Efiniprofen crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to an iflurprofen crystal form and a preparation method thereof, and the iflurprofen crystal form is characterized by XRPD (X-Ray Powder Diffraction) and DSC (Differential Scanning Calorimetry). The purity and chiral purity of the crystal form of Efiniprofen provided by the invention are not obviously changed under the conditions of high temperature, high humidity and intense illumination, the crystal form is not converted, and the crystal form has good stability and can form a regular crystal form state, so that the crystal form is beneficial to the technological treatment of drugs, the improvement of physical and chemical properties and the improvement of drug preparation properties; and the method is favorable for transportation, storage and development and utilization of medicinal preparations, and is relatively good in medicinal property, high in yield, simple to operate and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to an afluprofen crystal form and a preparation method thereof. Background Art

[0002] Aifenprofen is the S-enantiomer of flurbiprofen, which is a nonsteroidal anti-inflammatory drug developed by the British company Buzzard, and is widely used in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, etc. However, the anti-inflammatory activity of flurbiprofen mainly comes from its S-enantiomer, while the R-enantiomer lacks significant cyclooxygenase inhibitory activity. The structure of its S-enantiomer is as follows:

[0003]

[0004] The crystal form of a drug can affect the physical and chemical properties of the drug and directly affect the clinical treatment effect of the drug. Therefore, the crystal form of the drug is particularly important in the process of drug development and research. At present, there is no report on the crystal form of ifluprofen at home and abroad. Therefore, it is particularly important to develop a new crystal form of ifluprofen with good medicinal properties and suitable for pharmaceutical use. Summary of the invention

[0005] The purpose of the present invention is to provide a crystalline form of ifluprofen based on the prior art.

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned fluoroquinolone crystalline form.

[0007] The third object of the present invention is to provide a pharmaceutical composition or preparation containing the above-mentioned fluoroprofen crystal form.

[0008] The technical solution of the present invention is as follows:

[0009] A crystalline form of ifluprofen, whose reflection angle 2θ of an X-ray powder diffraction spectrum has characteristic absorption peaks at 10.816±0.2, 17.330±0.2, 17.584±0.2, 21.168±0.2, 22.7295±0.2, 23.047±0.2 and 26.0967±0.2.

[0010] In a preferred embodiment, the X-ray powder diffraction pattern of the crystalline form of ifluprofen provided by the present invention is as follows: Figure 1 For example, the reflection angle 2θ of its X-ray powder diffraction spectrum has characteristic absorption peaks at 10.816, 17.330, 17.584, 21.168, 22.7295, 23.047, and 26.0967.

[0011] The afluprofen crystal form provided by the present invention has an endothermic peak at 110-112°C.

[0012] In a preferred embodiment, the DSC spectrum of the crystalline form of ifluprofen provided by the present invention is as follows: Figure 2 As shown, there is an endothermic peak at 110.85°C.

[0013] The invention provides a method for preparing a crystalline form of iflorfen, comprising the following steps: stirring iflorfen and a solvent A at 45-50°C until dissolved, dripping a solvent B into the obtained mixed solution, stirring and crystallizing at 35-45°C for 20-60min after the dripping is completed, cooling to -5-15°C, keeping warm and stirring, filtering, washing, and drying to obtain the crystalline form of iflorfen.

[0014] In the present invention, solvent A is methanol, ethanol, isopropanol, acetone, ethyl acetate or methyl tert-butyl ether, preferably methanol, isopropanol or methyl tert-butyl ether.

[0015] In a preferred embodiment, the mass ratio of iflorfen to solvent A is 1:0.5-3, and may be but not limited to 1:0.5, 1:1, 1:1.5, 1:2 or 1:3. More preferably, the mass ratio of iflorfen to solvent A is 1:0.5-1.

[0016] In the present invention, solvent B is water, n-hexane, n-heptane, toluene, petroleum ether or cyclohexane, preferably water, n-heptane or toluene.

[0017] In a preferred embodiment, the mass ratio of iflorfen to solvent B is 1:1-5, and may be but not limited to 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4 or 1:5. More preferably, the mass ratio of iflorfen to solvent B is 1:1.5-3.

[0018] It is well known to those skilled in the art that when preparing a crystal form, the type of crystallization solvent or the crystallization temperature has a significant effect on the crystal form of the target substance produced. By adjusting the type and temperature of the solvent, it is easy to prepare a new crystal form. When preparing the crystal form of iflorfen, the present invention strictly controls the temperature of raw material dissolution, mixing and crystallization, dissolves iflorfen in an organic solvent at a relatively low temperature, and strictly controls the temperature of stirring and crystallization after adding solvent B dropwise, thereby obtaining an iflorfen crystal form, wherein the purity and chiral purity do not change significantly under high temperature, high humidity and strong light conditions, and the crystal form does not undergo transformation, has good stability, can form a regular crystal form, and is therefore beneficial to the process treatment of the drug, the improvement of the physicochemical properties and the improvement of the drug properties, and is also beneficial to the development and utilization of transportation, storage and pharmaceutical preparations, has good medicinal properties, high yield, simple operation, and is suitable for industrial production.

