Methylprednisolone Acetate with Specific Particle Size, Preparation Method and Application Thereof

Abstract

The present invention provides methylprednisolone acetate with a specific particle size, its preparation method and application, which relates to the technical field of medicine. The preparation method of methylprednisolone acetate with a specific particle size provided by the present invention adopts microchannel technology. The raw material drug solution containing methylprednisolone acetate and the anti-solvent are fully and uniformly contacted in a microreactor to achieve good micro-mixing, realize recrystallization, and obtain methylprednisolone acetate with a specific particle size. Compared with the traditional pulverization method, it can effectively control the size of the recrystallized particles, has a narrow particle size distribution, good fluidity, is not easy to agglomerate, has no bacterial growth during the preparation process, is beneficial to the stability of the preparation, is suitable for the preparation of sterile methylprednisolone acetate suspension injection, and meets the requirements of sterile preparations.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to methylprednisolone acetate with a specific particle size, its preparation method and application. Background Art

[0002] Methylprednisolone acetate is a medium-acting glucocorticoid, with anti-inflammatory, anti-allergic, anti-rheumatic and immunosuppressive effects. The Upjohn Company (now Pfizer) developed a suspension injection of methylprednisolone acetate in 1959 and launched it in the United States. It is administered by intramuscular injection, intra-articular injection, soft tissue injection or local injection, and is widely used in the treatment of endocrine disorders, rheumatic diseases, skin diseases, allergic conditions, collagen diseases, ophthalmic diseases, respiratory diseases and gastrointestinal diseases.

[0003] The suspension for injection of methylprednisolone acetate is a sterile preparation, so sterilization operation is required in the preparation process. Terminal sterilization has a great influence on the particle size of the preparation, and thus affects the quality of the preparation. Therefore, using sterile methylprednisolone acetate raw material is of great significance for improving the stability of the preparation. The United States Pharmacopeia requires that the particles within 10 μm in diameter should not be less than 75% of the total number, and the particles within 20 μm in diameter should not be less than 99% of the total number for injection solutions. According to the general rules of the Chinese Pharmacopeia, the particles within 15 μm in diameter should not be less than 90%, the particles with a diameter of 15 μm - 20 μm should not be more than 10%, and individual particles with a diameter of 20 - 50 μm are allowed to exist. Thus, the qualified limit of particle size is defined as D75 ≤ 10 μm, D90 ≤ 15 μm, D99 ≤ 20 μm. Through the analysis of commercially available original research products, the particle size distribution of the original preparation is obtained as D90 = 10 - 15 μm, D50 = 5 - 9 μm.

[0004] To obtain raw materials of methylprednisolone acetate with particle size meeting the requirements of the preparation, the most commonly used method is comminution. Comminution is mainly carried out by means of air jet milling, impact milling, splitting milling, extrusion milling and mechanical shearing milling, etc. However, these methods generally have problems such as low efficiency, wide particle size distribution of products, high energy consumption, easy destruction and degradation of the structure of heat-unstable drugs, and it is easy to grow bacteria during the comminution process. At the same time, the surface energy of the comminuted material is relatively high, and agglomeration is likely to occur.

[0005] Aiming at the technical problems existing in the preparation of methylprednisolone acetate raw materials, the present invention aims to find a method for preparing sterile and particle size-compliant methylprednisolone acetate, which is suitable for preparing a stable methylprednisolone acetate suspension injection. Summary of the Invention

[0006] The main purpose of the present invention is to provide methylprednisolone acetate with a specific particle size, its preparation method and application, in order to at least partially solve at least one of the above technical problems.

[0007] As a first aspect of the present invention, the present invention provides a method for preparing methylprednisolone acetate with a specific particle size, comprising the following steps: mixing a raw material drug solution containing methylprednisolone acetate with an antisolvent in a microreactor and performing recrystallization to obtain methylprednisolone acetate.

