Purification method of pregabalin and novel crystal form of pregabalin

Abstract

The invention discloses a purification method and a new crystal form of pregabalin, and the purification method comprises the following steps: (1) enabling pregabalin and organic alkali to form a salt in a ketone solvent, dissolving the salt in the ketone solvent, then cooling the solution to 0-10 DEG C, stirring, separating out a solid, and filtering to obtain a salt wet product of pregabalin; and (2) adding the wet salt product of pregabalin into a mixed solvent composed of a ketone solvent and water, heating to completely dissolve the salt of pregabalin, dropwise adding an acid, adjusting the pH value of the solution to 2.0-5.0, cooling, stirring, and precipitating crystals, in the mixed solvent composed of the ketone solvent and water, the volume ratio of the ketone solvent to the water is 3.5: 1-1.5: 1. The pregabalin crystal obtained by the purification method of the pregabalin is high in purity and high in yield. The obtained pregabalin crystal is in a novel crystal form, is a rhombus or blocky polyhedron, has good fluidity, and is suitable for preparing tablets or capsules.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for purifying an organic compound, more particularly, to a method for purifying pregabalin and a new crystal form of pregabalin obtained. BACKGROUND

[0002] Pregabalin, chemically named (S)-3-(aminomethyl)-5-methylhexanoic acid, is a structural analogue of gamma-aminobutyric acid (GABA) and has a wide range of neuromodulatory effects. The compound is widely used in the treatment of neuropathic pain, partial seizures and generalized anxiety disorder and other central nervous system diseases. Due to its good oral absorption rate, dose-linear pharmacokinetic characteristics and high bioavailability, pregabalin has become one of the central nervous system drugs widely used in the world.

[0003] In the preparation of bulk drug, the purity, crystal structure and physical properties of pregabalin have important influences on the adaptability of its preparation process and clinical efficacy. Especially in industrial production, how to obtain stable crystal form and excellent powder properties while ensuring high purity is the key to the development of high-quality oral preparations.

[0004] Currently, there are several prior arts that disclose the purification and crystallization methods of pregabalin. For example, prior art CN113801031A discloses a method for improving the crystalline purity of pregabalin by adjusting the pH value and crystallization conditions of a reaction solution containing pregabalin. However, this method cannot completely remove the double-bond positional isomer impurities similar in structure, affecting the overall purity and stability of the product.

[0005] Prior art CN108218649A provides a synthesis method of pregabalin and its intermediates. The product obtained by palladium-carbon-hydrogen gas reduction in the last step is recrystallized with isopropyl alcohol to achieve the purification of pregabalin. Although this purification method improves the purity of the product to some extent, the low crystallization yield (usually less than 80%) leads to poor economic benefits in industrial application.

[0006] Prior art CN103922950A discloses a preparation method of pregabalin, which involves recrystallizing the pregabalin crude product obtained from the treatment reaction solution with water and isopropyl alcohol in a volume ratio of 1:1 to obtain pregabalin crystals. However, this method has the problems of low yield (46-80%) and unsatisfactory HPLC purity (88-97.4%).

[0007] Prior art CN111170879A reports a small particle size of Pregabalin and its preparation method, by dissolving Pregabalin crude in a mixed solution of isopropyl alcohol, methanol or ethanol and water, and strictly controlling the cooling rate and holding time of the solution at different stages, to obtain Pregabalin crystals with a specific particle size range. Although this method can obtain ideal purity crystals (more than 99%), the yield is low (about 81-89%).

[0008] Prior art CN1634869A discloses a new crystal form of Pregabalin with a purity of about 85% by directly recrystallizing Pregabalin in an alcohol-water solution (e.g. isopropyl alcohol-water, ethanol-water, propanol-water, etc.), which is not ideal in purity.

[0009] Prior art CN1962612A discloses recrystallizing Pregabalin directly in a mixed solution of organic solvents (methanol, ethanol, propanol, isopropyl alcohol, propylene glycol, butanol, isobutyl alcohol, butanediol; acetonitrile, N,N-dimethylformamide, tetrahydrofuran, acetone and dioxane, etc.) and water to obtain crystals, without disclosing the purity and yield of the product.

[0010] When the present inventors repeated these prior arts (i.e. dissolving Pregabalin (crude) in an organic solvent or a mixed solution of organic solvent and water, dissolving by heating, and crystallizing by cooling), it was found that these methods had problems such as low yield of the obtained crystals, or not ideal purity, impurities with structures similar to Pregabalin could not be effectively removed, multiple recrystallization was required, and the obtained crystals were usually long strips or needles, which had problems such as poor flowability, poor compressibility, etc. in the operation of preparing tablets or capsules from powders, affecting the content uniformity and mechanical strength of the tablets.

[0011] Therefore, it is of great significance to develop a Pregabalin crystal with high purity, high yield and excellent powder performance, for improving the quality of the preparation and the clinical efficacy. SUMMARY

[0012] The present application discloses a purification method of Pregabalin, which comprises the following steps:

[0013] (1) forming a salt of Pregabalin and an organic base in a ketone solvent, and dissolving in the ketone solvent, then cooling the solution to 0-10℃, stirring, precipitating solid, filtering, to obtain a wet product of Pregabalin salt;

[0014] (2) adding the wet product of Pregabalin salt into a mixed solvent composed of a ketone solvent and water, heating to completely dissolve the Pregabalin salt, then adding acid dropwise to adjust the pH of the solution to 2.0-5.0, cooling, stirring, and precipitating crystals,

[0015] The volume ratio of the ketone solvent to water in the mixed solvent of the ketone solvent and water is 3.5:1 to 1.5:1.

[0016] In another preferred embodiment, in step (1), the ketone solvent is selected from acetone, butanone, cyclohexanone, methyl isobutyl ketone, phenylacetone, or methyl n-propyl ketone, more preferably acetone.

[0017] In another preferred embodiment, in step (1), the organic base is selected from triethylamine and / or diethylamine.

[0018] In another preferred embodiment, in step (1), the molar ratio of pregabalin to the organic base is 1:1.0 to 1.5, more preferably 1:1.1 to 1.3.

[0019] In another preferred embodiment, in step (1), the weight volume ratio of the ketone solvent to pregabalin is 3 to 10 mL / g, more preferably 4 to 6 mL / g.

[0020] In another preferred embodiment, in step (1), the formation of the salt of pregabalin and the organic base in the ketone solvent and the dissolution of the salt in the ketone solvent are carried out under heating, and the heating temperature is 40 to 70°C, more preferably 50 to 60°C.

[0021] In another preferred embodiment, in step (1), the stirring time is 0.5 to 3 hours, more preferably 1 to 1.5 hours.

[0022] In another preferred embodiment, in step (2), the ketone solvent is selected from acetone, butanone, cyclohexanone, methyl isobutyl ketone, phenylacetone, methyl n-propyl ketone, or a combination thereof, more preferably acetone.

[0023] In another preferred embodiment, in step (2), the acid is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, citric acid, malic acid, tartaric acid, or a combination thereof, more preferably hydrochloric acid.

[0024] In another preferred embodiment, in step (2), the pH of the solution is adjusted to 3.0 to 4.0.

[0025] In another preferred embodiment, in step (2), the volume ratio of the ketone solvent to water in the mixed solvent is 3:1 to 2:1.

[0026] In another preferred embodiment, in step (2), the volume weight ratio of the mixed solvent to pregabalin is 5 to 15 mL / g, more preferably 6 to 10 mL / g.

[0027] In another preferred embodiment, in step (2), the heating temperature is 40 to 70°C, more preferably 50 to 60°C.

[0028] In another preferred embodiment, in step (2), the temperature after cooling is 20-30°C, more preferably 20-25°C.

[0029] In another preferred embodiment, in step (2), the stirring time is 0.5-3 hours, more preferably 1-1.5 hours.

[0030] In another preferred embodiment, the method for purifying pregabalin further comprises the step of: (3) concentrating the crystal-containing solution obtained in step (2), after cooling, continuing to stir for crystallization, filtering, and obtaining pregabalin crystals.

[0031] In another preferred embodiment, in step (3), the crystal-containing solution is concentrated to a volume-to-weight ratio of 1.2-5.0 mL / g, more preferably 1.2-3.0 mL / g.

[0032] In another preferred embodiment, in step (3), the concentration temperature is 40-60°C.

