Flaky L-tryptophan / 2, 3-dipicolinic acid eutectic crystal and preparation process thereof

Abstract

The invention relates to the technical field of pharmaceutical co-crystals, and particularly discloses a flaky L-tryptophan / 2, 3-dipicolinic acid co-crystal and a preparation process thereof.The preparation process comprises the steps that L-tryptophan and 2, 3-dipicolinic acid are dissolved in water, the solution is heated to 40-50 DEG C, a crystal modifier is added, the temperature is reduced to 30-35 DEG C, heat preservation and crystal growing are conducted for 1-3 h, then the temperature is continuously reduced to 5-15 DEG C, heat preservation and crystal growing are conducted for 1-3 h, solid-liquid separation and drying are conducted, and the flaky L-tryptophan / 2, 3-dipicolinic acid / 2, 3-dipicolinic acid co-crystal is obtained. And carrying out crystallization to obtain the flaky L-tryptophan / 2, 3-dipicolinic acid eutectic crystal. The crystal modifier is calcium chloride, sodium chloride or lauryl sodium sulfate. The flaky L-tryptophan / 2, 3-dipicolinic acid eutectic crystal with uniform particle size distribution can be obtained through the process, the purity of the product can reach 99% or above, the yield can reach 78% or above, the fluidity, stability and solubility of the flaky L-tryptophan / 2, 3-dipicolinic acid eutectic crystal product are higher, and improvement of the market competitiveness of the L-tryptophan product is facilitated.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical co-crystals, and in particular to a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal and a preparation process thereof. Background Art

[0002] L-Tryptophan, whose chemical name is L-2-amino-3-indolylpropionic acid, has a molecular formula of C 11 H 12 N2O2 is white to yellowish white crystal or crystalline powder, soluble in dilute acid and dilute alkali, slightly soluble in water, insoluble in methanol, ethanol, acetone, etc. Its structural formula is as follows.

[0003]

[0004] L-tryptophan is an aromatic amino acid, an essential amino acid for humans and animals. It participates in the synthesis of body proteins and the regulation of metabolic networks. It is widely present in nature and has broad application prospects in the fields of medicine, food and feed. In medicine, L-tryptophan can be converted into hormones such as 5-hydroxytryptophan with central nervous system regulation function, as well as physiologically active substances such as pigments, alkaloids, coenzymes, and plant hormones through metabolism, so it has the effects of anti-depression, anti-anxiety, eliminating nervous tension and improving sleep. In food, L-tryptophan can be used as a food additive to enhance the body's utilization of protein, as a preservative to prevent milk powder from spoiling, or as a fish preservative to prevent protein decomposition and mold. In feed, L-tryptophan is very effective as an additive to increase the weight gain rate of poultry and livestock and enhance the disease resistance of poultry and livestock.

[0005] However, the L-tryptophan powder prepared by the current production process has some problems such as poor fluidity, low bulk density, and low solubility, which to a certain extent limit its clinical application. Therefore, finding a simple method to improve the physicochemical properties of L-tryptophan, increase its bioavailability, and enhance the efficacy is of great significance for expanding the clinical application of L-tryptophan. Summary of the invention

[0006] In view of the problem that L-tryptophan powder prepared by the existing process has poor fluidity, low bulk density and low solubility, which limits its clinical application, the present invention provides a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal and a preparation process thereof.

[0007] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0008] A process for preparing a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal comprises the following steps:

[0009] Step 1, dissolving L-tryptophan and 2,3-pyridinedicarboxylic acid in water to obtain an L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0010] Step 2: heating the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 40°C to 50°C, adding a crystal medium, cooling to 30°C to 35°C, keeping the temperature for 1h to 3h, and then cooling to 5°C to 15°C, keeping the temperature for 1h to 3h, separating the solid and the liquid, and drying to obtain a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic;

[0011] Wherein, the crystal medium is calcium chloride, sodium chloride or sodium dodecyl sulfate.