[0008] The method for preparing methylprednisolone acetate with a specific particle size provided by the present invention adopts microchannel technology. The raw material drug solution containing methylprednisolone acetate and the antisolvent are fully and evenly contacted in the microreactor to achieve good micromixing, realize recrystallization, and obtain methylprednisolone acetate with a specific particle size. Compared with the traditional pulverization method, it can effectively control the size of the recrystallized particles, has a narrow particle size distribution, good fluidity, is not easy to agglomerate, has no bacterial growth during the preparation process, is beneficial to the stability of the preparation, is suitable for the preparation of sterile methylprednisolone acetate suspension injection, and meets the requirements of sterile preparations.

[0009] Further, it comprises the following steps:

[0010] (a) Dissolving methylprednisolone acetate raw material in an organic solvent to prepare a raw material drug solution;

[0011] (b) Simultaneously introducing the raw material drug solution and the antisolvent into the microreactor at their respective flow rates, mixing the two in the microreactor and performing recrystallization to obtain methylprednisolone acetate.

[0012] Further, it comprises the following steps:

[0013] (a) Dissolving methylprednisolone acetate raw material in an organic solvent to prepare a raw material drug solution; the organic solvent is selected from one or a combination of several of DMF (N, N-dimethylformamide), acetonitrile or tetrahydrofuran; the antisolvent is selected from isopropyl ether and / or methyl tert-butyl ether;

[0014] (b) Simultaneously introducing the raw material drug solution and the antisolvent into the microreactor at flow rates of (1-5) mL / min and (55-60) mL / min respectively, mixing the two in the microreactor and performing recrystallization to obtain methylprednisolone acetate.

[0015] In the present invention, typical but non-limiting flow rates of the raw material drug solution can be, for example, 1 mL / min, 2 mL / min, 3 mL / min, 3.5 mL / min, 4 mL / min, 4.5 mL / min or 5 mL / min;

[0016] Typical but non-limiting flow rates of the antisolvent can be, for example, 55 mL / min, 56 mL / min, 57 mL / min, 58 mL / min, 59 mL / min or 60 mL / min.

[0017] The preparation method of methylprednisolone acetate with a specific particle size provided by the present invention adopts the microchannel technology. By selecting specific organic solvents and antisolvents, the raw materials are dissolved in the organic solvents to prepare a raw drug solution, and the flow rate of the raw drug solution and the flow rate of the antisolvent are strictly controlled and simultaneously introduced into the microreactor. They are mixed and recrystallized in the microreactor. With the joint cooperation of the above conditions, sterile and uniform particle size methylprednisolone acetate is obtained, which can be effectively used for methylprednisolone acetate suspension injection and meets the requirements of sterile preparations.

[0018] Further, in the step (a), the organic solvent is selected from the combination of DMF, acetonitrile and tetrahydrofuran.

[0019] Further, in the step (a), the volume ratio of DMF, acetonitrile and tetrahydrofuran in the organic solvent is (1 - 5):(0.5 - 3):(3 - 8).

[0020] In the present invention, typical but non-limiting volume ratios of DMF, acetonitrile and tetrahydrofuran in the organic solvent can be, for example, 1:3:8, 5:0.5:3, 3:2:5, 2:1:4 or 3:5:6.

[0021] The present invention obtains narrow particle size distribution, better stability and higher yield of methylprednisolone acetate by preferably selecting the organic solvent. When the organic solvent is selected from the combination of DMF, acetonitrile and tetrahydrofuran, and further, when the volume ratio of DMF, acetonitrile and tetrahydrofuran in the organic solvent is (1 - 5):(0.5 - 3):(3 - 8), in combination with other conditions.

[0022] Further, in the step (b), the raw drug solution and the antisolvent are simultaneously introduced into the microreactor at flow rates of (3.5 - 5) mL / min and (55 - 60) mL / min respectively.

[0023] The present invention obtains narrow particle size distribution, better stability and higher yield of methylprednisolone acetate by preferably selecting the flow rates of the raw drug solution and the antisolvent. When the flow rate of the raw drug solution is (3.5 - 5) mL / min and the flow rate of the antisolvent is (55 - 60) mL / min, in combination with other conditions.

[0024] Further, in the step (a), the mass-volume ratio of the methylprednisolone acetate raw material to the organic solvent is 1:(5 - 15) g / mL.

