Novel pregabalin eutectic and preparation method thereof

Abstract

The invention discloses a novel pregabalin eutectic and a preparation method thereof. The eutectic is composed of a pregabalin-cinnamic acid (1: 1) eutectic, a pregabalin-vanillic acid (2: 1) eutectic and a pregabalin-p-toluic acid (1: 1) eutectic. The preparation method comprises multi-step solvent mediated crystallization, and high-purity (more than or equal to 99.5%) and high-yield (more than or equal to 75%) preparation of the eutectic is realized by optimizing an ethyl acetate-ethanol-water solvent system, a reaction temperature (60 DEG C) and inert gas protection conditions. In an accelerated stability test, the increase amount of the content of related substances in the obtained co-crystal within 6 months is less than or equal to 0.3%, the relative bioavailability in a Beagle model reaches 2.2 times of that of a commercially available preparation, the plasma concentration peak value (Cmax) is improved by 1.8-2.5 times, and the half-life period (t1 / 2) is prolonged to 5-7 hours. The method is mild in process condition and low in solvent residue, the clinical curative effect and medication safety of pregabalin are remarkably improved, and the method has a wide industrial application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a novel pregabalin cocrystal and a preparation method thereof. Background Art

[0002] Pregabalin is a γ-aminobutyric acid (GABA) analog. Since its launch, it has become a first-line drug for the treatment of neuropathic pain, partial epileptic seizures, and generalized anxiety disorder. Its mechanism of action is primarily through binding to the α2-δ subunit of voltage-dependent calcium channels, reducing calcium influx and thereby inhibiting the release of excitatory neurotransmitters such as glutamate and norepinephrine, resulting in analgesic, anticonvulsant, and anxiolytic effects.

[0003] In clinical applications, pregabalin has demonstrated significant efficacy and safety. For chronic pain diseases such as diabetic peripheral neuropathy and postherpetic neuralgia, its analgesic effect is better than traditional analgesics and has low addiction. In the treatment of epilepsy, pregabalin can be used as an adjuvant drug to reduce the frequency and severity of epileptic seizures. In addition, its anxiolytic effect also makes it an important treatment option for generalized anxiety disorder.

[0004] Although pregabalin has significant clinical value, its physicochemical properties limit its full therapeutic effect. Pregabalin belongs to the biopharmaceutical system (BCS) Class I drug, which has the characteristics of high solubility and high permeability. However, its short half-life and rapid metabolism lead to poor efficacy and multiple side effects, and long-term use leads to drug dependence. To improve this defect, the existing technology attempts to improve its physicochemical properties by preparing pregabalin cocrystals. However, the existing technology has the following deficiencies:

[0005] (1) The existing method for preparing pregabalin cocrystals uses high temperature and high pressure conditions or multiple recrystallizations with organic solvents, which is cumbersome and has a final yield of less than 50%, making it difficult to meet the needs of industrial production.

[0006] (2) The existing method for preparing pregabalin cocrystals uses toxic solvents such as methanol and chloroform, and the residual solvent content in the final product is close to or exceeds the ICH limit (such as methanol residue ≥0.3%), which poses a safety hazard. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the above technical defects and provide a novel pregabalin cocrystal and a preparation method thereof.

[0008] In order to solve the above problems, the technical solution of the present invention is a novel pregabalin cocrystal, comprising the following cocrystals:

[0009] Pregabalin cinnamic acid cocrystal, the pregabalin cinnamic acid cocrystal further comprising the following 2θ angles and 2θ angle relative intensity values ​​in the X-ray powder diffraction pattern: 5.2±0.2°, 9.6±0.2°, 10.2±0.2°, 11.7±0.2°, 12.3±0.2°, 12.6±0.2°, 13.8±0.2°, 14.6±0.2°, 15.4±0.2°, 15.7±0.2°, 16.8±0.2°, 17.2±0.2°, 18.6±0.2°, 19.4±0.2°, 20.6±0.2°, 21.2±0.2°, 22.3±0.2°, 23.3±0.2°, 23.6±0.2°, 24.3±0.2°, 24.7±0.2°, 25.4±0.2°, 26.4±0.2°, 26.9±0.2°, 27.3±0.2°, 27.9±0.2°, 28.7±0.2°, 29.2±0.2°, 29.8±0.2°, 30.1±0.2°, 31.5±0.2°, 32.7±0.2°, 33.9±0.2°, 34.8±0.2°, said having characteristic peaks;