[0033] In another preferred embodiment, in step (3), the temperature after cooling is 10-18°C.

[0034] In another preferred embodiment, in step (3), the time for continuing to stir for crystallization is 1-4 hours, more preferably 1.5-3 hours.

[0035] In another preferred embodiment, the method for purifying pregabalin further comprises the step of: washing the obtained pregabalin with a ketone solvent 1-3 times after filtering.

[0036] In another preferred embodiment, the ketone solvent used for washing is the same as the ketone solvent used in step (2).

[0037] The present application also provides a new pregabalin crystal form, which has an X-ray powder diffraction pattern expressed by 2θ angles at 9.50°±0.2°, 12.21°±0.2°, 16.62°±0.2°, and 19.04°±0.2° using Cu-Kα radiation, and the new pregabalin crystal form has a rhombus and / or block polyhedral morphology.

[0038] In another preferred embodiment, the rhombus or block polyhedron has an aspect ratio of 1-3:1, more preferably 1-2:1.

[0039] In another preferred embodiment, the median particle size D50 of the crystal is 200-400 μm, and D90≤600 μm.

[0040] In another preferred embodiment, (iii) the tap density of the crystal is 0.620-0.630 g / mL, and the bulk density is 0.690-0.710 g / mL.

[0041] In another preferred embodiment, the X-ray powder diffraction pattern of the new pregabalin crystalline form, using Cu-Ka radiation, further has a characteristic peak at any one or more of 18.18° ± 0.2°, 19.75° ± 0.2°, 20.13° ± 0.2°, 22.15° ± 0.2°, 23.18° ± 0.2°, 23.48° ± 0.2°, 24.64° ± 0.2°, 26.92° ± 0.2°, 29.81° ± 0.2°, 35.58° ± 0.2°, and 38.66° ± 0.2° in terms of angles of two theta.

[0042] In another preferred embodiment, the X-ray powder diffraction pattern of the new pregabalin crystalline form is substantially as shown in Figure 1-b , Figure 2-b , Figure 3-b , Figure 4-b or Figure 5-b .

[0043] In another preferred embodiment, the differential scanning calorimetry (DSC) pattern of the new pregabalin crystalline form has an endothermic peak at 192.91 ± 5°C.

[0044] In another preferred embodiment, the differential scanning calorimetry pattern of the new pregabalin crystalline form is substantially as shown in Figure 1-e .

[0045] In another preferred embodiment, the thermogravimetric analysis pattern of the new pregabalin crystalline form has substantially no weight loss between 40°C and 105°C.

[0046] In another preferred embodiment, the thermogravimetric analysis (TGA) pattern of the new pregabalin crystalline form is substantially as shown in Figure 1-f .

[0047] In another preferred embodiment, the polarized light microscopy (PLM) pattern of the new pregabalin crystalline form is substantially as shown in Figure 1-c , Figure 2-c , Figure 3-c , Figure 4-c or Figure 5-c .

[0048] The present application also provides a pharmaceutical composition comprising the pregabalin crystal obtained by the above-mentioned purification method of pregabalin or the above-mentioned new pregabalin crystalline form, and a pharmaceutically acceptable excipient.

[0049] In another preferred embodiment, the composition is a tablet or a capsule suitable for a direct compression process. BRIEF DESCRIPTION OF DRAWINGS

[0050] Figure 1-a is the HPLC pattern of the new pregabalin crystalline form obtained in Example 1;

[0051] Figure 1-bis an XRPD pattern of the new pregabalin crystalline form obtained in Example 1 ;

[0052] Figure 1-c is an SEM image of the new pregabalin crystalline form obtained in Example 1 ;

[0053] Figure 1-d is a PSD result of the new pregabalin crystalline form obtained in Example 1 ;

[0054] Figure 1-e is a DSC result of the new pregabalin crystalline form obtained in Example 1 ;

[0055] Figure 1-f is a TGA result of the new pregabalin crystalline form obtained in Example 1 ;

[0056] Figure 1-g is an SEM image of the new pregabalin crystalline form obtained in Example 1 after 12 months storage at 30°C / 65% RH and light;

[0057] Figure 1-h is an HPLC pattern of the new pregabalin crystalline form obtained in Example 1 after 12 months storage at 30°C / 65% RH and light;

[0058] Figure 2-a is an HPLC pattern of the new pregabalin crystalline form obtained in Example 2;

[0059] Figure 2-b is an XRPD pattern of the new pregabalin crystalline form obtained in Example 2;

[0060] Figure 2-c is an SEM image of the new pregabalin crystalline form obtained in Example 2;

[0061] Figure 3-a is an HPLC pattern of the new pregabalin crystalline form obtained in Example 3;

[0062] Figure 3-b is an XRPD pattern of the new pregabalin crystalline form obtained in Example 3;

[0063] Figure 3-c is an SEM image of the new pregabalin crystalline form obtained in Example 3;

[0064] Figure 4-a is an HPLC pattern of the new pregabalin crystalline form obtained in Example 4;

[0065] Figure 4-b is an XRPD pattern of the new pregabalin crystalline form obtained in Example 4;

[0066] Figure 4-c is an SEM image of the new pregabalin crystalline form obtained in Example 4;

[0067] Figure 5-a is the HPLC pattern of the new pregabalin crystal form obtained in Example 5;

[0068] Figure 5-b is the XRPD pattern of the new pregabalin crystal form obtained in Example 5;

[0069] Figure 5-c is the SEM pattern of the new pregabalin crystal form obtained in Example 5;

[0070] Figure 6-a is the XRPD pattern of the pregabalin crystal form obtained in Comparative Example 1;

[0071] Figure 6-b is the SEM pattern of the pregabalin crystal form obtained in Comparative Example 1;

[0072] Figure 7 is the SEM pattern of the pregabalin crystal form obtained in Comparative Example 2;

[0073] Figure 8 is the SEM pattern of the pregabalin crystal form obtained in Comparative Example 3;

[0074] Figure 9 is the SEM pattern of the pregabalin crystal form obtained in Comparative Example 4. DETAILED DESCRIPTION

[0075] In view of the defects of the prior art pregabalin crystal forms and their preparation methods, the present inventors have made an unexpected discovery that a base formed by pregabalin and an organic base such as diethylamine and triethylamine can be easily dissolved in acetone at a high temperature, and can be easily precipitated as a solid upon cooling. The obtained pregabalin salt is dissolved in a mixed solvent of acetone and water in a specific ratio, the pH value of the solution is adjusted to 2.0-5.0, and the crystal is precipitated by stirring. The slurry containing the crystal is concentrated and then filtered, to obtain a new pregabalin crystal form with high purity and high yield. The new crystal form is rhombic or block polyhedron, and is very suitable for the preparation of tablet or capsule formulations. The present application is completed on this basis.

[0076] In the description of the present application, the pregabalin used in the purification method can be pregabalin products prepared according to the prior art (for example, with a purity of 70-99%) without recrystallization or column chromatography purification, or can be pregabalin products (for example, with a purity of 96-99%) purified by recrystallization or column chromatography but not meeting the required purity.

[0077] In the description of the present application, "rhombic" is understood according to the conventional understanding in the art, that is, the crystal shows a clear rhombic or parallelogram contour in two-dimensional projection, has two mutually perpendicular symmetry axes, the adjacent crystal faces have an angle close to 60° and 120°, and has a clear geometric proportion relationship between the long axis and the short axis.

[0078] In the description of the present application, "blocky polyhedron" means having more than three crystal faces, and the overall shape is blocky, with an appearance close to a cube or an irregular block, with clear crystal face intersections, but not obviously elongated in one direction like a needle or a thin strip. In other words, the size in each direction is relatively close, and no one direction is particularly "elongated".

[0079] Therefore, in the present application, "rhombus" and "blocky polyhedron" are two preferred crystal habit forms in parallel, in which "rhombus" emphasizes two-dimensional symmetry and regular geometric shape, and "blocky polyhedron" emphasizes three-dimensional polyhedral structure but without specific symmetry. Both are not as easy to break as needle-shaped crystals, and both are different from needle-shaped or long strip-shaped crystals in the prior art.

[0080] In the description of the present application, for a crystal with a rhombic morphology, the "aspect ratio of the crystal" refers to the ratio of the longest axis of the rhombus to the shortest axis. For a crystal with a blocky polyhedron morphology, the "aspect ratio of the crystal" refers to the ratio of the straight line distance between the two most distant vertices to the straight line distance between the two closest vertices perpendicular to it on the largest cross section of the blocky polyhedron.