[0025] In the present invention, the typical but non-limiting mass-volume ratios of methylprednisolone acetate raw material to organic solvent can be, for example, 1:5 g / mL, 1:6 g / mL, 1:7 g / mL, 1:8 g / mL, 1:9 g / mL, 1:10 g / mL, 1:11 g / mL, 1:12 g / mL, 1:13 g / mL, 1:14 g / mL or 1:15 g / mL.

[0026] Further, in the step (b), the recrystallization temperature is 25°C - 40°C.

[0027] In the present invention, the typical but non-limiting recrystallization temperatures can be, for example, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C or 40°C.

[0028] As the second aspect of the present invention, the present invention provides a methylprednisolone acetate with a specific particle size, which is prepared by the preparation method of the methylprednisolone acetate with the above specific particle size.

[0029] Further, the particle size of the methylprednisolone acetate is D90 = 9 - 15 μm and D50 = 3 - 8 μm.

[0030] Further, the particle size of the methylprednisolone acetate is D90 = 10 - 15 μm and D50 = 5 - 8 μm.

[0031] Further, the particle size of the methylprednisolone acetate is D90 = 10 - 13 μm and D50 = 6 - 8 μm.

[0032] As the third aspect of the present invention, the present invention provides the application of the methylprednisolone acetate prepared by the preparation method of the methylprednisolone acetate with the above specific particle size or the methylprednisolone acetate with the above specific particle size in the preparation of methylprednisolone acetate suspension injection.

[0033] When the methylprednisolone acetate prepared by the preparation method of the methylprednisolone acetate with the specific particle size provided by the present invention or the methylprednisolone acetate with the specific particle size provided is used in the preparation of methylprednisolone acetate injection, since the methylprednisolone acetate is sterile and has uniform particle size, it is beneficial to the stability of the preparation, and the sterilization step in the preparation of the suspension injection is omitted, simplifying the process steps.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The preparation method of methylprednisolone acetate with a specific particle size provided by the present invention adopts a microchannel technology. The raw material drug solution containing methylprednisolone acetate and an anti-solvent are in full and uniform contact in a microreactor, achieving good micro-mixing, realizing recrystallization, and obtaining methylprednisolone acetate with a specific particle size. Compared with the traditional grinding method, it can effectively control the size of the recrystallized particles, has a narrow particle size distribution, good fluidity, is not prone to agglomeration, has no bacterial growth during the preparation process, is beneficial to the stability of the preparation, is suitable for the preparation of a sterile suspension injection of methylprednisolone acetate, and meets the requirements of sterile preparations.

[0036] When the methylprednisolone acetate prepared by the preparation method of methylprednisolone acetate with a specific particle size provided by the present invention or the methylprednisolone acetate with a specific particle size provided is used for the preparation of a methylprednisolone acetate injection, since the methylprednisolone acetate is sterile and has a uniform particle size, it is beneficial to the stability of the preparation, omits the sterilization step in the preparation of the suspension injection, and simplifies the process steps. Description of the Drawings

[0037] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0038] Figure 1 It is the particle size distribution diagram of the methylprednisolone acetate prepared in Examples 1 - 10;

[0039] Figure 2 It is the scanning electron microscope image of the methylprednisolone acetate prepared in Examples 1 - 10;

[0040] Figure 3 It is the scanning electron microscope image of the methylprednisolone acetate prepared in Comparative Example 6 after being placed for 24 months in the stability test. Detailed Embodiments

[0041] The following will describe the implementation schemes of the present invention in detail in combination with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. Those not specified in the examples are carried out under conventional conditions. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0042] Corning microchannel G1 glass reactor, Corning Reactor Technologies Co., Ltd.

[0043] Example 1 Preparation Method of Methylprednisolone Acetate with a Specific Particle Size

[0044] Example 1-1

[0045] A preparation method of methylprednisolone acetate with a specific particle size, comprising the following steps:

[0046] 1) Take 10 g of methylprednisolone acetate and dissolve it in 50 mL of DMF to prepare a raw material drug solution of methylprednisolone acetate, and place it in a raw material drug solution storage tank; take 3 L of methyl tert-butyl ether and place it in an antisolvent storage tank;

[0047] 2) Pass the raw material drug solution and methyl tert-butyl ether into a microchannel reactor simultaneously through a first peristaltic pump and a second peristaltic pump respectively. The flow rate of the raw material drug solution in the first peristaltic pump is 1 mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump is 55 mL / min. After the two are mixed in the microchannel reactor, recrystallization is carried out at 40 °C to obtain a methylprednisolone acetate slurry;

[0048] 3) Filter, wash, and dry the methylprednisolone acetate slurry obtained by the above recrystallization to obtain 9.14 g of methylprednisolone acetate, and the yield is 91.4%.