[0010] Pregabalin-vanillic acid cocrystal, the pregabalin-vanillic acid cocrystal further comprises the following 2θ angles and 2θ angle relative intensity values ​​in the X-ray powder diffraction pattern: 7.3±0.2°, 9.5±0.2°, 10.3±0.2°, 11.6±0.2°, 13.0±0.2°, 14.6±0.2°, 15.9±0.2°, 16.7±0.2°, 17.3±0.2°, 18.2±0.2°, 19.1± 0.2°, 19.6±0.2°, 21.9±0.2°, 23.1±0.2°, 23.8±0.2°, 25.1±0.2°, 25.5±0.2°, 26.4±0.2°, 27.1±0.2°, 28.3±0.2°, 29.2±0.2°, 31.0±0.2°, 31.7±0.2°, 32.3±0.2°, 33.6±0.2°, said having characteristic peaks;

[0011] Pregabalin p-toluic acid cocrystal, the pregabalin p-toluic acid cocrystal further comprising the following 2θ angles and 2θ angle relative intensity values ​​in the X-ray powder diffraction pattern: 5.6±0.2°, 12.0±0.2°, 12.9±0.2°, 14.2±0.2°, 14.9±0.2°, 15.8±0.2°, 16.5±0.2°, 17.5±0.2°, 18.0±0.2°, 18.6±0.2°, 19.6±0.2°, 20.9±0.2°, 2 1.3±0.2°, 22.0±0.2°, 23.3±0.2°, 23.8±0.2°, 24.3±0.2°, 24.6±0.2°, 25.2±0.2°, 25.8±0.2°, 26.9±0.2°, 28.1±0.2°, 29.1±0.2°, 30.2±0.2°, 30.6±0.2°, 31.6±0.2°, 32.5±0.2°, 33.2±0.2°, 34.1±0.2°, which have characteristic peaks.

[0012] Furthermore, the pregabalin-cinnamic acid cocrystal has an orthorhombic crystal system and a P212121 space group. The asymmetric unit includes one pregabalin molecule and one cinnamic acid molecule, and the unit cell parameters are α / °=90, β / °=90, γ / °=90, the melting point of the pregabalin cinnamic acid eutectic is 148.0°C;

[0013] The pregabalin-vanillic acid cocrystal has a triclinic system and a P1 space group. The asymmetric unit includes two pregabalin molecules and one vanillic acid molecule. The unit cell parameters are α / °=86.3588(16), β / °=88.5344(15), γ / °=88.8594(16), the melting onset of the pregabalin-vanillic acid eutectic is 152°C;

[0014] The pregabalin-paratoluic acid cocrystal has an orthorhombic crystal system and a P212121 space group. The asymmetric unit includes a pregabalin molecule and a paratoluic acid molecule. The unit cell parameters are α / °=90, β / °=90, γ / °=90, and the melting starting point of the pregabalin-p-toluic acid eutectic is 152°C.

[0015] Furthermore, the differential scanning calorimetry analysis spectrum of the pregabalin-cinnamic acid cocrystal has a characteristic melting peak at 148°C to 153°C, the differential scanning calorimetry analysis spectrum of the pregabalin-vanillic acid cocrystal has a characteristic melting peak at 152°C to 156°C, and the differential scanning calorimetry analysis spectrum of the pregabalin-p-methylbenzoic acid cocrystal has a characteristic melting peak at 152°C to 157°C.

[0016] A novel method for preparing pregabalin cocrystal comprises the following steps:

[0017] S1. Dissolve pregabalin in ethyl acetate at a ratio of 1 g:5-15 mL, stir at room temperature for 20 minutes, heat to 60°C, add anhydrous ethanol at a ratio of 1 g:5-15 mL, and filter while hot to obtain filtrate A and filter cake A.