[0081] Purification method of pregabalin

[0082] In some specific embodiments of the present application, the method for purifying pregabalin of the present application comprises the following steps:

[0083] (1) forming a salt of pregabalin and an organic base in a ketone solvent, and dissolving in the ketone solvent, then cooling the solution to 0-10°C, stirring, precipitating a solid, filtering to obtain a pregabalin salt wet product;

[0084] (2) adding the pregabalin salt wet product into a mixed solvent composed of a ketone solvent and water, heating to completely dissolve the pregabalin salt, then adding an acid dropwise to adjust the pH of the solution to 2.0-5.0, cooling, stirring, and precipitating crystals to obtain a pregabalin crystal-containing feed solution,

[0085] (3) concentrating the pregabalin crystal-containing feed solution obtained in step (2), continuing to stir to precipitate crystals after cooling, filtering to obtain pregabalin crystals.

[0086] In the purifying method of the present application, the base used in step (1) is an organic base, which is triethylamine and / or diethylamine. The pregabalin and triethylamine or diethylamine form a salt of pregabalin in the ketone solvent. The solubility of the salt in the ketone solvent is higher at higher temperature and lower at lower temperature. Therefore, the salt of pregabalin and organic base can be dissolved in the ketone solvent by heating (for example, heating to 40-70°C), and then the temperature of the solution is decreased, i.e. the salt of pregabalin is precipitated (for example, cooling to 0-10°C). The step can remove the acidic impurities in pregabalin. The ketone solvent used in the step includes but is not limited to acetone, butanone, cyclohexanone, methyl isobutyl ketone, phenylacetone or methyl amyl ketone. The amount of the ketone solvent used is enough to make the salt of pregabalin and organic base completely dissolved at the heating temperature of 40-70°C. Too much amount of the ketone solvent will result in the decrease of the yield of the wet product of the salt of pregabalin in step (1).

[0087] Although the preparation of pregabalin in the prior art also involves the precipitation of solid under alkaline condition and then the crystallization under acidic condition, the alkaline condition is usually the alkaline reaction solution containing a large amount of impurities, and the inorganic base is used to provide the alkaline environment, which results in the impurities being easily wrapped in the precipitated solid, affecting the purity of the solid, and further resulting in the crystallization under the subsequent acidic condition, and the purity and yield of the obtained crystal are not ideal. Moreover, the pregabalin crystal form reported in the prior art is needle-like or long strip-shaped, and has poor flowability, which is not conducive to the preparation of oral preparations such as tablets and capsules.

[0088] In the purifying method of the present application, the acid used in step (2) is a strong acid, which includes but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, citric acid, malic acid and tartaric acid. The acid is used to neutralize the base in the salt of pregabalin obtained in step (1), and the free pregabalin can be crystallized and precipitated in the mixture of ketone solvent and water, and the step can remove the basic impurities. The ketone solvent used in the step includes but is not limited to acetone, butanone and cyclohexanone, methyl isobutyl ketone, phenylacetone or methyl amyl ketone. The ketone solvent used in the step can be the same as or different from that used in step (1). In the mixed solvent of ketone solvent and water, the ratio of the two is crucial to the shape (crystal habit) of the obtained crystal. When the ratio of the ketone solvent (for example, acetone) and water is 3.0:1-2.0:1, the rhombic or block polyhedral crystal can be obtained.

[0089] In the purifying method of the present application, the step (3) is performed by concentrating the solution containing the pregabalin crystals and cooling the concentrated solution to make the pregabalin in the solution fully crystallize, so that the pregabalin crystals are obtained in a high yield. It is possible to concentrate the solution containing the pregabalin crystals in the step (3) to make the pregabalin in the solution fully crystallize, because the step (1) of the purifying method of the present application removes most of the impurities, so that the content of the impurities in the recrystallization system of the step (2) is low. Thus, the purity of the obtained crystals is ensured, and the yield of the crystals is ensured at the same time.

[0090] In some embodiments of the present application, after the pregabalin crystals are filtered, the crystals are rinsed with a cold ketone solvent for 1 to 3 times to wash away the impurities adhered to the surface of the crystals.

[0091] New pregabalin crystal form

[0092] The pregabalin of the present application The new crystal form is prepared by the above The pregabalin of the present application New crystal form The X-ray powder diffraction pattern of the pregabalin of the present application is characterized by peaks at 9.50°±0.2°, 12.21°±0.2°, 16.62°±0.2° and 19.04°±0.2° in terms of 2θ angle using Cu-Kα radiation.

[0093] Further, the X-ray powder diffraction pattern of the pregabalin of the present application is further characterized by peaks at 18.18°±0.2°, 19.75°±0.2°, 20.13°±0.2°, 22.15°±0.2°, 23.18°±0.2°, 23.48°±0.2°, 24.64°±0.2°, 26.92°±0.2°, 29.81°±0.2°, 35.58°±0.2° and 38.66°±0.2° in terms of 2θ angle using Cu-Kα radiation.

[0094] Further, the X-ray powder diffraction pattern of the pregabalin of the present application is substantially as shown in Figure 1-b , Figure 2-b , Figure 3-b , Figure 4-b or Figure 5-b .

[0095] Further, the differential scanning calorimetry pattern of the pregabalin of the present application has an endothermic peak at 192.91±5°C.

[0096] Further, the differential scanning calorimetry pattern of the pregabalin of the present application is substantially as shown in Figure 1-e .

[0097] Further, the thermal gravimetric analysis diagram of the new pregabalin crystal form is substantially as shown in Figure 1-f

[0098] Further, the new pregabalin crystal form is a "rhombus" or "block polyhedral shape".

[0099] Further, the SEM diagram of the new pregabalin crystal form is substantially as shown in Figure 1-c 、 Figure 2-c 、 Figure 3-c 、 Figure 4-c 、 Figure 5-c

[0100] The purification method of the pregabalin crystal of the present application not only obtains a high-purity pregabalin product with high yield, but also obtains a new crystal of pregabalin product. The purification method of the pregabalin crystal of the present application not only significantly improves the purity of the pregabalin crystal, but also realizes the control of regular rhombus crystal habit, and the possible principle is as follows:

[0101] In the salting process of step (1), a weak ion-dipole association structure is formed between triethylamine or diethylamine and the carboxylate of pregabalin, and the molecules of the structure have good reversibility in ketone solvents - fully dissociate when heated, dissolve in the solvent, and orderly rearrange and precipitate from the solvent when cooled. In this process, most of the polar impurities remain in the mother liquor because they cannot be salified or have high solubility in ketone solvents, thereby being effectively removed in this step. The ketone solvent has moderate polarity, which can dissolve the target salt and is not conducive to the solvation of impurities. Therefore, the purification method of pregabalin of the present application obtains a high-purity intermediate before acidification and crystallization, and the purity of the product obtained by the final crystallization can reach more than 99.90%.

[0102] The salt of pregabalin and triethylamine or diethylamine has moderate stability in ketone reagents, is easy to precipitate at low temperature, and has high yield, while other solvents such as alcohols may be easily entrained or surface-adsorbed with impurities due to strong or weak hydrogen bonding, which is difficult to effectively separate. The salt of pregabalin and ammonia water or other small molecule bases has strong hydrophilicity and is difficult to precipitate, resulting in low yield of the product obtained by the purification method of pregabalin. Therefore, using other types of solvents and inorganic bases cannot achieve the purification effect of using ketone solvents as solvents and triethylamine or diethylamine as bases.

[0103] ​​During the crystallization process of step (2), the present inventors surprisingly found that the ratio of ketone solvent to water directly affects the supersaturation evolution and molecular stacking behavior during the crystallization process. When the volume ratio of ketone solvent to water is 3.0:1.0-2.0:1.0, the solvent system can steadily release supersaturation, allowing uniform growth of crystal nuclei, orderly arrangement of molecules, and formation of rhombic or block polyhedral crystals with good symmetry. When the ratio of ketone solvent is too high (excess organic phase), the molecules are desorbed too quickly, the anisotropy of crystal growth is enhanced, and needle-shaped or long strip-shaped crystals are formed. When the ratio of ketone solvent is too low (excess water phase), the solvation is too strong, the crystal face competition is disordered, and needle-shaped or long strip-shaped crystals are also formed. Therefore, the ratio of ketone solvent to water is determined by the present inventors through systematic screening and morphology feedback iteration.