[0049] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of the obtained methylprednisolone acetate was 7.618 μm, and D90 was 14.323 μm.

[0050] Example 1-2

[0051] A preparation method of methylprednisolone acetate with a specific particle size, comprising the following steps:

[0052] 1) Take 10 g of methylprednisolone acetate and dissolve it in 150 mL of acetonitrile to prepare a raw material drug solution of methylprednisolone acetate, and place it in a raw material drug solution storage tank; take 2 L of isopropyl ether and place it in an antisolvent storage tank;

[0053] 2) Pass the raw material drug solution and isopropyl ether into a microchannel reactor simultaneously through a first peristaltic pump and a second peristaltic pump respectively. The flow rate of the raw material drug solution in the first peristaltic pump is 5

[0054] mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump is 60 mL / min. After the two are mixed in the microchannel reactor, recrystallization is carried out at 25 °C to obtain a methylprednisolone acetate slurry;

[0055] 3) Filter, wash, and dry the methylprednisolone acetate slurry obtained by the above recrystallization to obtain 8.95 g of methylprednisolone acetate, and the yield is 89.5%.

[0056] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of the obtained methylprednisolone acetate was 7.328 μm, and D90 was 14.167 μm.

[0057] Examples 1 - 3

[0058] A preparation method of methylprednisolone acetate with a specific particle size, comprising the following steps:

[0059] 1) Take 10 g of methylprednisolone acetate and dissolve it in 100 mL of tetrahydrofuran to prepare a raw material drug solution of methylprednisolone acetate, and place it in the raw material drug solution storage tank; take 2 L of methyl tert-butyl ether and place it in the antisolvent storage tank;

[0060] 2) Pass the raw material drug solution and methyl tert-butyl ether into the microchannel reactor simultaneously through the first peristaltic pump and the second peristaltic pump respectively. The flow rate of the raw material drug solution in the first peristaltic pump is 3.5 mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump is 58 mL / min. After the two are mixed in the microchannel reactor, recrystallization is carried out at 30 °C to obtain a methylprednisolone acetate slurry;

[0061] 3) Filter, wash, and dry the methylprednisolone acetate slurry obtained by the above recrystallization to obtain 9.22 g of methylprednisolone acetate, with a yield of 92.2%.

[0062] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of the obtained methylprednisolone acetate was 6.834 μm, and D90 was 13.717 μm.

[0063] Examples 1 - 4

[0064] A preparation method of methylprednisolone acetate with a specific particle size, comprising the following steps:

[0065] 1) Take 10 g of methylprednisolone acetate and dissolve it in 80 mL of a DMF / acetonitrile mixed solution with a volume ratio of 1:1 to prepare a raw material drug solution of methylprednisolone acetate, and place it in the raw material drug solution storage tank; take 2.5 L of methyl tert-butyl ether and place it in the antisolvent storage tank;

[0066] 2) Pass the raw material drug solution and methyl tert-butyl ether into the microchannel reactor simultaneously through the first peristaltic pump and the second peristaltic pump respectively. The flow rate of the raw material drug solution in the first peristaltic pump is 2 mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump is 56 mL / min. After the two are mixed in the microchannel reactor, recrystallization is carried out at 26 °C to obtain a methylprednisolone acetate slurry;

[0067] 3) Filter, wash, and dry the methylprednisolone acetate slurry obtained by the above recrystallization to obtain 9.11 g of methylprednisolone acetate, with a yield of 91.1%.

[0068] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of the obtained methylprednisolone acetate was 5.493 μm, and D90 was 11.836 μm.

