Crystal form of 4-phenoxybenzoic acid and preparation method thereof

Abstract

The invention relates to the technical field of crystal form research, in particular to a crystal form of 4-phenoxybenzoic acid and a preparation method thereof, the crystal form is SMeOH or SEtOH, the SMeOH has characteristic absorption peaks at the following 2 theta angles in an XRD diffraction pattern: 17.0 + / -0.3, 18.0 + / -0.3, 19.0 + / -0.3, 20.0 + / -0.3, 22.0 + / -0.3, 24.0 + / -0.3, 25.0 + / -0.3, 27.0 + / -0.3, 2.0 + / -0.3 and 29.0 + / -0.3, and the SEtOH has characteristic absorption peaks at the following 2 theta angles in an XRD diffraction pattern: 17.0 + / -0.3, 18.0 + / -0.3, 20.0 + / -0.3, 23.0 + / -0.3 and 27.0 + / -0.3. According to the 4-phenoxy benzoic acid crystal form and the preparation method thereof, the problems that a 4-phenoxy benzoic acid original crystal form is small in density, large in occupied volume and prone to electrostatic phenomena are solved, and the 4-phenoxy benzoic acid crystal form is good in stability, good in crystal particle size, easy to flow and beneficial to industrial production and preparation production.

Description

Technical Field

[0001] The invention relates to the technical field of crystal form research, and in particular to a crystal form of 4-phenoxybenzoic acid and a preparation method thereof. Background Art

[0002] Polymorphism is the phenomenon that the chemical composition of a substance is the same, but the crystal structure is different. Although each crystal form of the same substance has the same molecular composition, the arrangement of the molecules and the interaction between the molecules may be very different. The discovery of polymorphism has a long history. The earliest discovery of polymorphism of inorganic substances was in 1788, when scientists discovered that aragonite and calcite were both calcium carbonate, but their structures were different. The study of polymorphism of organic matter began in 1832, when Russian scientist Uller and others discovered that benformamide had polymorphism. In recent years, with the advancement of science and technology, more and more substances have been found to have polymorphism, and different crystal forms have completely different properties. For example, diamond, graphite, fullerene and nanotubes are all different crystal forms of carbon, showing different properties respectively. Therefore, it can be said that the different properties and characteristics of polymorphism affect the application of substances in life. Among them, the greatest impact is solid organic drugs. Drugs with the same chemical composition may exhibit different physical and chemical properties in different crystal forms, such as density, crystal morphology, hardness, melting point and solubility. As a result, polymorphism can directly affect the efficacy, bioavailability and toxic side effects of drugs, which further affects the production and preparation process of drugs. Some scholars have also studied the therapeutic effects of different glycine crystal forms on hereditary systemic rigidity in mice and found that the therapeutic effect of the γ crystal form is relatively better than that of the α crystal form. Typical polymorphic drugs also include odorless chloramphenicol, an antibiotic used for children. It has three different crystal forms and an amorphous form. The metastable B crystal form is more easily and quickly hydrolyzed by enzymes than the other two crystal forms. During the use of ritonavir produced by Abbott, the metastable crystal form I that has been on the market will be converted into the stable crystal form II. Since the solubility of the metastable crystal form is greater than that of the stable crystal form, it ultimately leads to a decrease in drug efficacy. Since polymorphism can affect the efficacy and safety of drugs, in the United States Pharmacopoeia, the crystal form has been listed as one of the quality control indicators of drugs, and my country's drug research and development has gradually listed the crystal form control of drugs as an indispensable part.

[0003] In view of the above-mentioned defects, the inventors of the present invention finally obtained the present invention after a long period of research and practice. Summary of the invention

[0004] The purpose of the present invention is to solve the problem that the original crystal form of 4-phenoxybenzoic acid has low density, occupies a large volume and is prone to static electricity, and provides a crystal form of 4-phenoxybenzoic acid and a preparation method thereof.

[0005] In order to achieve the above object, the present invention discloses a crystalline form of 4-phenoxybenzoic acid, wherein the crystalline form is S MeOH or S EtOH , the S MeOH The following 2θ angles in the XRD diffraction pattern: 17.0±0.3, 18.0±0.3, 19.0±0.3, 20.0±0.3, 22.0±0.3, 24.0±0.3, 25.0±0.3, 27.0±0.3, 2.0±0.3, 29.0±0.3 have characteristic absorption peaks, and the S EtOH The following 2θ angles in the XRD diffraction pattern: 17.0±0.3, 18.0±0.3, 20.0±0.3, 23.0±0.3, and 27.0±0.3 have characteristic absorption peaks.

[0006] The present invention also discloses a method for preparing the above-mentioned crystalline form of 4-phenoxybenzoic acid, comprising the following steps:

[0007] S1, mixing 4-phenoxybenzoic acid solid with methanol or ethanol, and stirring to dissolve;

[0008] S2, after the solution in step S1 is completely dissolved, the stirring rate is maintained, the temperature is lowered, the solution is concentrated and evaporated under reduced pressure, crystallized, filtered, washed, and dried to obtain 4-phenoxybenzoic acid.