[0104] In addition, during the acidification and crystallization process, trace amounts of organic salts can be adsorbed on specific crystal faces, temporarily inhibiting their rapid extension and promoting the development of crystal symmetry. Ultimately, regular rhombic or block polyhedral crystals with flat crystal faces and sharp edges are formed. However, due to factors such as impurity interference, mismatched solvent polarity, and rapid crystallization, it is difficult to obtain high-purity pregabalin new crystal forms with high yield as in the present application.

[0105] Therefore, through the synergistic effect of early impurity removal and fine control of the crystallization process, the present application achieves a dual improvement in purity and crystal habit, with significant and unpredictable technical effects.

[0106] The characteristic peaks of the XRPD pattern of the pregabalin new crystal form obtained by the present application are basically consistent with those of the crystal form reported in the prior art, but the morphology is different from that of the crystal form reported in the prior art. The former is rhombic or block polyhedral, and the latter is needle-shaped or long strip-shaped. Therefore, the pregabalin crystal of the present application is more suitable for preparing tablets or capsules than the crystal reported in the prior art.

[0107] Compared with the prior art, the present application has the following beneficial effects:

[0108] The purification method of pregabalin of the present application can obtain pregabalin with high purity, the purity is above 99.94%, and the yield is high, reaching 94.2%-97.2%;

[0109] The pregabalin new crystal form obtained by the present application is rhombic or block polyhedral, has good flowability and compressibility, is suitable for direct tabletting process, and has good industrial application prospect;

[0110] The results show that the crystal of the present application has good physical and chemical stability, and is suitable for long-term storage and industrial application.

[0111] The application will be further described in connection with the following specific examples which are not intended to limit the scope of the application. The experimental methods in the following examples, unless otherwise specified, are generally carried out under conventional conditions.

[0112] The HPLC purity of the pregabalin to be purified in the following examples is about 98.2%, and it is mainly found to contain the following impurities:

[0113]

[0114] Impurity A and impurity B: are double-bond isomer by-products generated during synthesis, which have similar structures to the pregabalin nucleus, only differ in the position or configuration of the side chain double bond, have similar polarity, and are difficult to separate effectively by conventional recrystallization.

[0115] Impurity C: is a dehydration or degradation product of pregabalin during storage or reaction, has lower polarity, is easily retained in the organic phase, and can interfere with crystal growth as a heterogeneous nucleation center.

[0116] These impurities not only affect the chemical purity of the final product, but also can be trapped inside the crystal lattice or adsorbed on the crystal surface during the crystallization process, causing lattice distortion, growth anisotropy, forming needle-shaped or irregular crystals, and affecting the powder flowability and formulation performance.

[0117] Based on the physicochemical properties of the above impurities (structural similarity, close polarity, and difference in salt formation ability), the inventors speculate that if a selective salt formation strategy is adopted, using organic bases to specifically salt with pregabalin and controlling the precipitation behavior in ketone solvents, the target substance and isomers, degradation products can be effectively separated. Therefore, the inventors designed a multi-factor screening experiment, focusing on the effects of base type (organic base vs. inorganic base), solvent type (ketone, alcohol, etc.), solvent-water ratio, and base equivalent on the purity, yield, and crystal habit of the crystal. Through orthogonal experiment optimization, the organic base (especially triethylamine or diethylamine)-acetone / water (3.0:1.0-2.0:1.0) system was finally determined as the optimal condition, and high-purity rhombic or polyhedral crystal forms were obtained for the first time with high yield. On this basis, the present application was completed.

[0118] Raw materials and general methods:

[0119] 1. XRPD pattern determination method

[0120] X-ray powder diffraction instrument: Rigaku Miniflex 600 X-ray diffractometer; radiation source: Cu target; generator (Generator): 40kv; generator (Generator): 15mA; scanning range: 3.0-50.0°.

[0121] 2. DSC measurement method

[0122] Measurement instrument: DSC 3 / 500 / 4563-HP; temperature rising program: HP 30-400K.

[0123] 3. TGA measurement method

[0124] Instrument model: Tarsus TG209F3; temperature rising program: 40 to 400 degrees Celsius at 20k / min.

[0125] 4. D90 measurement method

[0126] The instrument used was a Malvern Mastersizer 3000

[0127] Detection method: wet method

[0128] Dispersion medium: liquid paraffin

[0129] Sample preparation method: washed with isopropyl alcohol for 5 minutes, washed with dichloromethane for 5 minutes, added with an appropriate amount of dispersant for background testing, then added with the test sample until the opacity reached 10-20%, and after 1 minute of equilibration, the test sample was tested.

[0130] Experimental Example 1

[0131] The purification process of this experimental example was as follows: in a 25 mL reaction bottle, pramipexole (purity about 98.2%, 2.5 g), base (1.2 eq) and solvent (12.5 mL) were added, heated to 55°C until the system was clear, the reaction solution was cooled to 5°C, stirred for 1 hour, and the solid was precipitated. The pramipexole salt wet product was obtained by filtration.

[0132] The obtained pramipexole salt wet product was transferred to another reaction bottle, solvent (15 mL) and water (7 mL) were added, and the temperature was raised to 55°C. The salt wet product was completely dissolved by stirring to obtain a clear solution. Hydrochloric acid was added dropwise to adjust the pH of the system to 3.5, and the temperature was naturally lowered to 25°C. The crystal was obtained by stirring for 1 hour. The crystal-containing liquid was concentrated under reduced pressure to a residual volume of 5.0 mL (concentration temperature about 50°C), and then cooled to 10°C. The crystal was obtained by continuing to stir for 2 hours, filtering, washing twice with pre-cooled solvent (2.5 mL x 2) at 5°C, and vacuum drying to obtain white crystals. The purity (HPLC purity) and yield of all solvents, bases, and products are shown in Table 1 below.

[0133] The solvents used to dissolve pramipexole (crude product), the solvents used to dissolve the salt wet product, and the solvents used in the mixture of water and washing are the same in the following experimental examples 1-1 to 1-21.

[0134] The solvents used to dissolve pramipexole (crude product), the solvents used to dissolve the salt wet product, and the solvents used in the mixture of water and washing are the same in the following experimental examples 1-1 to 1-21.

[0135] Table 1

[0136]

[0137]

[0138] As can be seen from Table 1, the combination of triethylamine and acetone for purifying pregabalin resulted in the best crystal in terms of purity, yield and crystal habit. The reason might be that the salt of pregabalin and triethylamine was completely dissolved in acetone at high temperature and selectively precipitated from acetone at low temperature, effectively removing inorganic salts and polar impurities and improving the purity of the crystal. Moreover, the mixed solvent of acetone-water had moderate polarity and weak hydrogen bonding, which made the desolvation rate of pregabalin molecules stable and the supersaturation controllable during the crystallization process, avoiding explosive nucleation, reducing impurity inclusion and improving the yield, and more importantly, helping the balanced growth of the crystal in all directions to form regular rhombus or block polyhedron. In other systems, the salt might not be soluble, or the solvation might be too strong, or the precipitation might be too fast, resulting in low purity, yield loss and disorder of crystal habit.

[0139] On the basis of the above experimental examples 1-1 to 1-21, the inventors further screened the types of bases and other ketone solvents in experimental examples 1-22 to 1-33. The reaction conditions and raw materials of experimental examples 1-22 to 1-33 were basically the same as those of example 1-15, except that the types of solvents and / or bases were different in some experimental examples. The solvents, bases, purity (HPLC purity) and yield of the products used in these experimental examples are shown in Table 2 below.

[0140] Table 2

[0141]

[0142]

[0143] As can be seen from Table 2, although other organic bases (such as pyridine, ammonia, hydrazine hydrate, methylamine, tetramethylguanidine and DBU) can also obtain regular rhombus crystals in the acetone system, the product purity is not ideal and the crystal yield is also low. The possible reason is that although pyridine, ammonia and methylamine can also form salts with pregabalin, their conjugate acid pKa is low or the molecular polarity is strong, resulting in poor stability of the salt in the ketone solvent. Strong bases such as DBU and tetramethylguanidine can cause local side reactions or too strong solvation, which is not conducive to the control of crystal purity. When diethylamine is used as a base, similar effects to triethylamine can be obtained, the crystal purity is high, and the yield is also high. The reason might be that diethylamine has moderate basicity, and the salt formed with pregabalin has good dissolution-precipitation behavior, complete salification and high selectivity of crystallization, which is conducive to the removal of impurities and the ordered growth of the crystal.