[0069] Examples 1 - 5

[0070] A preparation method of methylprednisolone acetate with a specific particle size, comprising the following steps:

[0071] Take 10 g of methylprednisolone acetate and dissolve it in 90 mL of a DMF / tetrahydrofuran mixed solution with a volume ratio of 1:1 to prepare a raw material drug solution of methylprednisolone acetate, and place it in the raw material drug solution storage tank; take 2.5 L of isopropyl ether and place it in the anti-solvent storage tank;

[0072] 2) Pass the raw material drug solution and isopropyl ether into the microchannel reactor through the first peristaltic pump and the second peristaltic pump respectively. The flow rate of the raw material drug solution in the first peristaltic pump is 2.5 mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump is 57 mL / min. After the two are mixed in the microchannel reactor, recrystallization is carried out at 28 °C to obtain a methylprednisolone acetate slurry;

[0073] 3) Filter, wash, and dry the methylprednisolone acetate slurry obtained by the above recrystallization to obtain 9.05 g of methylprednisolone acetate, and the yield is 90.5%.

[0074] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of the obtained methylprednisolone acetate was 5.818 μm, and D90 was 12.458 μm.

[0075] Examples 1 - 6

[0076] A preparation method of methylprednisolone acetate with a specific particle size, comprising the following steps:

[0077] Take 10 g of methylprednisolone acetate and dissolve it in 120 mL of a acetonitrile / tetrahydrofuran mixed solution with a volume ratio of 1:1 to prepare a raw material drug solution of methylprednisolone acetate, and place it in the raw material drug solution storage tank; take 2.5 L of isopropyl ether and place it in the anti-solvent storage tank;

[0078] 2) Pass the raw material drug solution and isopropyl ether into the microchannel reactor through the first peristaltic pump and the second peristaltic pump respectively. The flow rate of the raw material drug solution in the first peristaltic pump is 3

[0079] mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump is 55 mL / min. After the two are mixed in the microchannel reactor, recrystallization is carried out at 35 °C to obtain a methylprednisolone acetate slurry;

[0080] 3) Filter, wash, and dry the methylprednisolone acetate slurry obtained by the above recrystallization to obtain 9.08 g of methylprednisolone acetate, and the yield is 90.8%.

[0081] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of methylprednisolone acetate obtained was 6.061 μm, and D90 was 14.051 μm.

[0082] Examples 1 - 7

[0083] A method for preparing methylprednisolone acetate with a specific particle size includes the following steps:

[0084] 1) Take 10 g of methylprednisolone acetate and dissolve it in 60 mL of a DMF / acetonitrile / tetrahydrofuran mixed solution with a volume ratio of 1:1:1 to prepare a raw material solution of methylprednisolone acetate, and place it in a raw material solution storage tank; take 1 L of methyl tert-butyl ether and place it in an antisolvent storage tank;

[0085] 2) Pass the raw material solution and methyl tert-butyl ether into the microchannel reactor simultaneously through a first peristaltic pump and a second peristaltic pump respectively. The flow rate of the raw material solution in the first peristaltic pump is 4.5 mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump is 58 mL / min. After the two are mixed in the microchannel reactor, recrystallization is carried out at 38 °C to obtain a methylprednisolone acetate slurry;

[0086] 3) Filter, wash, and dry the methylprednisolone acetate slurry obtained by the above recrystallization to obtain 9.28 g of methylprednisolone acetate, and the yield is 92.8%.

[0087] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of methylprednisolone acetate obtained was 6.712 μm, and D90 was 12.893 μm.

[0088] Examples 1 - 8

[0089] The difference between this example and Examples 1 - 3 is that the organic solvent used to dissolve methylprednisolone acetate is 100 mL of a DMF / acetonitrile / tetrahydrofuran mixed solution with a volume ratio of 1:3:8, and the other conditions are the same. 9.45 g of methylprednisolone acetate is obtained, and the yield is 94.5%.

[0090] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of methylprednisolone acetate obtained was 6.747 μm, and D90 was 11.615 μm.

[0091] Examples 1 - 9

[0092] The difference between this example and Examples 1 - 3 is that the organic solvent used to dissolve methylprednisolone acetate is 100 mL of a DMF / acetonitrile / tetrahydrofuran mixed solution with a volume ratio of 5:0.5:3, and the other conditions are the same. 9.38 g of methylprednisolone acetate is obtained, and the yield is 93.8%.