[0009] In the step S1, the amount of 4-phenoxybenzoic acid solid used is 20 g, and the amount of methanol used is 100 to 400 mL.

[0010] In the step S1, the stirring temperature is 55° C. and the stirring speed is 300 rpm.

[0011] In step S2, the temperature is lowered to 30°C at a rate of 0.25°C / min.

[0012] In step S2, the crystal growing temperature is 5-10° C. and the crystal growing time is 1 hour.

[0013] In step S2, the drying temperature is 50-60°C.

[0014] Compared with the prior art, the beneficial effect of the present invention is that: the present invention optimizes the crystallization process of 4-phenoxybenzoic acid form I, investigates the effects of different crystallization methods and the amount of solvent on the product yield and particle size distribution, and finally determines the optimized crystallization process conditions of 4-phenoxybenzoic acid form I. After the optimization, the product particle size obtained by the crystallization process is larger and the particle size distribution is more concentrated. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is S obtained in Example 3 MeOH XRD diffraction pattern of

[0016] Figure 2 is S obtained in Example 7 EtOH XRD diffraction pattern of

[0017] Figure 3 is S obtained in Example 3 MeOH The crystal form;

[0018] Figure 4 is S obtained in Example 7 EtOH of crystal form. DETAILED DESCRIPTION

[0019] The above and other technical features and advantages of the present invention are described in more detail below in conjunction with the accompanying drawings.

[0020] 1. Solvent compound S MeOH Preparation:

[0021] Example 1

[0022] Weigh 20g of 4-phenoxybenzoic acid solid and 100mL of methanol, add them together into a 500mL single-mouth bottle, set the temperature to 55°C, stir at 300rpm to dissolve, maintain the stirring rate, cool to 30°C at a rate of 0.25°C / min after complete dissolution, concentrate under reduced pressure to evaporate 40ml of solvent, and grow crystals at 5-10°C for 1h. After filtration and washing, dry at 50-60°C to obtain 4-phenoxybenzoic acid compound S MeOH Product, yield 85%, product content 90%.

[0023] Example 2

[0024] Weigh 20g of 4-phenoxybenzoic acid solid and 200mL of methanol, add them together into a 500mL single-mouth bottle, set the temperature to 55°C, stir at 300rpm to dissolve, maintain stirring rate, cool to 30°C at a rate of 0.25°C / min after complete dissolution, evaporate 120ml of solvent under reduced pressure, and grow crystals at 5-10°C for 1h. Filter and wash, dry at 50-60°C to obtain 4-phenoxybenzoic acid compound S MeOH Product, yield 83%, product content 92%.

[0025] Example 3

[0026] Weigh 20g of 4-phenoxybenzoic acid solid and 300mL of methanol, add them together into a 500mL single-mouth bottle, set the temperature to 55°C, stir at 300rpm to dissolve, maintain the stirring rate after complete dissolution, cool to 30°C at a rate of 0.25°C / min, evaporate 250ml of solvent under reduced pressure, and grow crystals at 5-10°C for 1h. Filter and wash, then dry at 50-60°C to obtain 4-phenoxybenzoic acid compound SMeOH Product, yield 80%, product content 99%. XRD diffraction spectrum as Figure 1 shown.

[0027] Example 4

[0028] Weigh 20g of 4-phenoxybenzoic acid solid and 400mL of methanol, add them together into a 500mL single-mouth bottle, set the temperature to 55°C, stir at 300rpm to dissolve, maintain the stirring rate after complete dissolution, cool to 30°C at a rate of 0.25°C / min, evaporate 320ml of solvent under reduced pressure, and grow crystals at 5-10°C for 1h. Filter and wash, then dry at 50-60°C to obtain 4-phenoxybenzoic acid compound S MeOH Product, yield 65%, product content 99%.

[0029] 2. Solvent Compound S EtOH Preparation

[0030] Example 5

[0031] Weigh 20g of 4-phenoxybenzoic acid solid and 100mL of ethanol, add them together into a 500mL single-mouth bottle, set the temperature to 55°C, stir at 300rpm to dissolve, maintain the stirring rate after complete dissolution, cool to 30°C at a rate of 0.25°C / min, evaporate 40mL of solvent under reduced pressure, and grow crystals at 5-10°C for 1h. Filter and wash, then dry at 50-60°C to obtain 4-phenoxybenzoic acid compound S EtOH Product, yield 82%, product content 91%.

[0032] Example 6

[0033] Weigh 20g of 4-phenoxybenzoic acid solid and 200mL of ethanol, add them together into a 500mL single-mouth bottle, set the temperature to 55°C, stir at 300rpm to dissolve, maintain the stirring rate after complete dissolution, cool to 30°C at a rate of 0.25°C / min, evaporate 120mL of solvent under reduced pressure, and grow crystals at 5-10°C for 1h. Filter and wash, dry at 50-60°C to obtain 4-phenoxybenzoic acid compound S EtOH Product, yield 78%, product content 96%.