[0018] S2. Add anhydrous ethanol or a mixture of anhydrous ethanol and methanol to the filtrate A for washing and removing impurities. The volume ratio of the mixture to the filtrate A is 1:1 to 5:1. The mixture is allowed to stand at room temperature for 24 hours. The filtrate B and filter cake B are obtained by suction filtration. The filter cake B is vacuum dried at 40°C for 4 hours.

[0019] S3. Add 50% ethanol-water solution to filtrate B for washing and impurity removal, let stand at room temperature for 24 hours, and filter to obtain filtrate C and filter cake C;

[0020] S4. Add a eutectic former to the filtrate C at a ratio of eutectic former to ethyl acetate of 1 mL: 10-40 g, and stir at 60° C. for 3 hours to obtain a mixture D.

[0021] S5. Cool the mixture D to room temperature, add the filter cake B, the mass ratio of the mixture D to the filter cake B is 1:2-4, stir for 1 hour, and filter to obtain the filter cake D and the filtrate D;

[0022] S7. Wash the filter cake D with methanol until it becomes colorless, and dry it in vacuo at 40° C. for 4 hours to obtain pregabalin cocrystals.

[0023] Furthermore, in step S2, the volume ratio of the mixed solution of anhydrous ethanol and methanol is 1:0.5 to 1:2, and the number of washings is 2 to 3 times, and a suction filtration operation is performed after each washing. The mass concentration of pregabalin in the filtrate B is 2.9 to 9.3 g / mL.

[0024] Furthermore, in step S5, the filter cake B is added in batches, with the amount of each batch being 10% to 20% of the mass of the mixture D, and the stirring rate being 100 to 300 rpm, and the water content of the filter cake D being ≤5%.

[0025] Furthermore, all steps are carried out under the protection of an inert gas to prevent oxidation of pregabalin and its cocrystal, and the inert gas is nitrogen or argon.

[0026] Furthermore, in step S1, the volume ratio of ethyl acetate to anhydrous ethanol is 1:1 to 3:1, the heating temperature is 60°C ± 2°C, the stirring rate is 200 to 400 rpm, and the mass concentration of pregabalin in the filtrate A is 2.9 to 9.3 g / mL.

[0027] Furthermore, in step S4, the eutectic former is added dropwise at a rate of 0.5 to 2 mL / min, and nitrogen protection is continuously introduced during the reaction. The pH value of the mixture D is 4.5 to 6.5.

[0028] Furthermore, in step S6, the number of methanol washings is 3 to 5 times, the amount of methanol used in each washing is 5 to 10 times the mass of the filter cake D, the vacuum drying temperature is 40°C ± 2°C, the pressure is 0.08 to 0.1 MPa, and the purity of the pregabalin cocrystal is ≥99.5%.

[0029] The advantages of the present invention compared with the existing technology are:

[0030] 1. The present invention provides a novel pregabalin cocrystal and a method for preparing the same. The cocrystal is formed through crystal engineering to improve the solubility and intrinsic dissolution rate of pregabalin, thereby achieving sustained release of pregabalin and improving the bioavailability of pregabalin to fully exert its therapeutic effect.

[0031] 2. The present invention provides a novel pregabalin cocrystal and a method for preparing the same. By optimizing the solvent system (ethyl acetate-ethanol-water) and reaction conditions (stirring reaction at 60°C), the cocrystal is synthesized in a one-step process, with an overall yield of over 75%. Furthermore, the process conditions are mild (room temperature to 60°C), and no special equipment is required.

[0032] 3. The present invention provides a novel pregabalin cocrystal and a method for preparing the same. The solvents used are all low-toxic or non-toxic reagents (such as ethanol and water). The residual solvent content in the final product is far below the ICH limit (methanol residue ≤ 0.05%), complying with international drug safety standards. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a schematic diagram of the single crystal structure model of the pregabalin cinnamic acid cocrystal of the present invention.

[0034] Figure 2 Schematic diagram of the single crystal structure model of the pregabalin-vanillic acid cocrystal of the present invention.