[0093] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of methylprednisolone acetate was 7.043 μm and the D90 was 12.882 μm.

[0094] Examples 1 - 10

[0095] The difference between this example and Examples 1 - 3 is that the organic solvent used to dissolve methylprednisolone acetate is 100 mL of a DMF / acetonitrile / tetrahydrofuran mixed solution with a volume ratio of 3:2:5. The other conditions are the same, and 9.47 g of methylprednisolone acetate is obtained with a yield of 94.7%.

[0096] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000, as Figure 1 shown. The D50 of methylprednisolone acetate was 6.286 μm and the D90 was 12.097 μm. The scanning electron micrograph is as Figure 2 shown, showing a uniform particle distribution and no agglomeration.

[0097] Examples 1 - 11

[0098] The difference between this example and Examples 1 - 3 is that the organic solvent used to dissolve methylprednisolone acetate is 100 mL of DMF. The other conditions are the same, and 8.56 g of methylprednisolone acetate is obtained with a yield of 85.6%.

[0099] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of methylprednisolone acetate was 7.145 μm and the D90 was 14.772 μm.

[0100] Examples 1 - 12

[0101] The difference between this example and Examples 1 - 3 is that the organic solvent used to dissolve methylprednisolone acetate is 100 mL of acetonitrile. The other conditions are the same, and 9.05 g of methylprednisolone acetate is obtained with a yield of 90.5%.

[0102] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of methylprednisolone acetate was 7.006 μm and the D90 was 14.083 μm.

[0103] Examples 1 - 13

[0104] The difference between this example and Examples 1 - 3 is that the organic solvent used to dissolve methylprednisolone acetate is 100 mL of a DMF / acetonitrile / tetrahydrofuran mixed solution with a volume ratio of 1:1:1. The other conditions are the same, and 9.27 g of methylprednisolone acetate is obtained with a yield of 92.7%.

[0105] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of the methylprednisolone acetate particles obtained was 6.898 μm, and the D90 was 13.457 μm.

[0106] Example 1-14

[0107] The difference between this example and Examples 1-3 is that the flow rate of the API solution in the first peristaltic pump was 3.5 mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump was 60 mL / min. The other conditions were the same. 9.42 g of methylprednisolone acetate was obtained, and the yield was 94.2%.

[0108] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of the methylprednisolone acetate particles obtained was 6.834 μm, and the D90 was 11.985 μm.

[0109] Example 1-15

[0110] The difference between this example and Examples 1-3 is that the flow rate of the API solution in the first peristaltic pump was 5 mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump was 55 mL / min. The other conditions were the same. 9.36 g of methylprednisolone acetate was obtained, and the yield was 93.6%.

[0111] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of the methylprednisolone acetate particles obtained was 7.052 μm, and the D90 was 12.343 μm.

[0112] Example 1-16

[0113] The difference between this example and Examples 1-3 is that 6.5 L of methyl tert-butyl ether was placed in the antisolvent storage tank; the flow rate of the API solution in the first peristaltic pump was 1

[0114] mL / min, and the flow rate of methyl tert-butyl ether in the second peristaltic pump was 60 mL / min. The other conditions were the same. 9.04 g of methylprednisolone acetate was obtained, and the yield was 90.4%.

[0115] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of the methylprednisolone acetate particles obtained was 3.778 μm, and the D90 was 9.442 μm.

[0116] Example 1-17

[0117] This example is different from Examples 1 - 3 in that 3 L of methyl tert - butyl ether is placed in the antisolvent storage tank; the flow rate of the API solution in the first peristaltic pump is 2 mL / min, and the flow rate of methyl tert - butyl ether in the second peristaltic pump is 55 mL / min. Under the same other conditions, 9.01 g of methylprednisolone acetate is obtained, and the yield is 90.1%.

[0118] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of the obtained methylprednisolone acetate was 4.118 μm, and D90 was 9.869 μm.

[0119] Comparative Example 1

[0120] This comparative example is different from Examples 1 - 3 in that 8.5 L of methyl tert - butyl ether is placed in the antisolvent storage tank; the flow rate of the API solution in the first peristaltic pump is 1 mL / min, and the flow rate of methyl tert - butyl ether in the second peristaltic pump is 80 mL / min. Under the same other conditions, 9.51 g of methylprednisolone acetate is obtained, and the yield is 95.1%.

