Preparation method of amorphous imrecoxib and application of amorphous imrecoxib in preparation

Abstract

The invention relates to the technical field of medicine preparation, and particularly discloses a preparation method of amorphous imrecoxib. The preparation method of the amorphous imrecoxib comprises the following steps: (1) dissolving imrecoxib in any crystal form in a mixed solution of a benign solvent and an inert solvent in a certain proportion, and heating for dissolving until the imrecoxib is clear; (2) cooling to 55-60 DEG C, keeping the system clear, and adding a proper amount of inert solvent in a non-devitrification state; and (3) adjusting the stirring speed of the system to 1000-1200 revolutions per minute, rapidly cooling to 5-10 DEG C, stirring and crystallizing for 2 hours, carrying out suction filtration, and carrying out vacuum drying at 40-50 DEG C to obtain the amorphous imrecoxib. The prepared amorphous imrecoxib has the advantages of good solubility, fluidity, good filtering property and high stability, and is suitable for being applied to an imrecoxib preparation to solve the technical problems of low solubility and low oral bioavailability of an imrecoxib I-type crystal.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and particularly relates to a preparation method of amorphous ixabepilone and its application in preparations. Background Art

[0002] There are two subtypes of cyclooxygenase isoenzymes: cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). Cyclooxygenase 1 is a constitutive enzyme present in normal tissues, and its physiological function is to catalyze the oxidation of arachidonic acid into prostaglandins, maintaining the protective function of the gastrointestinal mucosa and normal kidney function; cyclooxygenase 2 is an inducible enzyme, which is generated by stimulating cells with endotoxins, cytokines or hormones, etc., and can catalyze the production of prostaglandins to cause inflammation. Currently, a variety of non-steroidal anti-inflammatory drugs can inhibit the actions of both of these enzymes. While inhibiting cyclooxygenase 2, they also inhibit cyclooxygenase 1. Therefore, when taking these drugs for a long time to treat chronic inflammation, it will cause gastrointestinal and kidney damage. Selective COX-2 inhibitors only have anti-inflammatory, analgesic and antipyretic effects, and do not have toxic and side effects on the gastrointestinal tract and kidneys. Currently, the marketed selective COX-2 inhibitors include celecoxib and ixabepilone.

[0003] Ixabepilone was originally developed by Jiangsu Hengrui Medicine Co., Ltd. and was approved for domestic listing on May 20, 2011, with the trade name Hengyang. It is a selective COX-2 inhibitor, and the approved indication is to relieve the pain symptoms of osteoarthritis. The specification is 100 mg / tablet, and the recommended dose is 2 times a day, 100 mg each time.

[0004] Patent ZL00105899.1 discloses the chemical structure formula of ixabepilone, and its chemical structure formula is as follows: ; The chemical name of ixabepilone is: N-n-propyl-3-(4-methylphenyl)-4-(4-methylsulfonylphenyl)-2,5-dihydropyrrol-2-one, and it is a white powdery solid.

[0005] To date, only one patent has publicly reported on research on the crystal forms of erlotinib: CN101774958 discloses a method for preparing a crystalline form of erlotinib. The method involves dissolving erlotinib solid in any crystalline form by heating in an appropriate amount of an organic solvent selected from methanol, ethanol, isopropanol, or an aqueous solution thereof, followed by slow cooling to crystallize, thereby obtaining erlotinib Form I crystals. erlotinib is a poorly soluble drug, classified as a Class II drug in the Biopharmaceutical Classification System (BCS), meaning it has low solubility and high permeability, resulting in poor oral absorption. It is well known to those skilled in the art that the crystal structure of a pharmaceutically active compound often affects the long-term stability of the drug and the bioavailability of the resulting formulation. Crystalline compounds have higher stability than amorphous compounds, but lower solubility. For poorly soluble drugs, preparing the active ingredient in an amorphous form to improve the bioavailability of the formulation is a new approach to enhancing the oral bioavailability of poorly soluble drugs.