[0035] Figure 3 Schematic diagram of the single crystal structure model of the pregabalin methylbenzoic acid cocrystal of the present invention.

[0036] Figure 4 It is a comparative analysis diagram of the X-ray diffraction patterns of pregabalin, cinnamic acid, and pregabalin-cinnamic acid cocrystal of the present invention.

[0037] Figure 5 It is a comparative analysis diagram of the X-ray diffraction patterns of pregabalin, vanillic acid, and pregabalin-vanillic acid cocrystal of the present invention.

[0038] Figure 6 It is a comparative analysis diagram of the X-ray diffraction patterns of pregabalin, methyl benzoic acid, and pregabalin methyl benzoic acid cocrystal of the present invention.

[0039] Figure 7 It is a comparison diagram of thermal analysis curves of pregabalin-cinnamic acid multi-component crystals of the present invention.

[0040] Figure 8 This is a comparison diagram of thermal analysis curves of pregabalin-vanillic acid multi-component crystals of the present invention.

[0041] Figure 9 It is a comparison diagram of thermal analysis curves of pregabalin-methylbenzoic acid multi-component crystals of the present invention.

[0042] Figure 10 It is a graph showing the in vitro release kinetics of pregabalin and its complex of the present invention. DETAILED DESCRIPTION

[0043] Exemplary embodiments will be described in detail herein, examples of which are illustrated in the accompanying drawings. In the following description, when referring to the drawings, identical numerals in different figures represent identical or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments are not intended to represent all embodiments consistent with the present disclosure. Rather, they are merely examples of devices consistent with certain aspects of the present disclosure, as detailed in the appended claims.

[0044] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0045] like Figures 1 to 10 As shown, this embodiment proposes a novel pregabalin cocrystal, including the following cocrystals:

[0046] Pregabalin cinnamic acid cocrystal, pregabalin cinnamic acid cocrystal also includes the following 2θ angle and 2θ angle relative intensity values ​​in the X-ray powder diffraction pattern: 5.2±0.2°, 9.6±0.2°, 10.2±0.2°, 11.7±0.2°, 12.3±0.2°, 12.6±0.2°, 13.8±0.2°, 14.6±0.2°, 15.4±0.2°, 15.7±0.2°, 16.8±0.2°, 17.2±0.2°, 18.6±0.2°, 19.4±0.2°, 20.6±0.2°, 21.2±0.2°, 22.3±0.2°, 23.3±0.2°, 23.6±0.2°, 24.3±0.2°, 24.7±0.2°, 25.4±0.2°, 26.4±0.2°, 26.9±0.2°, 27.3±0.2°, 27.9±0.2°, 28.7±0.2°, 29.2±0.2°, 29.8±0.2°, 30.1±0.2°, 31.5±0.2°, 32.7±0.2°, 33.9±0.2°, 34.8±0.2°, with characteristic peaks;

[0047] Pregabalin-vanillic acid cocrystal, pregabalin-vanillic acid cocrystal also includes the following 2θ angles and 2θ angle relative intensity values ​​in the X-ray powder diffraction pattern: 7.3±0.2°, 9.5±0.2°, 10.3±0.2°, 11.6±0.2°, 13.0±0.2°, 14.6±0.2°, 15.9±0.2°, 16.7±0.2°, 17.3±0.2°, 18.2±0.2°, 19.1± 0.2°, 19.6±0.2°, 21.9±0.2°, 23.1±0.2°, 23.8±0.2°, 25.1±0.2°, 25.5±0.2°, 26.4±0.2°, 27.1±0.2°, 28.3±0.2°, 29.2±0.2°, 31.0±0.2°, 31.7±0.2°, 32.3±0.2°, 33.6±0.2°, with characteristic peaks;