[0144] In addition, other ketone solvents such as butanone, cyclohexanone, methyl isobutyl ketone, etc. can also obtain regular rhombic crystals or block polyhedral crystals when used in combination with triethylamine, and the yield is higher, indicating that ketone solvents have good applicability. The reason may be that: the polarity range of these ketone solvents is similar, the hydrogen bond acceptor ability is moderate, which can effectively dissolve the base salt of pregabalin, and realize mild desolvation in the presence of water, which is conducive to the ordered stacking of molecules. Although acetophenone and methyl amyl ketone have slightly lower polarity, but due to the larger molecular volume, it may inhibit the diffusion of impurities, and is more conducive to the integrity of the crystal.

[0145] On the basis of the above experimental examples 1-22 to 1-33, the inventors further screened the type of solvent and the ratio of solvent to water using triethylamine as a base. The reaction conditions and raw materials of experimental examples 1-34 to 1-44 are basically the same as those of example 1-15, except that the solvent and / or the ratio of solvent to water is different in step (2) of some examples. The solvents used in these examples, the ratio of solvent to water, the purity (HPLC purity) and yield of the product are shown in Table 3 below.

[0146] Table 3

[0147]

[0148]

[0149] As can be seen from Table 3, in step (2), the ratio of solvent to water has a decisive influence on the crystal morphology. When the volume ratio of ketone solvent to water is 2:1 to 3:1, the system has moderate polarity, the molecular desolvation rate is stable, the supersaturation degree is controllable, which is conducive to the balanced growth of crystals in all directions, forming regular rhombic structure; while when the water phase ratio is too high (such as 1:1 and above), although the yield is slightly improved due to the decrease of solubility, the water phase has high polarity, which leads to the rapid attachment of molecules on specific crystal faces, the anisotropic growth is enhanced, and needle-shaped or strip-shaped crystals are formed. In addition, high water phase ratio may cause rapid local precipitation of crystals, dense nucleation of crystals, and inhibition of normal crystal growth. Therefore, under the premise of ensuring yield and purity, selecting a solvent-water ratio of 2:1 to 3:1 is the key to realizing the synergistic control of high yield and ideal crystal habit of pregabalin crystals.

[0150] On the basis of the above experimental examples 1-34 to 1-44, the inventors further screened the amount of triethylamine as a base. The reaction conditions and raw materials of these experimental examples are basically the same as those of example 1-34, except that the amount of triethylamine is different. The amount of base, the purity (HPLC purity) and yield of the product of these experimental examples are shown in Table 4 below.

[0151] Table 4

[0152] Experimental example Alkali and its amount Product purity Product yield 1-45 Triethylamine 1.0 eq 99.89％ 93.2％ 1-46 Triethylamine 1.2 eq 99.96％ 94.2％ 1-47 Triethylamine 1.4 eq 99.96％ 94.1％ 1-48 Triethylamine 2.0 eq 99.96％ 94.0％ 1-49 Triethylamine 3.0 eq 99.95％ 93.9％ 1-50 Triethylamine 0.5 eq 85.92％ 94.8％

[0153] Note: In Table 4, the equivalent (eq) of base is the molar ratio of base to Pregabalin.

[0154] As can be seen from Table 4, when the amount of triethylamine is too small (0.5 eq), the purity of the product is low. The reason can be that the amount of base is insufficient to convert Pregabalin completely into a soluble salt, resulting in part of the free acid remaining in the reaction system, co-solubilizing with impurities or forming amorphous substances, affecting the purity and integrity of crystallization. In addition, the low salt formation rate also reduces the selectivity of subsequent crystallization, making it easier for impurities to be hidden in the crystals.

[0155] When the amount of triethylamine exceeds 1.2 eq, the purity and yield of the product tend to be stable and almost no longer improve. The reason can be that at this amount, Pregabalin has been completely salted, and the reaction has reached saturated conversion. Increasing the amount of base does not help to improve the conversion rate, but can introduce excess organic base or its salt by-products, increasing the complexity of the mother liquor, and having no positive contribution to the crystallization behavior. Therefore, considering the conversion efficiency, purification effect and process economy, the optimal amount of triethylamine is about 1.2 eq.

[0156] Example 1

[0157] Pregabalin (HPLC purity about 98.2%, 50.0 g, 308.4 mmol), triethylamine (37.4 g, 370.1 mmol, 1.2 eq) and acetone (250 mL) were added to a 500 mL reaction bottle, heated to 55°C until the system was clear, cooled to 5°C, stirred for 1 hour, and solid was precipitated. The Pregabalin salt wet product was obtained by filtration.

[0158] The obtained salt wet product was transferred to another reaction bottle, acetone (300 mL) and water (125 mL) were added, and the temperature was increased to 55°C until the wet product was completely dissolved to obtain a clear solution. Hydrochloric acid was slowly added dropwise to adjust the pH to 3.5, and the temperature was naturally reduced to 25°C. The Pregabalin crystal-containing mother liquor was obtained by stirring for 1 hour.

[0159] The Pregabalin crystal-containing mother liquor was concentrated under reduced pressure to a weight volume ratio of 1.5 mL / g (75 mL, the concentration temperature was 50°C), and then the temperature was reduced to 15°C. The crystals were separated by filtration, washed twice with pre-cooled acetone at 5°C, and dried under vacuum to obtain 47.6 g of white crystals.

[0160] The purity of the product was 99.964% by HPLC detection (HPLC spectrum is shown in Figure 1-a ), and the yield was 95.2%. The obtained XRPD spectrum is shown in Figure 1-aAs shown in the XRPD pattern expressed in 2θ angle, the crystal has characteristic peaks at 9.50°±0.2°, 12.21°±0.2°, 16.62°±0.2°, 18.18°±0.2°, 19.04°±0.2°, 19.75°±0.2°, 20.13°±0.2°, 22.15°±0.2°, 23.18°±0.2°, 23.48°±0.2°, 24.64°±0.2°, 26.92°±0.2°, 29.81°±0.2°, 35.58°±0.2° and 38.66°±0.2°, etc.

[0161] Crystal morphology observation and analysis of the crystal obtained in Example 1

[0162] The crystal obtained in Example 1 was observed by scanning electron microscope (SEM). The structure as shown in the figure is diamond-shaped or block polyhedron. Figure 1-c The diamond-shaped crystal has obvious two-dimensional symmetry structure, with flat crystal surface, sharp and linear edges, and adjacent crystal surface junction angle close to 60° and 120°, showing good crystalline symmetry. Under multiple field observations, most of the crystal particles exhibit this characteristic morphology, with regular structure, uniform distribution, and the proportion of diamond-shaped morphology more than 80%, and the particle size distribution is concentrated, with D50 of 315 μm (see Figure 1-d ).

[0163] In comparison, the crystal of pregabalin prepared by the conventional method (see Comparative Example 1 below), as well as the crystal obtained from other solvents (see Comparative Example 3) and other solvent ratios (see Comparative Example 4) mainly presents long strip or needle-shaped structure, with large aspect ratio, obvious crystal surface extension direction, and lack of symmetry.

[0164] The diamond-shaped or block polyhedron structure of the crystal of the present application helps to improve the stacking order of the particles, improve the flowability and compressibility of the powder, and reduce the sliding and delamination phenomenon in the tabletting process. The significantly different crystal habit characteristics show that the crystallization process of the present application effectively controls the growth habit of the crystal, and obtains pregabalin crystal with novel morphology.

[0165] Physical property test of the crystal obtained in Example 1

[0166] The tap density and the bulk density of the crystal obtained in Example 1 were tested, and the testing process and the obtained results are shown in Table 5.

[0167] Table 5

[0168]

[0169] Compared with the needle-shaped pregabalin crystals in the prior art (bulk density 0.614 g / mL, tap density 0.716 g / mL), the rhombic or block polyhedral pregabalin crystals obtained in Example 1 have lower compressibility, higher tap density, more uniform particle size, and better flowability.