[0012] Compared with the prior art, the preparation process of the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic provided by the present invention adopts water as a crystallization solvent, calcium chloride, sodium chloride or sodium dodecyl sulfate as a crystal medium, and controls the conditions of the crystallization process, such as the addition temperature of the crystal medium, the crystal growth temperature and time, etc., to regulate the crystal growth conditions, and obtain a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product with uniform particle size distribution, complete crystal habits and no agglomeration. At the same time, the inventor unexpectedly discovered that the eutectic product obtained by crystallization is a eutectic product of a new crystal form. Studies have shown that the fluidity and stability of the L-tryptophan / 2,3-pyridinedicarboxylic acid product are significantly improved, and compared with L-tryptophan, the solubility is also significantly improved, which is beneficial to improve the stability of L-tryptophan during storage, and improve the bioavailability of L-tryptophan, which is beneficial to improve the market competitiveness of L-tryptophan products and has a high value for promotion and application.

[0013] Furthermore, in step 1, the molar ratio of L-tryptophan to 2,3-pyridinedicarboxylic acid is 1:1 to 3:1.

[0014] Preferably, in step 1, the molar ratio of L-tryptophan to 2,3-pyridinedicarboxylic acid is 1:1.

[0015] Furthermore, in step 1, the total mass concentration of the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution is 2.5% to 6%.

[0016] If the mass ratio of L-tryptophan and 2,3-pyridinedicarboxylic acid to the crystallization solvent is too low, the product yield will be reduced. If the mass ratio is too high, although the product yield can be improved, the supersaturation in the system is not easy to control within a range that is conducive to good crystal growth, resulting in too fast crystallization nucleation rate and too high crystal slurry suspension density, which easily causes fine crystals to adhere to the crystal surface, resulting in uneven product particle size distribution and agglomeration.

[0017] The preferred mass ratio is conducive to obtaining L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystals with complete and uniform crystal habits while ensuring the product yield, and makes the particle size distribution of the prepared L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystals more uniform.

[0018] Furthermore, in step 2, the amount of the crystal medium added is 1% to 5% of the total mass of L-tryptophan and 2,3-pyridinedicarboxylic acid.

[0019] Preferably, in step 2, the amount of the crystal mediator added is 3% of the total mass of L-tryptophan and 2,3-pyridinedicarboxylic acid.

[0020] The preferred crystal mediator and its specific addition amount can achieve fine control of the crystal growth process, avoid the formation of too many small crystals or too large crystals, and improve the uniformity of particle size; and can also promote the preferential growth of specific crystal faces, thereby obtaining a lamellar L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic with good crystal habits.

[0021] Furthermore, step 2 is specifically as follows: heating the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 40°C to 50°C, adding a crystallizing agent under stirring conditions of 300r / min to 350r / min, and after the crystallizing agent is dissolved, continuing to stir for 25min to 35min, then cooling to 30°C to 35°C and keeping the temperature for 1h to 3h, and then continuing to cool to 5°C to 15°C, keeping the temperature for 1h to 3h, separating the solid and the liquid, and drying to obtain flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectics.

[0022] Preferably, in step 2, the temperature is lowered to 30°C to 35°C at a rate of 0.8°C / min to 1.2°C / min.

[0023] Preferably, in step 2, the temperature is lowered to 5°C to 15°C at a rate of 0.1°C / min to 0.5°C / min.

[0024] The optimal cooling rate can make the crystal grow according to the most stable crystal plane, form a more regular lamellar crystal habit, and is also beneficial to improving the uniformity of crystal particle size.

[0025] The present invention also provides a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal, which is prepared by any of the above-mentioned preparation processes for the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal.