[0048] The pregabalin p-toluic acid cocrystal, the pregabalin p-toluic acid cocrystal also comprises the following 2θ angle and 2θ angle relative intensity values ​​in the X-ray powder diffraction pattern: 5.6±0.2°, 12.0±0.2°, 12.9±0.2°, 14.2±0.2°, 14.9±0.2°, 15.8±0.2°, 16.5±0.2°, 17.5±0.2°, 18.0±0.2°, 18.6±0.2°, 19.6±0.2°, 20.9±0.2°, 2 1.3±0.2°, 22.0±0.2°, 23.3±0.2°, 23.8±0.2°, 24.3±0.2°, 24.6±0.2°, 25.2±0.2°, 25.8±0.2°, 26.9±0.2°, 28.1±0.2°, 29.1±0.2°, 30.2±0.2°, 30.6±0.2°, 31.6±0.2°, 32.5±0.2°, 33.2±0.2°, 34.1±0.2°, with characteristic peaks.

[0049] Furthermore, the cocrystal of pregabalin and cinnamic acid has an orthorhombic system and a space group of P212121. The asymmetric unit includes one pregabalin molecule and one cinnamic acid molecule. The unit cell parameters are α / ° = 90, β / ° = 90, γ / ° = 90, the melting onset of the pregabalin cinnamic acid eutectic is 148.0°C;

[0050] Pregabalin-vanillic acid cocrystal, triclinic system, P1 space group, the asymmetric unit includes two pregabalin molecules and one vanillic acid molecule, the unit cell parameters are α / °=86.3588(16), β / °=88.5344(15), γ / °=88.8594(16), the melting onset of pregabalin-vanillic acid eutectic is 152℃;

[0051] Pregabalin-p-toluic acid cocrystal, orthorhombic system, P212121 space group, the asymmetric unit includes one pregabalin molecule and one p-toluic acid molecule, the unit cell parameters are α / °=90, β / °=90, γ / °=90, and the melting onset of the pregabalin-toluic acid eutectic is 152°C.

[0052] Furthermore, the differential scanning calorimetry analysis spectrum of the pregabalin-cinnamic acid cocrystal has a characteristic melting peak at 148°C to 153°C, the differential scanning calorimetry analysis spectrum of the pregabalin-vanillic acid cocrystal has a characteristic melting peak at 152°C to 156°C, and the differential scanning calorimetry analysis spectrum of the pregabalin-p-methylbenzoic acid cocrystal has a characteristic melting peak at 152°C to 157°C.

[0053] A novel method for preparing pregabalin cocrystal comprises the following steps:

[0054] S1. Dissolve pregabalin in ethyl acetate at a ratio of 1 g:5-15 mL, stir at room temperature for 20 minutes, heat to 60°C, add anhydrous ethanol at a ratio of 1 g:5-15 mL, and filter while hot to obtain filtrate A and filter cake A.

[0055] S2. Add anhydrous ethanol or a mixture of anhydrous ethanol and methanol to the filtrate A for washing and removing impurities. The volume ratio of the mixture to the filtrate A is 1:1 to 5:1. The mixture is allowed to stand at room temperature for 24 hours. The filtrate B and filter cake B are obtained by suction filtration. The filter cake B is vacuum dried at 40°C for 4 hours.

[0056] S3. Add 50% ethanol-water solution to filtrate B for washing and impurity removal, let stand at room temperature for 24 hours, and filter to obtain filtrate C and filter cake C;

[0057] S4. Add a eutectic former to the filtrate C at a ratio of eutectic former to ethyl acetate of 1 mL: 10-40 g, and stir at 60° C. for 3 hours to obtain a mixture D.

[0058] S5. Cool the mixture D to room temperature, add the filter cake B, the mass ratio of the mixture D to the filter cake B is 1:2-4, stir for 1 hour, and filter to obtain the filter cake D and the filtrate D;

[0059] S7. Wash the filter cake D with methanol until it becomes colorless, and dry it in vacuo at 40° C. for 4 hours to obtain pregabalin cocrystals.

[0060] Furthermore, in step S1, the volume ratio of ethyl acetate to anhydrous ethanol is 1:1 to 3:1, the heating temperature is 60°C ± 2°C, the stirring rate is 200 to 400 rpm, and the mass concentration of pregabalin in filtrate A is 2.9 to 9.3 g / mL.