[0006] Amorphous forms lack a regular crystal structure, generally have finer particle sizes, are difficult to filter, and exhibit poor fluidity. Optimizing the refining process to produce amorphous erlotoxib API with stable quality and excellent fluidity, and applying this to formulations to address the low oral bioavailability of erlotoxib, remains an unresolved technical challenge. Our company, through optimization of the erlotoxib crystallization process, aims to provide an industrialized method for preparing amorphous erlotoxib API with stable quality and excellent fluidity, addressing the existing shortcomings of the low solubility of erlotoxib type I crystals and the resulting low bioavailability of oral solid formulations. Summary of the Invention

[0007] To address the problems of poor solubility of existing Type I crystals of the irelcoxib API and low bioavailability of the resulting formulations, the present invention aims to provide an industrialized method for preparing an amorphous irelcoxib API with stable quality and excellent fluidity, thereby overcoming the existing shortcomings of the irelcoxib Type I crystals and the low bioavailability of the resulting oral solid formulations. Compared to the existing technology, the amorphous irelcoxib prepared by the technical features of the present invention has significant advantages such as stable quality, good fluidity, and good solubility, and has commercial application value.

[0008] In order to achieve the above-mentioned objectives, the present invention adopts the following technical solutions: (1) dissolving any crystalline form of erlotinib in a mixed solution of a benign solvent and an inert solvent in a certain proportion, and heating to dissolve; (2) Cool down to 55-60°C, keep the system clear, and add an appropriate amount of inert solvent before crystallization; (3) Adjust the stirring speed of the system to 1000-1200 rpm, quickly cool to 5-10°C, stir and crystallize for 2 h, filter, and vacuum dry at 40-50°C to obtain amorphous erlotinib.

[0009] In the above technical solution, in step (1), the good solvent is selected from one or a mixture of two of DMF, DMAC, ethylene glycol, propylene glycol, and butylene glycol, and the inert solvent is one or a mixture of two of water, isopropyl ether, and petroleum ether; the ratio of the good solvent to the inert solvent is 1:0.2 to 1:0.5; the amount of the mixed solution is 15:1 to 20:1 by weight of etoricoxib.

[0010] In step (2), the added inert solvent is one or a mixture of two of water, isopropyl ether, and petroleum ether, and the amount of the added inert solvent or solvent mixture is 10:1 to 15:1 by weight of etoricoxib.

[0011] In step (3), the stirring speed is 1000 to 1200 revolutions per minute, and while maintaining a rapid stirring state, it is rapidly cooled to 5 to 10 °C.

[0012] Compared with the prior art, the present invention provides a method for preparing amorphous etoricoxib with stable quality, good fluidity, and good solubility. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 It is the X-ray powder diffraction pattern of the amorphous etoricoxib prepared in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0014] In order to make the technical problems, technical solutions and beneficial effects solved by the present invention clearer, the present invention will be further described in detail below with reference to the embodiments, but it is not a limitation to the present invention. Any equivalent replacement in the art based on the disclosed content of the present invention belongs to the protection scope of the present invention.

[0015] Example 1 10 g of etoricoxib type I crystal solid was added to a three-necked flask, and then 200 ml of a DMF-water (1:0.5) mixed solution was added. The reaction solution was heated to 80 - 85 °C until the system became clear. The stirring speed was adjusted to 1000 revolutions per minute, and the temperature was lowered to 55 - 60 °C while maintaining the clarity of the system. 100 ml of the inert solvent water was added, and the reaction solution was rapidly cooled to 5 - 10 °C. The system became turbid and a large amount of powdery solid was precipitated. Crystallization was carried out at 5 - 10 °C for 2 h, followed by suction filtration and vacuum drying at 40 - 50 °C to obtain amorphous etoricoxib.

[0016] Examples 2 to 11 Add 10 g of the solid of etoricoxib type I crystals into a three-necked flask, and then add a certain proportion of Solvent 1 (a mixed solvent of a good solvent and an inert solvent). Heat the reaction solution to 80 - 85 °C until the system becomes clear. Adjust the stirring speed to 1200 revolutions per minute, cool down to 55 - 60 °C, and keep the system clear. Add Solvent 2 (an inert solvent), and quickly cool the reaction solution to 5 - 10 °C. The system becomes turbid and a large amount of powdery solid precipitates. Keep the crystallization at 5 - 10 °C for 2 h, then perform suction filtration, and dry it under vacuum at 40 - 50 °C to obtain etoricoxib. The detailed information of the solvents and solvent ratios in Examples 2 - 11 is shown in Table 1.

[0017] Table 1 Summary Table of Detailed Information of Solvent Ratio / Solvent Amount 。

[0018] The test results of the flowability parameters of the amorphous etoricoxib prepared in Examples 1 - 11 are summarized in Table 2.

[0019] Table 2 Summary Table of Flowability Test Results of Amorphous Etoricoxib Prepared in Examples 1 - 11 。

[0020] The evaluation indexes of powder flowability are as follows in Table 3.