[0121] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of the obtained methylprednisolone acetate was 2.453 μm, and D90 was 4.109 μm.

[0122] Comparative Example 2

[0123] This comparative example is different from Examples 1 - 3 in that the flow rate of the API solution in the first peristaltic pump is 1 mL / min, and the flow rate of methyl tert - butyl ether in the second peristaltic pump is 10 mL / min. Under the same other conditions, 8.54 g of methylprednisolone acetate is obtained, and the yield is 85.4%.

[0124] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of the obtained methylprednisolone acetate was 1.363 μm, and D90 was 4.168 μm.

[0125] Comparative Example 3

[0126] This comparative example is different from Examples 1 - 3 in that the organic solvent used to dissolve methylprednisolone acetate is 100 mL of methanol. Under the same other conditions, 9.01 g of methylprednisolone acetate is obtained, and the yield is 90.1%.

[0127] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The particle size D50 of the obtained methylprednisolone acetate was 2.314 μm, and D90 was 5.023 μm.

[0128] Comparative Example 4

[0129] The difference between this comparative example and Examples 1-3 is that the organic solvent used to dissolve methylprednisolone acetate is 100 mL of acetone, and the other conditions are the same. 8.71 g of methylprednisolone acetate is obtained, and the yield is 87.1%.

[0130] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of the obtained methylprednisolone acetate was 1.345 μm, and the D90 was 4.787 μm.

[0131] Comparative Example 5

[0132] The difference between this comparative example and Examples 1-3 is that the organic solvent used to dissolve methylprednisolone acetate is 100 mL of dichloromethane, and the other conditions are the same. 8.53 g of methylprednisolone acetate is obtained, and the yield is 85.3%.

[0133] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of the obtained methylprednisolone acetate was 1.542 μm, and the D90 was 4.657 μm.

[0134] Comparative Example 6

[0135] Take 200 g of methylprednisolone acetate raw material and add it to a jet mill. The feeding speed is 0.5 kg / h, and the pulverizing air flow is 1.0 MPa. Under the above conditions, it is pulverized 3 times.

[0136] The particle size distribution was automatically measured by a Malvern laser particle size analyzer MS2000. The D50 of the obtained methylprednisolone acetate was 6.531 μm, and the D90 was 12.114 μm. After being placed for 24 months in the stability test, the scanning electron micrograph is as Figure 3 shown. The figure shows that the particle distribution is non-uniform and serious agglomeration has occurred.

[0137] Test Example 1 Raw Material Stability Test

[0138] The methylprednisolone acetate prepared in Examples 1-3, Examples 8-10 and the methylprednisolone acetate prepared in Comparative Examples 1-6 were placed at a temperature of 25°C ± 2°C and a humidity of 60% RH ± 5% RH for 24 months. The particle size, content and microbial limit at 0, 3, 6, 18 and 24 months were measured respectively. The measurement results are shown in Table 1.

[0139] Table 1 Raw Material Stability Test

[0140]

[0141]

[0142]

[0143] As can be seen from the data in the table, for the methylprednisolone acetate prepared in Examples 1-3 and Examples 8-10 of the present invention, compared with the content at 0 hour during long-term storage, there is no obvious change; the particle size has a tendency to increase, but the change is not obvious; the sterility test meets the standards. For the methylprednisolone acetate prepared in Examples 4-7 and Examples 11-17 of the present invention, during the long-term stability investigation, it has similar effects to the above-mentioned examples and will not be elaborated here.

[0144] For the methylprednisolone acetate prepared in Comparative Examples 1-4, compared with the content at 0 hour during long-term storage, the content decreases significantly; the particle size increases significantly and there is an agglomeration phenomenon; the sterility test meets the standards. For the methylprednisolone acetate prepared in Comparative Example 5, compared with the content at 0 hour during long-term storage, the content decreases significantly; the particle size increases significantly and there is an agglomeration phenomenon; the sterility test does not meet the standards.