[0019] In the present invention, after the dropwise addition is completed, the mixture is stirred and crystallized at 35-45°C for 20-60 minutes, and then cooled to -5-15°C and kept stirred. The stirring and crystallization time can be but is not limited to 20 minutes, 30 minutes, 40 minutes or 60 minutes. Preferably, the stirring and crystallization time is 30 minutes.

[0020] Further, the temperature is lowered to 0-10°C and stirred for 1-2 hours.

[0021] Furthermore, the drying method is air drying.

[0022] The present invention provides a pharmaceutical composition, which comprises afluprofen crystal form as an active ingredient or a main active ingredient, and pharmaceutically acceptable excipients.

[0023] The present invention also relates to a preparation, characterized in that it contains an effective dose of the crystalline form of ifluprofen.

[0024] Adopt the technical scheme of the present invention, the advantages are as follows:

[0025] The invention provides an ifluprofen crystal form, wherein the purity and chiral purity do not undergo obvious changes under high temperature, high humidity and strong light conditions, and the crystal form does not undergo transformation, the crystal form has good stability, and can form a regular crystal form, thereby being beneficial to the process treatment of drugs, improving the physicochemical properties and the performance of finished drugs, and also beneficial to the transportation, storage and development and utilization of drug preparations, having good medicinal properties, high yield, simple operation and being suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the XRPD pattern of the crystalline form of ifluprofen prepared in Example 1;

[0027] Figure 2 The DSC graph of the crystalline form of ifluprofen prepared in Example 1;

[0028] Figure 3 This is the XRPD pattern of the crystalline form of iflorfen prepared in Example 1 after 6 months of acceleration. DETAILED DESCRIPTION

[0029] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0030] Example 1

[0031] Add 1kg of ifluprofen and 500g of isopropanol to a 5L kettle, stir and heat to 45-50°C, stir and dissolve, add 1.5kg of purified water to the kettle, and after the addition is complete, keep warm and stir at 35-45°C for 30 minutes to crystallize, then cool to 0-10°C and keep warm and stir for 1-2 hours, filter, and wash the obtained filter cake with a mixed solution of isopropanol and purified water in a volume ratio of 1:3, and air dry to obtain 970g of crystalline solid, with a yield of 97%. Among them, the XRPD spectrum is shown in Figure 1 , DSC spectrum see Figure 2 .

[0032] Example 2

[0033] Add 1kg of ifluprofen and 500g of methanol to a 5L kettle, stir and heat to 45-50°C, stir and dissolve, add 1.5kg of purified water to the kettle, and after the addition is complete, keep warm and stir at 35-45°C for 30 minutes to crystallize, then cool to 0-10°C and keep warm and stir for 1-2 hours, filter, and wash the obtained filter cake with a mixed solution of methanol and purified water in a volume ratio of 1:3, and air dry to obtain 880g of crystalline solid, with a yield of 88%. XRPD spectrum and Figure 1 Basically the same.

[0034] Example 3

[0035] Add 1kg of ifluprofen and 500g of methanol to a 5L kettle, stir and heat to 45-50°C, stir and dissolve, add 3kg of toluene to the kettle, and after the addition is complete, keep warm and stir at 35-45°C for 30 minutes to crystallize, then cool to 0-10°C and keep warm and stir for 1-2 hours, filter, and wash the obtained filter cake with a mixed solution of methanol and toluene in a volume ratio of 1:6, and air dry to obtain 790g of crystalline solid, with a yield of 79%. XRPD spectrum and Figure 1 Basically the same.

[0036] Example 4

[0037] Add 1kg of ifluprofen and 1kg of methyl tert-butyl ether to a 5L kettle, stir and heat to 45-50°C, stir and dissolve, add 2kg of toluene to the kettle, and after the addition is complete, keep warm and stir at 35-45°C for 30 minutes to crystallize, then cool to 0-10°C and keep warm and stir for 1-2 hours, filter, and wash the obtained filter cake with a mixed solution of methyl tert-butyl ether and toluene in a volume ratio of 1:2, and air dry to obtain 970g of crystalline solid, with a yield of 97%. XRPD spectrum and Figure 1 Basically the same.