[0021] Table 3 Evaluation Indexes of Powder Flow Characteristics 。

[0022] It can be seen from the test results of the flowability evaluation indexes in Table 2 and the flowability evaluation criteria that the amorphous etoricoxib prepared in Examples 1 - 11 has good flowability and can meet the process requirements.

[0023] Comparative Example 2 Use the amorphous etoricoxib and the solid of etoricoxib type I crystals prepared in Example 1, seal them with a double-layer PE bag, and package the outer layer with a composite film bag. Place them under accelerated conditions (40 ± 2 °C, 75% ± 5% RH) for 6 months, and the stability test results are shown in Table 4.

[0024] Table 4 Summary Table of Accelerated Stability Test Results of Amorphous and Type I Crystals 。

[0025] It can be seen from the above table that the amorphous etoricoxib prepared in the example is packaged with a double-layer PE bag + composite film bag, and has comparable stability properties to etoricoxib crystal form I, and can be used in the preparation.

[0026] Comparative Example 3 Respectively use the amorphous etoricoxib prepared in Example 1 and the etoricoxib type I crystal raw material medicine, and prepare 1000 etoricoxib tablets by granulation, tabletting, and coating according to the following prescription ratio.

[0027] Table 5 Prescription Ratio of Parecoxib Tablets 。

[0028] The following method was used to test the dissolution of tablets prepared from amorphous parecoxib and parecoxib Form I crystals in a standard medium.

[0029] According to the dissolution and release determination method: Necessary debugging was carried out on the instrument device. Separately measure 1000 ml of 0.1 mol / L hydrochloric acid solution (containing 1% sodium dodecyl sulfate) after degassing as the dissolution medium, place it in each dissolution cup, turn on the power of the dissolution apparatus, turn on the circulation pump, set the heating temperature to 37°C ± 0.5°C, and after the temperature reaches the set temperature, put 12 test samples, rotate at 50 revolutions per minute, and take samples at 5 min, 10 min, 20 min, 30 min, and 45 min respectively to measure the cumulative dissolution.

[0030] The results are summarized in the following table. Table 6 Summary Table of Dissolution Curves of Tablets Prepared from Different Crystal Forms in Standard Medium 。

[0031] As can be seen from the above table, the dissolution and release of tablets prepared from amorphous parecoxib are significantly better than those of tablets prepared from Form I crystals in vitro.

Claims

1. A preparation method of amorphous etoricoxib, characterized in that, It includes the following steps: (1) Dissolve ariceptib in any crystal form in a mixed solvent of a certain proportion of a benign solvent and an inert solvent, heat it to 80 - 85 °C until the system becomes clear; (2) Adjust the stirring speed of the system to 1000 - 1200 revolutions per minute, cool it down to 55 - 60 °C, keep the system clear, and add a certain proportion of the inert solvent; (3) Rapidly cool the system to 5 - 10 °C, the reaction solution becomes turbid, a large amount of powdery solid precipitates, keep the crystallization at 5 - 10 °C for 2 h, filter by suction, and dry it under vacuum at 40 - 50 °C.

2. The method for preparing amorphous ixabepilone according to claim 1, characterized in that, In step (1), the benign solvent is any one or a mixture of two of DMF, DMAC, ethylene glycol, propylene glycol, and butylene glycol.

3. The method for preparing amorphous loxoprofen sodium according to claim 1, characterized in that, In step (1), the inert solvent is any one or a mixture of two of water, isopropyl ether, and petroleum ether.

4. The method for preparing amorphous loxoprofen sodium according to claim 1, characterized in that, In step (1), the ratio of the benign solvent to the inert solvent is 1:0.2 - 1:0.

5.

5. The method for preparing amorphous etoricoxib according to claim 1, characterized in that, In step (1), the weight ratio of the amount of the mixed solution of the benign solvent and the inert solvent to the weight of ariceptib is 15:1 - 20:

1.

6. The method for preparing amorphous loxoprofen sodium according to claim 1, characterized in that, In step (1), the weight ratio of the amount of the mixed solution of the benign solvent and the inert solvent to the weight of ariceptib is 15:1 - 20:

1.

7. The method for preparing amorphous loxoprofen sodium according to claim 1, characterized in that, In step (2), the inert solvent is any one or a mixture of two of water, isopropyl ether, and petroleum ether.

8. The method for preparing amorphous etoricoxib according to claim 1, characterized in that, In step (2), the weight ratio of the amount of the inert solvent to the weight of ariceptib is 10:1 - 15:1.

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