[0026] The preparation process of the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic provided by the present invention realizes effective control of the growth process of the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic by controlling the combination strategies such as water as the crystallization solvent, the addition time and type of the medium, the crystal cultivation temperature and time, etc., and a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic with moderate particle size and uniform particle size distribution can be prepared by one crystallization. The purity of the product can reach more than 99%, and the yield can reach more than 78%. At the same time, the prepared flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product has higher fluidity, stability and solubility, which helps to improve the market competitiveness of the L-tryptophan product. In addition, the amount of crystallization solvent used is small, non-toxic and harmless, low cost, easy to achieve large-scale industrial production, and has a high value of promotion and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a microscope photo of L-tryptophan;

[0028] Figure 2 This is a microscope photo of 2,3-pyridinedicarboxylic acid;

[0029] Figure 3 This is a microscope photograph of the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal prepared in Example 1;

[0030] Figure 4 The X-ray powder diffraction pattern of the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal prepared in Example 1;

[0031] Figure 5 A schematic diagram of the crystal structure of the flake L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal prepared in Example 1;

[0032] Figure 6 This is a microscope photograph of the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in Comparative Example 1;

[0033] Figure 7 This is a microscope photograph of the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in Comparative Example 2;

[0034] Figure 8 This is a microscope photograph of the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in Comparative Example 3;

[0035] Fig. 9 This is a microscope photograph of the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in Comparative Example 4;

[0036] Fig.10 This is a microscope photograph of the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in Comparative Example 5;

[0037] Fig.11 This is a microscope photograph of the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in Comparative Example 6;

[0038] Fig.12 This is a microscope photograph of the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in Comparative Example 7;

[0039] Fig.13 The X-ray powder diffraction pattern of the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in Comparative Example 7;

[0040] Fig.14 It is a comparison chart of the particle size distribution of L-tryptophan, the flake-like L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal prepared in Example 1, and the needle-like L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal prepared in Comparative Example 1. DETAILED DESCRIPTION

[0041] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0042] The purity of the L-tryptophan raw material used in the following examples is 97%, and the purity of the 2,3-pyridinedicarboxylic acid raw material is 96%.

[0043] Test method:

[0044] 1. Single crystal X-ray diffraction

[0045] Instrument: Bruker D8 Venture Metal Jet Photon II

[0046] wavelength:

[0047] Target: Ga-Kα radiation.

[0048] 2. X-ray powder diffraction

[0049] Instrument: D / MAX-2500 (Rigaku, Japan)

[0050] Scanning range (2θ): 2.0°~50.0°

[0051] Target: Cu-Kα radiation

[0052] Light tube voltage: 40kV

[0053] Light tube current: 100mA

[0054] Scanning step: 0.02°.

[0055] 3. Particle size analysis

[0056] The particle sizes of L-tryptophan, the flake-like L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals prepared in the examples, and the needle-like L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals prepared in the comparative examples were all measured by Master size 3000 Malvern particle size analyzer.

[0057] 4. High Performance Liquid Chromatography Analysis

[0058] Instrument: High performance liquid chromatography (Agilent 1220)

[0059] Chromatographic column: Hypersil BDS C18 (250mm*4.6mm, 5μm)

[0060] Mobile phase: 0.025% phosphoric acid: methanol = 30:70

[0061] Flow rate: 1mL / min

[0062] Detection wavelength: 265nm

[0063] Column temperature: 30℃.

[0064] Example 1

[0065] This embodiment provides a method for preparing a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal, comprising the following steps:

[0066] Step 1: Accurately weigh 1 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in 50 mL of water to obtain a L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0067] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 45°C, add 0.0546 g of anhydrous calcium chloride under stirring conditions of 350 r / min, and continue stirring for 30 minutes after dissolution. Cool to 35°C at a rate of 1°C / min, keep warm for 2 hours, then cool to 5°C at a rate of 0.2°C / min, keep warm for 2 hours, filter, and dry in a vacuum oven at 45°C to obtain a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0068] The flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this example was measured by high performance liquid chromatography, and the measurement results showed that the purity was 99.81%, and the product yield was 81.5%.

[0069] Microscope photos of L-tryptophan, 2,3-pyridinedicarboxylic acid, and the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this example are shown in Figure 1. Figure 1 to Figure 3 As shown in the figure, it can be seen that the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this example is a flaky crystal with complete crystal habits and no agglomeration.