[0170] Particle size analysis of the crystal obtained in Example 1

[0171] The laser particle size analysis of the pregabalin crystals obtained in Example 1 was performed, and the particle size distribution graph obtained is shown in Figure 1-d . The results show that the crystals have a relatively uniform particle size distribution, with a median particle size (D50) of about 315 μm, a D10-D90 distribution range of 142-550 μm, and a target control range of 100-600 μm. The peak shape of the particle size distribution curve is narrow and symmetrical, indicating that the crystal particles are uniform in size and have good dispersibility. The crystals of the present application have a significant advantage in particle size and are suitable for direct tabletting process, and have a good prospect of industrial application.

[0172] Thermal analysis (DSC and TGA) of the crystal obtained in Example 1

[0173] The differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of the pregabalin crystals obtained in Example 1 were performed, and the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs obtained are shown in Figure 1-e and Figure 1-f .

[0174] The DSC graph shows that the pregabalin crystals obtained in Example 1 have a single endothermic peak, indicating that the crystals have high purity and stable thermal behavior.

[0175] The TGA graph of the pregabalin crystal form obtained in Example 1 shows that there is no obvious weight loss (weight reduction) during the heating process (40°C-105°C), indicating that the crystal does not contain crystalline water or solvent and has good stability.

[0176] Stability test of the crystal obtained in Example 1

[0177] The pregabalin crystals obtained in Example 1 were packaged with double-layer polyethylene (PE) bags and stored at 30°C, 65% RH and light for 12 months, and the changes in crystal habit, purity and physical properties were observed. The results show that the crystal morphology has no obvious change (see Figure 1-g ); the purity (HPLC) is maintained at more than 99.90%, and no new impurities are generated (see Figure 1-h ), the bulk density is 0.626 g / mL, the tap density is 0.700 g / mL, the compressibility and other indicators are stable, the crystals are not easy to break during tabletting, and the flowability is good.

[0178] Example 2:

[0179] In a 500 mL reaction flask, add pramipexole (HPLC purity about 98.2%, 50.0 g, 308.4 mmol), diethylamine (27.1 g, 370.1 mmol, 1.2 eq) and acetone (250 mL), heat to 55 °C until the system is clear, cool to 5 °C, stir for 1 hour, and precipitate the solid. Filter to obtain the salt wet product of pramipexole.

[0180] Transfer the salt wet product to another reaction flask, add acetone (300 mL) and water (125 mL) (volume ratio 2.4:1), heat to 55 °C, stir until the wet product is completely dissolved to obtain a clear solution, add hydrochloric acid dropwise to adjust the pH of the system to 3.5, and naturally cool to 25 °C. Stir for 1 hour to precipitate the crystals, and obtain a solution containing pramipexole crystals.

[0181] Concentrate the solution containing pramipexole crystals under reduced pressure to a remaining volume of 75 mL (concentration temperature is 50 °C), cool to 15 °C, and continue to stir for 2 hours to precipitate the crystals. Filter, wash the obtained crystals with 5 °C acetone (50 mL x 2), and vacuum dry to obtain white crystals 47.7 g. HPLC detection shows that the purity of the white crystals is 99.966% (HPLC spectrum is shown in Figure 2), and the yield is 95.4%. The XRPD spectrum of the crystals shows characteristic peaks at 9.57°±0.2°, 12.30°±0.2°, 16.72°±0.2°, 18.29°±0.2°, 19.12°±0.2°, 19.82°±0.2°, 22.22°±0.2°, 23.55°±0.2°, 26.95°±0.2°, 38.71°±0.2°, etc. (XRPD spectrum is shown in Figure 3), which is basically consistent with the XRPD spectrum of the crystals of Example 1. SEM observation shows that most of the crystals are rhombic (see Figure 4), and a small amount are block-shaped polyhedrons, which are highly similar to the crystals of Example 1, and have good fluidity. The crystal form of the crystals is basically consistent with the crystal form of the crystals of Example 1. Figure 2-a Figure 2-b ), which is basically consistent with the XRPD spectrum of the crystals of Example 1. SEM observation shows that most of the crystals are rhombic (see Figure 4), and a small amount are block-shaped polyhedrons, which are highly similar to the crystals of Example 1, and have good fluidity. The crystal form of the crystals is basically consistent with the crystal form of the crystals of Example 1. Figure 2-c Example 3

[0182] In a 500 mL reaction flask, add pramipexole (HPLC purity about 98.2%, 50.0 g, 308.4 mmol), diethylamine (27.1 g, 370.1 mmol, 1.2 eq) and acetone (250 mL), heat to 55 °C until the system is clear, cool to 5 °C, stir for 1 hour, and precipitate the solid. Filter to obtain the salt wet product of pramipexole.

[0183] Transfer the salt wet product to another reaction flask, add acetone (300 mL) and water (125 mL) (volume ratio 2.4:1), heat to 55 °C, stir until the wet product is completely dissolved to obtain a clear solution, add hydrochloric acid dropwise to adjust the pH of the system to 3.5, and naturally cool to 25 °C. Stir for 1 hour to precipitate the crystals, and obtain a solution containing pramipexole crystals.

[0184] Concentrate the solution containing pramipexole crystals under reduced pressure to a remaining volume of 75 mL (concentration temperature is 50 °C), cool to 15 °C, and continue to stir for 2 hours to precipitate the crystals. Filter, wash the obtained crystals with 5 °C acetone (50 mL x 2), and vacuum dry to obtain white crystals 47.7 g. HPLC detection shows that the purity of the white crystals is 99.966% (HPLC spectrum is shown in Figure 2), and the yield is 95.4%. The XRPD spectrum of the crystals shows characteristic peaks at 9.57°±0.2°, 12.30°±0.2°, 16.72°±0.2°, 18.29°±0.2°, 19.12°±0.2°, 19.82°±0.2°, 22.22°±0.2°, 23.55°±0.2°, 26.95°±0.2°, 38.71°±0.2°, etc. (XRPD spectrum is shown in Figure 3), which is basically consistent with the XRPD spectrum of the crystals of Example 1. SEM observation shows that most of the crystals are rhombic (see Figure 4), and a small amount are block-shaped polyhedrons, which are highly similar to the crystals of Example 1, and have good fluidity. The crystal form of the crystals is basically consistent with the crystal form of the crystals of Example 1.The obtained salt wet product was transferred to another reaction flask, and cyclohexanone (300 mL) and water (125 mL) were added. The system was heated to 55°C and stirred until the salt wet product was completely dissolved to obtain a clear solution. Hydrochloric acid was added dropwise to adjust the pH of the system to 3.5, and the system was naturally cooled to 25°C. The system was stirred for 1 hour to obtain a solution containing pregabalin crystals.

[0185] The solution containing pregabalin crystals was concentrated under reduced pressure to a remaining volume of 90 mL (the concentration temperature was 60°C). The system was cooled to 10°C and stirred for 2 hours to obtain crystals. The obtained crystals were washed with pre-cooled cyclohexanone (50 mL x 2) and vacuum dried to obtain white crystals (47.9 g).

[0186] The purity of the crystals prepared in this example was 99.963% (HPLC spectrum is shown in Figure 1), and the yield was 95.8%. The XRPD spectrum of the crystals showed characteristic peaks at 9.49°±0.2°, 12.24°±0.2°, 16.67°±0.2°, 18.36°±0.2°, 19.06°±0.2°, 19.78°±0.2°, 22.18°±0.2°, 23.20°±0.2°, 26.86°±0.2°, 38.68°±0.2°, etc. (XRPD spectrum is shown in Figure 2), which was basically consistent with the XRPD spectrum of the crystals of Example 1. Figure 3-a ), and the yield was 95.8%. The XRPD spectrum of the crystals showed characteristic peaks at 9.49°±0.2°, 12.24°±0.2°, 16.67°±0.2°, 18.36°±0.2°, 19.06°±0.2°, 19.78°±0.2°, 22.18°±0.2°, 23.20°±0.2°, 26.86°±0.2°, 38.68°±0.2°, etc. (XRPD spectrum is shown in Figure 2), which was basically consistent with the XRPD spectrum of the crystals of Example 1. Figure 3-b Figure 3-c SEM observation showed that most of the crystals were rhombic (see Figure 3), and a small amount of crystals had slightly blurred edges, but still maintained the characteristics of block polyhedron, and had good fluidity. The crystal form of pregabalin obtained in this example was basically consistent with the crystal form of Example 1.

