.1 0 0 0.05 0.06

[0051] Table 6 Comparative Example 1 Stability test of budesonide (0 day, 20 day, 40 day, 60 day)

[0052] The data show that when the budesonide prepared in Comparative Example 1 after airflow pulverization was subjected to 20-day, 40-day and 60-day stability tests, the content of impurity L and unknown impurities tended to increase compared with the product prepared in Example 1.

[0053] The budesonide obtained by this process has no agglomeration phenomenon, no change in particle size, no change in quality, and has high stability during a 60-day stability test.

[0054] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing fine particle budesonide crystals, characterized in that: The following steps are involved: (1) mixing budesonide and ethanol, heating and stirring until completely dissolved to obtain a clear solution; (2) Add the clear solution into rapidly stirred purified water and stir rapidly at 0-20°C for 10-60 minutes; (3) stopping stirring, filtering, and drying to obtain a budesonide product with a particle size of D95≤5 μm.

2. The method for preparing fine particle budesonide crystals according to claim 1, characterized in that: In step (1), the mass ratio of ethanol to budesonide is 8-12:1; the heating temperature is 50-90° C.; and the weight ratio of purified water to the ethanol in step (1) is 4-10:

1.

3. A method for preparing fine particle budesonide crystals according to claim 1 or 2, characterized in that: In step (2), the rotation speed of the rapid stirring is 1500-10000 rpm; and the temperature of the purified water is 0-20°C.

4. The method for preparing fine particle budesonide crystals according to claim 1, characterized in that: In step (3), the drying method is vacuum drying, the drying temperature is 50-80° C., and the negative pressure is 0.07-0.1 MPa.

5. The method for preparing fine particle budesonide crystals according to claim 3, characterized in that: In step (1), the heating and stirring temperature is 65-75°C; in step (2), rapid stirring is performed at 0-20°C for 30-50 minutes; in step (3), the filtered filter cake temperature is 55-70°C, and the filter cake is dried at a negative pressure of 0.090-0.100 MPa for 7-10 hours.

6. The method for preparing fine particle budesonide crystals according to claim 5, characterized in that: The ratio of budesonide to ethanol is 1:10, the heating and stirring temperature is 70-75°C, the rapid stirring speed is 2500 rpm, the purified water is 350 g at 10°C, the rapid stirring time is 30 minutes; and the filter cake temperature is 60-65°C.

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