[0070] The XRD pattern of the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in this example is as follows: Figure 4 shown.

[0071] In order to detect the structural data of the flake-like L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal prepared by the present invention, a single crystal of the flake-like L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal was prepared as follows.

[0072] Accurately weigh 0.1 g of L-tryptophan and 0.0819 g of crude 2,3-pyridinedicarboxylic acid and dissolve them in 10 mL of water. Stir and dissolve at room temperature. Filter the solution into a glass container. Slowly evaporate the filtrate at room temperature until yellow crystals appear to obtain single crystals of flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals.

[0073] The single crystal sample prepared above was measured by single crystal X-ray diffraction, and its single crystal molecular structure is shown in the figure below: Figure 5 As shown, the results prove that the cocrystal is composed of 1 molecule of L-tryptophan, 1 molecule of 2,3-pyridinedicarboxylic acid and 3 molecules of water. The single crystal data are shown in Table 1.

[0074] Table 1

[0075]

[0076]

[0077] Example 2

[0078] This embodiment provides a method for preparing a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal, comprising the following steps:

[0079] Step 1: Accurately weigh 2 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in 45 mL of water to obtain a L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0080] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 40°C, add 0.141 g of sodium chloride under stirring at 320 r / min, continue stirring for 25 min after dissolution, cool to 30°C at a rate of 0.8°C / min, keep warm for 1 h, then cool to 15°C at a rate of 0.5°C / min, keep warm for 3 h, filter, and dry in a vacuum oven at 45°C to obtain a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0081] The flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this example was measured by high performance liquid chromatography, and the measurement results showed that the purity thereof was 99.57%, and the product yield was 85.5%.

[0082] Example 3

[0083] This embodiment provides a method for preparing a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal, comprising the following steps:

[0084] Step 1: accurately weigh 3 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in 130 mL of water to obtain a L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0085] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 50°C, add 0.0382 g of sodium dodecyl sulfate under stirring conditions at 300 r / min, and continue stirring for 35 minutes after dissolution. Cool to 40°C at a rate of 1.2°C / min, keep warm for 3 hours, then cool to 10°C at a rate of 0.1°C / min, keep warm for 1 hour, filter, and dry in a vacuum oven at 45°C to obtain a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0086] The flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this example was measured by high performance liquid chromatography, and the measurement results showed that the purity thereof was 99.20%, and the product yield was 78.2%.

[0087] Comparative Example 1

[0088] This comparative example provides a method for preparing needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals, which is different from Example 1 only in that the crystal medium is ammonium chloride, and the rest is exactly the same. The specific steps are as follows:

[0089] Step 1: Accurately weigh 1 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in 50 mL of water to obtain a L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0090] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 45°C, add 0.0546 g of ammonium chloride under stirring conditions of 350 r / min, and continue stirring for 30 minutes after dissolution. Cool to 35°C at a rate of 1°C / min, keep warm for 2 hours, then cool to 5°C at a rate of 0.2°C / min, keep warm for 2 hours, filter, and dry in a vacuum oven at 45°C to obtain a needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0091] The needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this comparative example was measured by high performance liquid chromatography, and the measurement results showed that the purity thereof was 98.27%, and the product yield was 60.8%.

[0092] The microscopic picture of the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is as follows: Figure 6 As shown in the figure, it can be seen that the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example has a large aspect ratio and is in the shape of dispersed needles.

[0093] Comparative Example 2

[0094] This comparative example provides a method for preparing needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals. The only difference from Example 1 is that the crystal medium is sodium dodecylbenzenesulfonate, and the rest is exactly the same. The specific steps are as follows:

[0095] Step 1: Accurately weigh 1 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in 50 mL of water to obtain a L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0096] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 45°C, add 0.0546 g of sodium dodecylbenzene sulfonate under stirring conditions of 350 r / min, and continue stirring for 30 minutes after dissolution. Cool to 35°C at a rate of 1°C / min, keep warm for 2 hours, then cool to 5°C at a rate of 0.2°C / min, keep warm for 2 hours, filter, and dry in a vacuum oven at 45°C to obtain a needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0097] The needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this comparative example was measured by high performance liquid chromatography, and the measurement results showed that the purity thereof was 97.85%, and the product yield was 58.7%.