[0061] Furthermore, in step S2, the volume ratio of the mixed solution of anhydrous ethanol and methanol is 1:0.5 to 1:2, and the number of washings is 2 to 3 times, and a suction filtration operation is performed after each washing. The mass concentration of pregabalin in the filtrate B is 2.9 to 9.3 g / mL.

[0062] Furthermore, in step S4, the eutectic former is added dropwise at a rate of 0.5 to 2 mL / min, and nitrogen protection is continuously introduced during the reaction. The pH value of the mixture D is 4.5 to 6.5.

[0063] Furthermore, in step S5, the filter cake B is added in batches, with the amount of each batch being 10% to 20% of the mass of the mixture D, and the stirring rate being 100 to 300 rpm, and the water content of the filter cake D being ≤5%.

[0064] Furthermore, in step S6, the number of methanol washings is 3 to 5 times, the amount of methanol used in each washing is 5 to 10 times the mass of the filter cake D, the vacuum drying temperature is 40°C ± 2°C, the pressure is 0.08 to 0.1 MPa, and the purity of the pregabalin cocrystal is ≥99.5%.

[0065] Furthermore, all steps are carried out under inert gas protection to prevent oxidation of pregabalin and its cocrystal, and the inert gas is nitrogen or argon.

[0066] The specific implementation process is as follows: pregabalin is dissolved in ethyl acetate at a ratio of 1g:515mL and stirred at room temperature for 20 minutes. Then, it is heated to 60℃±2℃ and stirred at a speed of 200-400rpm. Anhydrous ethanol is added (the ratio of pregabalin to anhydrous ethanol is 1g:515mL). At this time, the volume ratio of ethyl acetate to anhydrous ethanol should be 1:13:1. Filter while hot to obtain filtrate A and filter cake A. Ensure that the mass concentration of pregabalin in filtrate A is between 2.9-9.3g / mL.

[0067] Anhydrous ethanol or a mixture of anhydrous ethanol and methanol (volume ratio of anhydrous ethanol to methanol: 1:0.5-1:2) was added to filtrate A for washing and impurity removal. The volume ratio of the mixture to filtrate A was 1:15:1. After standing at room temperature for 24 hours, the mixture was filtered to obtain filtrate B and filter cake B. This step was repeated 2-3 times, filtering after each washing to ensure that the mass concentration of pregabalin in filtrate B remained at 2.9-9.3 g / mL. Filter cake B was vacuum dried at 40°C for 4 hours.

[0068] An ethanol-water solution with a mass concentration of 50% was added to the filtrate B for washing and removing impurities. The filtrate was allowed to stand at room temperature for 24 hours and then filtered to obtain a filtrate C and a filter cake C.

[0069] Add the eutectic former dropwise to filtrate C at a rate of 0.5-2 mL / min. Continuously purge with nitrogen and ensure that the pH of mixture D is controlled between 4.5-6.5. Stir the reaction at 60°C for 3 hours.

[0070] The mixture D was cooled to room temperature, and filter cake B was added in batches (the amount added in each batch was 10%-20% of the mass of the mixture D, and the mass ratio of the total mixture D to the filter cake B was 1:24). The mixture was stirred at 100-300 rpm for 1 hour and then filtered to obtain filter cake D and filtrate D.

[0071] Filter cake D was washed 3-5 times with methanol, using 5-10 times the mass of filter cake D in each wash, until the filtrate was colorless. Finally, the filter cake was vacuum dried at 40°C ± 2°C and a pressure of 0.08-0.1 MPa for 4 hours to ensure that the water content of filter cake D was ≤5%. The pregabalin cocrystal obtained through the above steps had a purity of ≥99.5%.

[0072] It should be noted that, in this document, relational terms such as first and second, etc., are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprises," "comprising," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements but also other elements not explicitly listed, or elements inherent to such process, method, article, or apparatus.

[0073] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

[0074] The present invention and its embodiments are described above. This description is not restrictive. The drawings show only one embodiment of the present invention, and the actual structure is not limited thereto. In short, if a person skilled in the art is inspired by this and, without departing from the purpose of the present invention, designs structures and embodiments similar to this technical solution without inventiveness, they shall fall within the scope of protection of the present invention.