[0034] Example 7

[0035] Weigh 20g of 4-phenoxybenzoic acid solid and 300mL of ethanol, add them together into a 500mL single-mouth bottle, set the temperature to 55°C, stir at 300rpm to dissolve, and after complete dissolution, maintain the stirring rate, cool to 30°C at a rate of 0.25°C / min, evaporate 250mL of solvent under reduced pressure, and grow crystals at 5-10°C for 1h. After filtration and washing, dry at 50-60°C to obtain 4-phenoxybenzoic acid compound S EtOH The product has a yield of 75% and a product content of 98.5%. The XRD diffraction pattern is as follows Figure 2 shown.

[0036] Example 8

[0037] Weigh 20g of 4-phenoxybenzoic acid solid and 400mL of ethanol, add them together into a 500mL single-mouth bottle, set the temperature to 55°C, stir at 300rpm to dissolve, maintain the stirring rate after complete dissolution, cool to 30°C at a rate of 0.25°C / min, evaporate 320mL of solvent under reduced pressure, and grow crystals at 5-10°C for 1h. Filter and wash, dry at 50-60°C to obtain 4-phenoxybenzoic acid compound S EtOH Product, yield 64%, product content 99%.

[0038] The crystal morphology of 4-phenoxybenzoic acid polymorphs was characterized by polarizing microscopy. Figure 3 , Figure 4 As shown. Figure 3 and Figure 4 As can be seen, the solvate S MeOH and S EtOH It is a rod-shaped crystal, in which S MeOH The aspect ratio of the solvate S is the largest. MeOH The solvent-free crystalline form obtained by desolvation of the solvate basically maintains the same morphology as the solvate precursor. MeOH The crystal form I obtained after desolventization is rod-shaped, S MeOH The crystal form I obtained after desolvation is in block form, and its boundary layer is slightly blurred due to the destruction of solvent desolvation. It can be seen that the same crystal form obtained by different crystallization processes may also have different crystal habits. EtOH The crystal form II obtained after desolvation is rod-shaped, S EtOH Some of the amorphous materials obtained after precipitation are aggregated into rods, while others undergo lattice destruction and collapse into small pieces as shown in the right figure.

[0039] The above description is only a preferred embodiment of the present invention, which is only illustrative and not restrictive of the present invention. Those skilled in the art understand that many changes, modifications, and even equivalences may be made to the present invention within the spirit and scope defined by the claims of the present invention, but all of them will fall within the scope of protection of the present invention.

Claims

1. A crystalline form of 4-phenoxybenzoic acid, characterized in that: The crystal form is S MeOH or S EtOH , the S MeOH The following 2θ angles in the XRD diffraction pattern: 17.0±0.3, 18.0±0.3, 19.0±0.3, 20.0±0.3, 22.0±0.3, 24.0±0.3, 25.0±0.3, 27.0±0.3, 2.0±0.3, 29.0±0.3 have characteristic absorption peaks, and the S EtOH The following 2θ angles in the XRD diffraction pattern have characteristic absorption peaks: 17.0±0.3, 18.0±0.3, 20.0±0.3, 23.0±0.3, and 27.0±0.

3.

2. A method for preparing the crystalline form of 4-phenoxybenzoic acid as claimed in claim 1, characterized in that: The following steps are involved: S1, mixing 4-phenoxybenzoic acid solid with methanol or ethanol, and stirring to dissolve; S2, after the solution in step S1 is completely dissolved, the stirring rate is maintained, the temperature is lowered, the solution is concentrated and evaporated under reduced pressure, crystallized, filtered, washed, and dried to obtain 4-phenoxybenzoic acid.

3. The method for preparing a crystalline form of 4-phenoxybenzoic acid according to claim 2, characterized in that: In the step S1, the amount of 4-phenoxybenzoic acid solid used is 20 g, and the amount of methanol or ethanol used is 100 to 400 mL.

4. The method for preparing a crystalline form of 4-phenoxybenzoic acid according to claim 2, characterized in that: In the step S1, the stirring temperature is 55° C. and the stirring speed is 300 rpm.

5. The method for preparing a crystalline form of 4-phenoxybenzoic acid according to claim 2, characterized in that: In step S2, the temperature is lowered to 30°C at a rate of 0.25°C / min.

6. The method for preparing a crystalline form of 4-phenoxybenzoic acid according to claim 2, characterized in that: In step S2, the crystal growing temperature is 5-10° C. and the crystal growing time is 1 hour.

7. The method for preparing a crystalline form of 4-phenoxybenzoic acid according to claim 2, characterized in that: In step S2, the drying temperature is 50-60°C.

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