[0098] The microscopic picture of the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is as follows: Figure 7As shown in the figure, it can be seen that the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example has a large aspect ratio, is needle-shaped, has severe agglomeration and uneven particle size distribution.

[0099] Comparative Example 3

[0100] This comparative example provides a method for preparing needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals, which is different from Example 1 only in that the crystal medium is imidazole, and the rest is exactly the same. The specific steps are as follows:

[0101] Step 1: Accurately weigh 1 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in 50 mL of water to obtain a L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0102] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 45°C, add 0.0546 g of imidazole under stirring at 350 r / min, continue stirring for 30 min after dissolution, cool to 35°C at a rate of 1°C / min, keep warm for 2 h, then cool to 5°C at a rate of 0.2°C / min, keep warm for 2 h, filter, and dry in a vacuum oven at 45°C to obtain a needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0103] The needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this comparative example was measured by high performance liquid chromatography, and the measurement results showed that the purity thereof was 98.87%, and the product yield was 62.9%.

[0104] The microscopic picture of the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is as follows: Figure 8 As shown in the figure, it can be seen that the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example has a large aspect ratio and is in the shape of dispersed needles.

[0105] Comparative Example 4

[0106] This comparative example provides a method for preparing needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals, which is different from Example 1 only in that the crystallization solvent is a mixed solution of ethanol and water, and specifically comprises the following steps:

[0107] Step 1: accurately weigh 1 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in a mixed solution of 25 mL of water and 25 mL of ethanol to obtain an L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0108] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 45°C, add 0.0546 g of anhydrous calcium chloride under stirring conditions of 350 r / min, and continue stirring for 30 minutes after dissolution. Cool to 35°C at a rate of 1°C / min, keep warm for 2 hours, then cool to 5°C at a rate of 0.2°C / min, keep warm for 2 hours, filter, and dry in a vacuum oven at 45°C to obtain a needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0109] The needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this comparative example was measured by high performance liquid chromatography, and the measurement results showed that the purity thereof was 98.71%, and the product yield was 59.2%.

[0110] The microscopic picture of the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is as follows: Fig. 9 As shown in the figure, it can be seen that the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is needle-shaped and severely aggregated.

[0111] Comparative Example 5

[0112] This comparative example provides a method for preparing needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals, which is different from Example 1 only in that the crystallization solvent is a mixed solution of ethanol and water, and the medium is sodium chloride. The method specifically comprises the following steps:

[0113] Step 1: accurately weigh 1 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in a mixed solution of 25 mL of water and 25 mL of ethanol to obtain an L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0114] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 45°C, add 0.0546 g of sodium chloride under stirring conditions of 350 r / min, and continue stirring for 30 minutes after dissolution. Cool to 35°C at a rate of 1°C / min, keep warm for 2 hours, then cool to 5°C at a rate of 0.2°C / min, keep warm for 2 hours, filter, and dry in a vacuum oven at 45°C to obtain a needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0115] The needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this comparative example was measured by high performance liquid chromatography, and the measurement results showed that the purity thereof was 97.93%, and the product yield was 55.4%.

[0116] The microscopic picture of the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is as follows: Fig.10As shown in the figure, it can be seen that the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is needle-shaped and severely aggregated.

[0117] Comparative Example 6

[0118] This comparative example provides a method for preparing needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals, which is different from Example 1 only in that the crystallization solvent is a mixed solution of ethanol and water, and the medium is sodium dodecyl sulfate. The method specifically comprises the following steps:

[0119] Step 1: accurately weigh 1 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in a mixed solution of 25 mL of water and 25 mL of ethanol to obtain an L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0120] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 45°C, add 0.0546 g of sodium dodecyl sulfate under stirring at 350 r / min, and continue stirring for 30 minutes after dissolution. Cool to 35°C at a rate of 1°C / min, keep warm for 2 hours, then cool to 5°C at a rate of 0.2°C / min, keep warm for 2 hours, filter, and dry in a vacuum oven at 45°C to obtain a needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0121] The needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this comparative example was measured by high performance liquid chromatography, and the measurement results showed that the purity thereof was 98.51%, and the product yield was 61.3%.