[0187] Example 4

[0188] Pregabalin (HPLC purity of about 98.2%, 50.0 g, 308.4 mmol), triethylamine (37.4 g, 370.0 mmol, 1.2 eq) and cyclohexanone (250 mL) were added to a 500 mL reaction flask. The system was heated to be clear at 55°C, and then cooled to 5°C. After stirring for 1 hour, a solid was precipitated, and the pregabalin salt wet product was obtained by filtration.

[0189] The obtained salt wet product was transferred to another reaction flask, and cyclohexanone (300 mL) and water (125 mL) were added. The system was heated to 55°C and stirred until the salt wet product was completely dissolved to obtain a clear solution. Hydrochloric acid was added dropwise to adjust the pH of the system to 3.5, and the system was naturally cooled to 20°C. The system was stirred for 1 hour to obtain a solution containing pregabalin crystals.

[0190] ​The solution containing the pramipexole crystals was concentrated under reduced pressure to a remaining volume of 75 mL (the concentration temperature was 95°C), and the temperature was lowered to 15°C. Crystallization was continued for 2 hours with stirring, and the crystals were filtered. The obtained crystals were washed with 5°C cyclohexanone (50 mL x 2) and vacuum dried to obtain white crystals 48.6 g.

[0191] The purity was 99.965% by HPLC (the HPLC spectrum is shown in Figure 1) and the yield was 97.2%. The XRPD spectrum of the crystals showed characteristic peaks at 9.53°±0.2°, 12.26°±0.2°, 16.68°±0.2°, 18.23°±0.2°, 19.08°±0.2°, 19.75°±0.2°, 22.18°±0.2°, 23.24°±0.2°, 26.89°±0.2°, 38.61°±0.2°, etc. (the XRPD spectrum is shown in Figure 2), which was basically consistent with the XRPD spectrum of the crystals of Example 1. Figure 4-a The purity was 99.965% by HPLC (the HPLC spectrum is shown in Figure 1) and the yield was 97.2%. The XRPD spectrum of the crystals showed characteristic peaks at 9.53°±0.2°, 12.26°±0.2°, 16.68°±0.2°, 18.23°±0.2°, 19.08°±0.2°, 19.75°±0.2°, 22.18°±0.2°, 23.24°±0.2°, 26.89°±0.2°, 38.61°±0.2°, etc. (the XRPD spectrum is shown in Figure 2), which was basically consistent with the XRPD spectrum of the crystals of Example 1. Figure 4-b SEM observation showed that the crystals were still rhombic or block polyhedral structures (see Figure 3), and the morphology was highly similar to that of Example 1, and the crystals had good fluidity. The crystal form of pramipexole obtained in this example was basically consistent with the crystal form of Example 1. Figure 4-c The purity was 99.965% by HPLC (the HPLC spectrum is shown in Figure 1) and the yield was 97.2%. The XRPD spectrum of the crystals showed characteristic peaks at 9.53°±0.2°, 12.26°±0.2°, 16.68°±0.2°, 18.23°±0.2°, 19.08°±0.2°, 19.75°±0.2°, 22.18°±0.2°, 23.24°±0.2°, 26.89°±0.2°, 38.61°±0.2°, etc. (the XRPD spectrum is shown in Figure 2), which was basically consistent with the XRPD spectrum of the crystals of Example 1.

[0192] Example 5

[0193] Pramipexole (HPLC purity about 98.2%, 50.0 g, 308.4 mmol), triethylamine (37.4 g, 370.0 mmol, 1.2 eq) and acetone (250 mL) were added into a 500 mL reaction flask, and the system was heated to be clear at 55°C. The temperature was lowered to 5°C, and the system was stirred for 1 hour. The solid was precipitated, and pramipexole salt wet product was obtained by filtration.

[0194] The obtained salt wet product was transferred into another reaction flask, and acetone (300 mL) and water (100 mL) were added. The system was heated to 55°C, and the wet product was stirred until it was completely dissolved to obtain a clear solution. Hydrochloric acid was added dropwise to adjust the pH of the system to 3.5, and the temperature was naturally lowered to 20°C. The system was stirred for 1 hour to obtain a solution containing pramipexole crystals.

[0195] The solution containing the pramipexole crystals was concentrated under reduced pressure to a remaining volume of 75 mL (the concentration temperature was 95°C), and the temperature was lowered to 15°C. Crystallization was continued for 2 hours with stirring, and the crystals were filtered. The obtained crystals were washed with 5°C cyclohexanone (50 mL x 2) and vacuum dried to obtain white crystals 48.6 g.

[0196] The purity was 99.965% by HPLC (the HPLC spectrum is shown in Figure 1) and the yield was 97.2%. The XRPD spectrum of the crystals showed characteristic peaks at 9.53°±0.2°, 12.26°±0.2°, 16.68°±0.2°, 18.23°±0.2°, 19.08°±0.2°, 19.75°±0.2°, 22.18°±0.2°, 23.24°±0.2°, 26.89°±0.2°, 38.61°±0.2°, etc. (the XRPD spectrum is shown in Figure 2), which was basically consistent with the XRPD spectrum of the crystals of Example 1. Figure 5-aThe yield was 94.6%. The XRPD spectrum showed characteristic peaks at 2θ values ​​of 9.48°±0.2°, 12.29°±0.2°, 16.63°±0.2°, 18.26°±0.2°, 19.05°±0.2°, 19.79°±0.2°, 22.19°±0.2°, 23.21°±0.2°, 26.86°±0.2°, and 38.65°±0.2° (see XRPD spectrum). Figure 5-b The XRPD pattern of the crystal is basically consistent with that of the crystal in Example 1. SEM observation shows that most of the crystals have a rhombic structure (see...). Figure 5-c A small number of crystals were blocky polyhedra with morphology highly similar to those in Example 1 and exhibited good fluidity, indicating that the crystal forms were identical.

[0197] Comparative Example 1 (Preparation of conventional needle-shaped or strip-shaped pregabalin crystals according to existing techniques)

[0198] Pregabalin crystals were prepared using the method disclosed in the prior art CN113801031A, resulting in elongated or needle-shaped crystals with a bulk density of 0.614 g / mL and a tap density of 0.716 g / mL. These crystals were easily broken during tableting and had poor flowability.

[0199] The XRPD spectrum of this crystal shows characteristic peaks at 2θ values ​​of 9.59°±0.2°, 12.32°±0.2°, 16.73°±0.2°, 18.32°±0.2°, 19.15°±0.2°, 19.82°±0.2°, 22.25°±0.2°, 23.28°±0.2°, 27.01°±0.2°, and 38.74°±0.2° (see XRPD spectrum). Figure 6-a The peak positions of the crystals are basically consistent with those of the XRPD spectrum in Example 1, but the crystals are needle-shaped or elongated (see SEM image of the crystals). Figure 6-b The crystals in this example are significantly different from those in Example 1.

[0200] Comparative Example 2

[0201] Add crude pregabalin (HPLC purity approximately 98.2%, 50.0 g, 308.4 mmol), saturated ammonia (27.9 mL, approximately 371.1 mmol ammonia, approximately 1.2 eq), and acetone (250 mL) to a 500 mL reaction flask. Heat at 55 °C until the system becomes clear, then cool to 5 °C and stir for 1 hour. A solid precipitates out, and the solid is filtered to obtain wet pregabalin salt.

[0202] The obtained salt wet product was transferred to another reaction flask, and acetone (300 mL) and water (125 mL) were added. The temperature was raised to 55°C, and the wet product was stirred until it was completely dissolved to obtain a clear solution. Hydrochloric acid was added dropwise to adjust the pH of the system to 3.5, and the temperature was naturally lowered to 25°C. The crystal was separated by stirring for 1 hour to obtain a solution containing pramipexole crystals.