[0038] Example 5

[0039] Add 1kg of ifluprofen and 500g of isopropanol to a 5L kettle, stir and heat to 45-50°C, stir and dissolve, add 1.5kg of n-heptane to the kettle, and after the addition is complete, keep warm and stir at 35-45°C for 30 minutes to crystallize, then cool to 0-10°C and keep warm and stir for 1-2 hours, filter, and wash the filter cake with a mixed solution of isopropanol and n-heptane in a volume ratio of 1:3, and air dry to obtain 950g of crystalline solid, with a yield of 95%. XRPD spectrum and Figure 1 Basically the same.

[0040] The influencing factors and accelerated experiments were conducted on the crystalline form of ifluprofen obtained in Example 1. The experimental method was based on Appendix 2 XIXC "Guidelines for the Pharmacological Properties of APIs and Pharmaceutical Preparations" of the Chinese Pharmacopoeia (2015).

[0041] (I) Test of influencing factors

[0042] a. High temperature test: The crystalline form of ifluprofen prepared in Example 1 was placed at 60°C for 10 days, samples were taken on the 5th and 10th days, and various indicators were measured and compared with those on the 0th day. The test results are shown in Table 1.

[0043] b. High humidity test: The ioprofen crystal prepared in Example 1 was placed at a humidity of 75% for 10 days. Samples were taken on the 5th and 10th days, and various indicators were measured and compared with those on the 0th day. The test results are shown in Table 1.

[0044] c. Strong light test: The ioprofen crystal prepared in Example 1 was placed under light of (4500±500) Lux for 10 days, samples were taken on the 5th and 10th days, and various indicators were measured and compared with those on day 0. The test results are shown in Table 1.

[0045] Table 1 Test results of influencing factors

[0046]

[0047] (II) Accelerated Pharmacological Test

[0048] The crystalline form of ifluprofen prepared in Example 1 was subjected to an accelerated pharmaceutical test in a constant temperature and humidity chamber for 6 months. Test conditions: temperature 40°C / 75% relative humidity. Samples were taken at 0, 1, 2, 3, and 6 months for purity, isomers, and XRPD testing.

[0049] Table 2 Accelerated medicinal properties test results

[0050]

[0051] It can be seen from the above-mentioned influencing factor test and accelerated test that the purity and chiral purity of the ifluprofen crystal form of the present invention do not change significantly under high temperature, high humidity and strong light conditions, and the crystal form does not undergo transformation, and the stability is good. The accelerated medicinal property test proves that the product quality has good medicinal properties.

[0052] In summary, the iflorfen crystal form of the present invention has good medicinal properties, high product quality, is conducive to transportation, storage and development and utilization of pharmaceutical preparations, has high yield, is simple to operate, and is suitable for industrial production.

[0053] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A crystalline form of ifluprofen, characterized in that: The reflection angle 2θ of its X-ray powder diffraction spectrum has characteristic absorption peaks at 10.816±0.2, 17.330±0.2, 17.584±0.2, 21.168±0.2, 22.7295±0.2, 23.047±0.2, and 26.0967±0.

2.

2. The crystalline form of ifluprofen according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystalline form of ifluprofen is shown in FIG1 .

3. The crystalline form of ifluprofen according to claim 1 or 2, characterized in that: The afluprofen crystal form has an endothermic peak at 110-112°C.

4. The crystalline form of ifluprofen according to claim 3, characterized in that: The afluprofen crystal form has an endothermic peak at 110.85°C.

5. A method for preparing the crystalline form of iflorfen according to claim 1, characterized in that: The method comprises the following steps: stirring iflorfen and solvent A at 45-50°C until dissolved, dripping solvent B into the obtained mixed solution, stirring and crystallizing at 35-45°C for 20-60min after the dripping is completed, cooling to -5-15°C, keeping warm and stirring, filtering, washing and drying to obtain iflorfen crystal form.

6. The method for preparing the crystalline form of iflorfen according to claim 5, characterized in that: The solvent A is methanol, ethanol, isopropanol, acetone, ethyl acetate or methyl tert-butyl ether, preferably methanol, isopropanol or methyl tert-butyl ether; the mass ratio of ifluprofen to solvent A is 1:0.5-3, preferably 1:0.5-1.

7. The method for preparing the crystalline form of iflorfen according to claim 5, characterized in that: The solvent B is water, n-hexane, n-heptane, toluene, petroleum ether or cyclohexane, preferably water, n-heptane or toluene; the mass ratio of ifluprofen to solvent B is 1:1-5, preferably 1:1.5-3.

8. The method for preparing the crystalline form of iflorfen according to claim 5, characterized in that: The stirring crystallization time is 30 minutes; then the temperature is lowered to 0-10°C and kept stirring for 1-2 hours; the drying method is air drying.

9. A pharmaceutical composition, characterized in that The composition comprises afluprofen crystal form as an active ingredient or a main active ingredient, and pharmaceutically acceptable auxiliary materials.

10. A preparation characterized in that The invention comprises an effective amount of crystalline form of ifluprofen.

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