[0122] The microscopic picture of the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is as follows: Fig.11 As shown in the figure, it can be seen that the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is needle-shaped, severely aggregated, and has an uneven particle size distribution.

[0123] Comparative Example 7

[0124] This comparative example provides a method for preparing needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals, which is different from Example 1 only in that no crystal mediator is added, and specifically comprises the following steps:

[0125] Step 1: Accurately weigh 1 g of L-tryptophan and 0.819 g of 2,3-pyridinedicarboxylic acid and dissolve them in 50 mL of water to obtain a L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution;

[0126] Step 2: Heat the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 45°C, dissolve it with stirring at 350 r / min, continue stirring for 30 min, cool it to 35°C at a rate of 1°C / min, keep it warm for 2 h, then cool it to 5°C at a rate of 0.2°C / min, keep it warm for 2 h, filter it, and dry it in a vacuum oven at 45°C to obtain a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product.

[0127] The flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in this example was measured by high performance liquid chromatography, and the measurement results showed that the purity was 98.37% and the product yield was 60.1%.

[0128] The microscopic picture of the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is as follows: Fig.12 As shown in the figure, it can be seen that the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is needle-shaped, severely aggregated, and has an uneven particle size distribution.

[0129] The XRD pattern of the L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product prepared in this comparative example is as follows: Fig.13 shown.

[0130] Particle size testing

[0131] The particle sizes of L-tryptophan, the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals prepared in Examples 1 to 3, and the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals prepared in Comparative Examples 1 to 7 were measured. The results are shown in Tables 2 and Fig.14 shown.

[0132] Table 2

[0133]

[0134]

[0135] The above results prove that the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic prepared in the embodiment of the present invention has a smaller diameter and a more uniform particle size distribution than L-tryptophan and the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic product in the comparative example.

[0136] Liquidity test

[0137] The repose angles of L-tryptophan, the flake L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals prepared in Examples 1 to 3, and the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals prepared in Comparative Examples 1 to 7 were measured according to the method provided in the "Guidelines for Determination of Powder Flowability" issued by the National Pharmacopoeia Commission. The results are shown in Table 3.

[0138] Table 3

[0139]

[0140]

[0141] The above results prove that the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal product prepared in the embodiment of the present invention has a smaller repose angle and better fluidity than the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal, can effectively avoid the agglomeration problem during transportation and storage, and has better drugability and additivity.

[0142] Bulk density and tap density testing

[0143] The bulk density and tap density of L-tryptophan, the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectics prepared in Examples 1 to 3, and the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid eutectics prepared in Comparative Examples 1 to 7 were tested as follows:

[0144] Bulk density test: Place an appropriate amount of product into a 10mL measuring cylinder, shake it slightly horizontally to make the upper part of the powder in the cylinder flat, and read the volume.

[0145] Tap density test: The bulk density measuring cylinder was repeatedly shaken until the volume of the powder in the measuring cylinder no longer decreased, and the volume was read. The results are shown in Table 4.

[0146] Table 4

[0147]

[0148]

[0149] Note: Carr's index = (tapped density - bulk density) / tapped density. Carr's index reflects the quality of fluidity. The smaller the value, the better the fluidity.

[0150] The above results prove that the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectics prepared in the embodiment of the present invention have a smaller angle of repose and a better bulk density than the raw material and needle-shaped eutectics. The fluidity of the product is greatly improved, and the agglomeration problem during transportation and storage is effectively avoided.

[0151] Stability test

[0152] L-tryptophan, the flake L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals prepared in Examples 1 to 3, and the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystals prepared in Comparative Examples 1 to 7 were subjected to a 10-day accelerated stability study, and the test results at high temperature (45° C., 75% RH) and light (4500 lx) are shown in Table 5. The purity of the samples was determined by high performance liquid chromatography.