[0203] The solution containing pramipexole crystals was concentrated under reduced pressure to a volume ratio of 1.5 mL / g (75 mL) of the weight of the pramipexole crude product (concentration temperature was 50°C). Then, the temperature was lowered to 15°C, and the crystal was separated by stirring for 2 hours. The obtained solid was washed twice with acetone pre-cooled to 5°C, and vacuum dried to obtain 45.5 g of white crystals. The purity of the crystals was 99.94% as detected by HPLC, and the yield was 90.9%. SEM observation (see Figure 1) showed that the crystals were regular rhombic or block polyhedron. Figure 7

[0204] Comparative Example 3

[0205] The purification conditions and raw materials of this comparative example were basically the same as those of Example 1, except that the solvent was replaced by ethanol. Finally, 44.7 g of white crystals were obtained, with a purity of 99.93% and a yield of 89.3%. SEM observation (see Figure 2) showed that the crystals were in a mixed morphology of elongated needles and irregular long strips, with small particles and poor flowability, which made it difficult to directly compress the tablets. Figure 8

[0206] Although high-purity pramipexole crystals can be obtained by using ethanol as the solvent, the crystals are in an elongated needle or irregular long strip morphology, and have poor flowability. The reason may be that ethanol has strong polarity and hydrogen bond donor ability, forms a stable solvation layer with pramipexole molecules, inhibits the growth of lateral crystal faces, and promotes rapid extension along the main axis. At the same time, the polarity of the ethanol-water system changes dramatically, resulting in a sharp increase in supersaturation, a dense nucleation, and uneven crystal development. Acetone is an aprotic solvent with weak hydrogen bonding, and the molecules are more stable in the solution, which is conducive to balanced growth in all directions and the formation of regular rhombic structures.

[0207] Comparative Example 4

[0208] The purification conditions and raw materials of this comparative example were basically the same as those of Example 1, except that the ratio of acetone and water in step (2) was replaced by 6:1 instead of 2.4:1. Finally, 45.4 g of white crystals were obtained, with a purity of 99.97% and a yield of 90.8%. SEM observation (see Figure 3) showed that the crystals were in a mixed morphology of elongated needles and irregular long strips, with small particles and poor flowability, which made it difficult to directly compress the tablets. Figure 9 ​​)The crystal is in the form of fine needle, long strip or amorphous particle, and the flowability is very poor. It is shown that the ratio of acetone and water deviating from the scope of the present application will result in the deterioration of the crystallization. The reason can be that when the ratio of acetone and water is adjusted from 2.4:1 to 6:1 (water phase is too little), the polarity of the system is reduced, the solvent desolvation ability of the pregabalin molecule is enhanced, the supersaturation degree is rapidly increased, the nucleation is dense and the growth is out of control, the crystal is rapidly extended along a single direction, and the fine needle or long strip or amorphous particle is formed. At the same time, the lack of water phase weakens the repulsion to impurities, the interface is disorderly, and the regular crystal face is inhibited from orderly stacking. Under the ratio of ketone-water in Example 1, the ketone and water cooperatively regulate the polarity and hydrogen bond environment, the supersaturation degree evolves smoothly, and the symmetrical development of the rhombic crystal is facilitated. It is shown that the fine adjustment of the ratio of acetone and water can significantly change the crystallization kinetics, and the precision control of the process of the present application is embodied.

Claims

1. A method for purifying pregabalin, characterized in that, The purification method includes the following steps: (1) Pregabalin and an organic base are made into a salt in a ketone solvent and dissolved in the ketone solvent. Then the solution is cooled to 0-10°C, stirred, and the solid is precipitated. The solid is filtered to obtain the wet salt of pregabalin. (2) The wet sample of pregabalin salt is added to a mixed solvent consisting of a ketone solvent and water. After heating to completely dissolve the pregabalin salt, acid is added dropwise to adjust the pH of the solution to 2.0–5.

0. After cooling, the solution is stirred to precipitate crystals. In a mixed solvent composed of ketone solvent and water, the volume ratio of ketone solvent to water is 3.5:1 to 1.5:

1.

2. The purification method according to claim 1, characterized in that, In step (1), the ketone solvent is selected from acetone, butanone, cyclohexanone, methyl isobutyl ketone, acetophenone, or methyl methyl ketone, more preferably, acetone, and / or The organic base is selected from triethylamine and / or diethylamine, and / or The molar ratio of pregabalin to an organic base is 1:1.0–1.5, more preferably 1:1.1–1.3, and / or The weight-to-volume ratio of ketone solvent to pregabalin is 3–10 mL / g, more preferably 4–6 mL / g, and / or The dissolution of the salt formed by pregabalin and an organic base in a ketone solvent is carried out under heating conditions, at a temperature of 40–70°C, more preferably 50–60°C, and / or The stirring time is 0.5 to 3 hours, more preferably 1 to 1.5 hours.

3. The purification method according to claim 1, characterized in that, In step (2), The ketone solvent is selected from acetone, butanone, cyclohexanone, methyl isobutyl ketone, acetophenone, methyl methyl ethyl ketone, or combinations thereof, preferably acetone, and / or The acid is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, citric acid, malic acid, tartaric acid, or a combination thereof, preferably hydrochloric acid, and / or Adjust the pH of the solution to 3.0–4.

0. The volume ratio of ketone solvent to water in the mixed solvent is 3:1 to 2:1, and / or The volume-to-weight ratio of the mixed solvent to pregabalin is 5–15 mL / g, more preferably 6–10 mL / g, and / or The heating temperature is 40–70°C, more preferably 50–60°C, and / or The temperature of the system after cooling is 20–30°C, and / or The stirring time is 0.5 to 3 hours, more preferably 1 to 1.5 hours.

4. The purification method according to claim 1, characterized in that, The method further includes the following steps: (3) After the liquid containing crystals obtained in step (2) is cooled down, it is stirred and crystallized again. After filtration, pregabalin crystals are obtained.

5. The purification method according to claim 4, characterized in that, The solution containing crystals is concentrated until the volume-to-weight ratio of its remaining volume to pregabalin is 1.2–5.0 mL / g, more preferably 1.2–3.0 mL / g, and / or Concentration temperature is 40–60°C, and / or The cooled temperature is 5–20°C, more preferably 10–18°C, and / or Continue stirring for 1 to 4 hours, more preferably 1.5 to 3 hours, to allow crystallization to occur.

6. The purification method according to claim 4, characterized in that, The method further includes the step of washing the obtained pregabalin 1 to 3 times with a ketone solvent after filtration. Preferably, the ketone solvent used for washing is the same as the ketone solvent used in step (2).

7. A new crystal form of pregabalin, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern, expressed in 2θ angles, shows characteristic peaks at 9.50°±0.2°, 12.21°±0.2°, 16.62°±0.2°, and 19.04°±0.2°. The new crystal form of pregabalin has a rhombic and / or blocky polyhedral morphology.

8. The pregabalin crystal according to claim 7, characterized in that, The new crystal form of pregabalin also has one or more of the following characteristics: (i) The aspect ratio of the rhombic or blocky polyhedron is 1 to 3:1, more preferably 1 to 2:

1. (ii) The median grain size D50 of the new crystal form is 200–400 μm, and D90 ≤ 600 μm. (iii) The bulk density of the new crystal form is 0.620 to 0.630 g / mL and the tap density is 0.690 to 0.710 g / mL.

9. The pregabalin crystal according to claim 7 or 8, characterized in that, The new crystal form of pregabalin also has one or more of the following characteristics: (iv) Using Cu-Kα radiation, the X-ray powder diffraction pattern, expressed in 2θ angles, also exhibits characteristic peaks at one or more of the following locations: 18.18°±0.2°, 19.75°±0.2°, 20.13°±0.2°, 22.15°±0.2°, 23.18°±0.2°, 23.48°±0.2°, 24.64°±0.2°, 26.92°±0.2°, 29.81°±0.2°, 35.58°±0.2°, and 38.66°±0.2°. (v) Its X-ray powder diffraction pattern is basically as shown in Figure 1-b, Figure 2-b, Figure 3-b, Figure 4-b or Figure 5-b; (vi) Its differential scanning calorimetry (DSC) curve shows an endothermic peak at 192.91±5℃. (vii) Its differential scanning calorimetry (DSC) plot is basically shown in Figure 1-e. (viii) Its thermogravimetric analysis showed that there was basically no weight loss at 40℃ to 105℃; (ix) Its thermogravimetric analysis diagram is basically shown in Figure 1-f. (x) Its polarized light microscope images are basically shown in Figure 1-c, Figure 2-c, Figure 3-c, Figure 4-c or Figure 5-c.

10. A pharmaceutical composition, characterized in that, It comprises pregabalin crystals obtained by the purification method according to any one of claims 1-6 or the new crystal form of pregabalin according to any one of claims 7-9, and pharmaceutically acceptable excipients.

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