[0145] Experimental Example II Preparation Stability Test

[0146] According to the information provided in the specification, the prescription of the methylprednisolone acetate suspension injection is as follows:

[0147] Each milliliter contains: 20 mg of methylprednisolone acetate, 29.5 mg of polyethylene glycol 3350, 1.97 mg of polysorbate 80, 6.9 mg of sodium dihydrogen phosphate, 1.44 mg of disodium hydrogen phosphate, 9.3 mg of benzyl alcohol, adjusted to isotonic with sodium chloride, and the pH is adjusted to 3.5 - 7.0 with hydrochloric acid or sodium hydroxide.

[0148] The methylprednisolone acetate prepared in Examples 1-3 and Examples 8-10 was respectively used to prepare methylprednisolone acetate suspension injection according to the above prescription. The preparation method is as follows:

[0149] Take 80% of the total amount of water for injection and dissolve the prescription amounts of polyethylene glycol 3350, polysorbate 80, disodium hydrogen phosphate, sodium dihydrogen phosphate, and benzyl alcohol, and let it swell overnight. Then add the prescription amount of methylprednisolone acetate raw material, shear and stir at a speed of 13000 r / min for 10 min, adjust to isotonic with sodium chloride, add water for injection to a total volume of 100 L, and then shear and stir at a speed of 10000 r / min for 10 min.

[0150] The methylprednisolone acetate suspension injection prepared in each of the above groups was placed at 40°C ± 2°C and a humidity of 75% RH ± 5% RH for 3 months. Samples were taken at the end of the 0th, 1st, 2nd, and 3rd months respectively for investigation, and the measurement results are shown in Table 2.

[0151] Table 2 Preparation Stability Test

[0152]

[0153]

[0154] As can be seen from the data in the table, after methylprednisolone acetate prepared in Examples 1-3 and Examples 8-10 of the present invention was formulated into a suspension injection, during the accelerated test, compared with that at 0 hour, the content did not change significantly; the particle size had an increasing trend, but the change was not obvious; the sterility test met the standards. Therefore, methylprednisolone acetate prepared by the preparation method of the present invention is used to prepare a suspension injection, which has good stability and meets the requirements of sterile preparations.

[0155] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing methylprednisolone acetate with a specific particle size, characterized in that, It includes the following steps: (a) Dissolve methylprednisolone acetate raw material in an organic solvent to prepare a raw drug solution; the organic solvent is selected from one or a combination of DMF, acetonitrile or tetrahydrofuran; the antisolvent is selected from isopropyl ether and / or methyl tert-butyl ether; (b) Simultaneously introduce the raw drug solution and the antisolvent into a microreactor at flow rates of (1-5) mL / min and (55-60) mL / min respectively, and the two are mixed in the microreactor and recrystallized to obtain methylprednisolone acetate; The particle size of the methylprednisolone acetate is D90 = 9-15 μm and D50 = 3-8 μm; In step (b), the recrystallization temperature is 25°C - 40°C.

2. The method for preparing methylprednisolone acetate with a specific particle size according to claim 1, characterized in that, In step (a), the organic solvent is selected from a combination of DMF, acetonitrile and tetrahydrofuran.

3. The method for preparing methylprednisolone acetate with a specific particle size according to claim 2, characterized in that, In step (a), the volume ratio of DMF, acetonitrile and tetrahydrofuran in the organic solvent is (1-5):(0.5-3):(3-8).

4. The method for preparing methylprednisolone acetate with a specific particle size according to claim 1, characterized in that, In step (b), the raw drug solution and the antisolvent are simultaneously introduced into the microreactor at flow rates of (3.5-5) mL / min and (55-60) mL / min respectively.

5. The method for preparing methylprednisolone acetate with a specific particle size according to claim 1, characterized in that: In step (a), the mass-volume ratio of the methylprednisolone acetate raw material to the organic solvent is 1:(5-15) g / mL.

6. The method for preparing methylprednisolone acetate with a specific particle size according to any one of claims 1-5, characterized in that: The particle size of the methylprednisolone acetate is D90 = 10-15 μm and D50 = 5-8 μm.

7. The method for preparing methylprednisolone acetate with a specific particle size according to claim 6, characterized in that: The particle size of the methylprednisolone acetate is D90 = 10-13 μm and D50 = 6-8 μm.

Images