Claims

1. A novel pregabalin cocrystal, characterized in that: The following cocrystals are included: Pregabalin cinnamic acid cocrystal, the pregabalin cinnamic acid cocrystal further comprising the following 2θ angles and 2θ angle relative intensity values ​​in the X-ray powder diffraction pattern: 5.2±0.2°, 9.6±0.2°, 10.2±0.2°, 11.7±0.2°, 12.3±0.2°, 12.6±0.2°, 13.8±0.2°, 14.6±0.2°, 15.4±0.2°, 15.7±0.2°, 16.8±0.2°, 17.2±0.2°, 18.6±0.2°, 19.4±0.2°, 20.6±0.2°, 21.2±0.2°, 22.3±0.2°, 23.3±0.2°, 23.6±0.2°, 24.3±0.2°, 24.7±0.2°, 25.4±0.2°, 26.4±0.2°, 26.9±0.2°, 27.3±0.2°, 27.9±0.2°, 28.7±0.2°, 29.2±0.2°, 29.8±0.2°, 30.1±0.2°, 31.5±0.2°, 32.7±0.2°, 33.9±0.2°, 34.8±0.2°, said having characteristic peaks; Pregabalin-vanillic acid cocrystal, the pregabalin-vanillic acid cocrystal further comprises the following 2θ angles and 2θ angle relative intensity values ​​in the X-ray powder diffraction pattern: 7.3±0.2°, 9.5±0.2°, 10.3±0.2°, 11.6±0.2°, 13.0±0.2°, 14.6±0.2°, 15.9±0.2°, 16.7±0.2°, 17.3±0.2°, 18.2±0.2°, 19.1± 0.2°, 19.6±0.2°, 21.9±0.2°, 23.1±0.2°, 23.8±0.2°, 25.1±0.2°, 25.5±0.2°, 26.4±0.2°, 27.1±0.2°, 28.3±0.2°, 29.2±0.2°, 31.0±0.2°, 31.7±0.2°, 32.3±0.2°, 33.6±0.2°, said having characteristic peaks; Pregabalin methyl benzoic acid cocrystal, the pregabalin p-methyl benzoic acid cocrystal further comprises the following 2θ angles and 2θ angle relative intensity values ​​in the X-ray powder diffraction pattern: 5.6±0.2°, 12.0±0.2°, 12.9±0.2°, 14.2±0.2°, 14.9±0.2°, 15.8±0.2°, 16.5±0.2°, 17.5±0.2°, 18.0±0.2°, 18.6±0.2°, 19.6±0.2°, 20.9±0.2°, 21 .3±0.2°, 22.0±0.2°, 23.3±0.2°, 23.8±0.2°, 24.3±0.2°, 24.6±0.2°, 25.2±0.2°, 25.8±0.2°, 26.9±0.2°, 28.1±0.2°, 29.1±0.2°, 30.2±0.2°, 30.6±0.2°, 31.6±0.2°, 32.5±0.2°, 33.2±0.2°, 34.1±0.2°, which have characteristic peaks.

2. The novel pregabalin cocrystal according to claim 1, characterized in that: The pregabalin-cinnamic acid cocrystal has an orthorhombic crystal system and a P212121 space group. The asymmetric unit includes a pregabalin molecule and a cinnamic acid molecule. The unit cell parameters are α / °=90, β / °=90, γ / °=90, the pregabalin cinnamic acid eutectic melting onset is 148.0°C; The pregabalin-vanillic acid cocrystal has a triclinic system and a P1 space group. The asymmetric unit includes two pregabalin molecules and one vanillic acid molecule. The unit cell parameters are α / °=86.3588(16), β / °=88.5344(15), γ / °=88.8594(16), the melting onset of the pregabalin-vanillic acid eutectic is 152°C; The pregabalin-paratoluic acid cocrystal has an orthorhombic crystal system and a P212121 space group. The asymmetric unit includes a pregabalin molecule and a paratoluic acid molecule. The unit cell parameters are α / °=90, β / °=90, γ / °=90, and the melting starting point of the pregabalin-p-toluic acid eutectic is 152°C.

3. The novel pregabalin cocrystal according to claim 1, characterized in that: The differential scanning calorimetry analysis spectrum of the pregabalin-cinnamic acid cocrystal has a characteristic melting peak at 148°C to 153°C, the differential scanning calorimetry analysis spectrum of the pregabalin-vanillic acid cocrystal has a characteristic melting peak at 152°C to 156°C, and the differential scanning calorimetry analysis spectrum of the pregabalin-p-methylbenzoic acid cocrystal has a characteristic melting peak at 152°C to 157°C.

4. A novel method for preparing pregabalin cocrystal, characterized in that: The following steps are involved: S1. Dissolve pregabalin in ethyl acetate at a ratio of 1 g:5-15 mL, stir at room temperature for 20 minutes, heat to 60°C, add anhydrous ethanol at a ratio of 1 g:5-15 mL, and filter while hot to obtain filtrate A and filter cake A. S2. Add anhydrous ethanol or a mixture of anhydrous ethanol and methanol to the filtrate A for washing and removing impurities. The volume ratio of the mixture to the filtrate A is 1:1 to 5:

1. The mixture is allowed to stand at room temperature for 24 hours. The filtrate B and filter cake B are obtained by suction filtration. The filter cake B is vacuum dried at 40°C for 4 hours. S3. Add 50% ethanol-water solution to filtrate B for washing and impurity removal, let stand at room temperature for 24 hours, and filter to obtain filtrate C and filter cake C; S4. Add a eutectic former to the filtrate C at a ratio of eutectic former to ethyl acetate of 1 mL: 10-40 g, and stir at 60° C. for 3 hours to obtain a mixture D. S5. Cool the mixture D to room temperature, add the filter cake B, the mass ratio of the mixture D to the filter cake B is 1:2-4, stir for 1 hour, and filter to obtain the filter cake D and the filtrate D; S7. Wash the filter cake D with methanol until it becomes colorless, and dry it in vacuo at 40° C. for 4 hours to obtain pregabalin cocrystals.

5. The method for preparing the novel pregabalin cocrystal according to claim 4, characterized in that: In step S1, the volume ratio of ethyl acetate to anhydrous ethanol is 1:1 to 3:1, the heating temperature is 60°C ± 2°C, the stirring rate is 200 to 400 rpm, and the mass concentration of pregabalin in the filtrate A is 2.9 to 9.3 g / mL.

6. The method for preparing the novel pregabalin cocrystal according to claim 4, characterized in that: In step S2, the volume ratio of the mixed solution of anhydrous ethanol and methanol is 1:0.5 to 1:2, and the number of washings is 2 to 3 times. After each washing, a suction filtration operation is performed. The mass concentration of pregabalin in the filtrate B is 2.9 to 9.3 g / mL.

7. The method for preparing the novel pregabalin cocrystal according to claim 4, characterized in that: In step S4, the eutectic former is added dropwise at a rate of 0.5 to 2 mL / min, and nitrogen protection is continuously introduced during the reaction. The pH value of the mixture D is 4.5 to 6.

5.

8. The method for preparing the novel pregabalin cocrystal according to claim 4, wherein: In step S5 , the filter cake B is added in batches, with the amount of each batch being 10% to 20% of the mass of the mixture D, and the stirring rate being 100 to 300 rpm. The water content of the filter cake D is ≤5%.

9. The method for preparing the novel pregabalin cocrystal according to claim 4, wherein: In step S6, the number of methanol washings is 3 to 5 times, the amount of methanol used in each washing is 5 to 10 times the mass of the filter cake D, the vacuum drying temperature is 40° C.±2° C., and the pressure is 0.08 to 0.1 MPa. The purity of the pregabalin cocrystal is ≥99.5%.

10. The method for preparing the novel pregabalin cocrystal according to any one of claims 4 to 9, characterized in that: All the steps are carried out under the protection of an inert gas to prevent oxidation of pregabalin and its cocrystal. The inert gas is nitrogen or argon.

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