[0153] Table 5

[0154]

[0155]

[0156] It can be seen from the above table that the stability of the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal prepared in the embodiment of the present invention is better than that of L-tryptophan and the needle-shaped L-tryptophan / 2,3-pyridinedicarboxylic acid co-crystal, which helps to improve the quality of the L-tryptophan product.

[0157] Solubility test

[0158] The solubility test refers to the relevant content of the Chinese Pharmacopoeia (2020 edition). L-tryptophan, the sheet-like L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic prepared in Examples 1 to 3, the needle-like L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic prepared in Comparative Examples 1 to 7, and the physical mixture of L-tryptophan / 2,3-pyridinedicarboxylic acid (molar ratio 1: 1) were respectively passed through a 100 mesh sieve, and 10 mL of the medium (phosphate buffer of pH = 6.8) was measured respectively, and an excess of sample was added respectively, and placed in a water bath constant temperature oscillator, equilibrated at 37 ° C, 200r / min for 24h, filtered through a 0.45μm microporous membrane, and its solubility was calculated by peak area using a high performance liquid chromatograph. The results are shown in Table 6.

[0159] Table 6

[0160]

[0161]

[0162] The above results prove that the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal prepared in the embodiment of the present invention can improve the solubility properties of L-tryptophan, and its solubility in pH=6.8 phosphate buffer is significantly improved, which is of great significance for improving the bioavailability and efficacy of L-tryptophan.

[0163] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A process for preparing a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal, characterized in that: The following steps are involved: Step 1, dissolving L-tryptophan and 2,3-pyridinedicarboxylic acid in water to obtain an L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution; Step 2: heating the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 40°C to 50°C, adding a crystal medium, cooling to 30°C to 35°C, keeping the temperature for 1h to 3h, and then cooling to 5°C to 15°C, keeping the temperature for 1h to 3h, separating the solid and the liquid, and drying to obtain a flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic; Wherein, the crystal medium is calcium chloride, sodium chloride or sodium dodecyl sulfate.

2. The process for preparing the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal according to claim 1, characterized in that: In step 1, the molar ratio of L-tryptophan to 2,3-pyridinedicarboxylic acid is 1:1 to 3:

1.

3. The process for preparing the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal according to claim 2, characterized in that: In step 1, the molar ratio of L-tryptophan to 2,3-pyridinedicarboxylic acid is 1:

1.

4. The process for preparing the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal according to claim 1, characterized in that: In step 1, the total mass concentration of the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution is 2.5% to 6%.

5. The process for preparing the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal according to claim 1, characterized in that: In step 2, the amount of the crystal mediator added is 1% to 5% of the total mass of L-tryptophan and 2,3-pyridinedicarboxylic acid.

6. The process for preparing the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal according to claim 5, characterized in that: In step 2, the amount of the crystal mediator added is 3% of the total mass of L-tryptophan and 2,3-pyridinedicarboxylic acid.

7. The process for preparing the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal according to claim 1, characterized in that: Step 2 is specifically as follows: heating the L-tryptophan / 2,3-pyridinedicarboxylic acid mixed solution to 40°C to 50°C, adding a crystallizing agent under stirring conditions of 300r / min to 350r / min, and after the crystallizing agent is dissolved, continuing to stir for 25min to 35min, then cooling to 30°C to 35°C and keeping the temperature for 1h to 3h, and then continuing to cool to 5°C to 15°C, keeping the temperature for 1h to 3h, separating the solid and the liquid, and drying to obtain flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectics.

8. The process for preparing the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal according to claim 1 or 7, characterized in that: In step 2, the temperature is lowered to 30°C to 35°C at a rate of 0.8°C / min to 1.2°C / min.

9. The process for preparing the flaky L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal according to claim 1 or 7, characterized in that: In step 2, the temperature is lowered to 5°C to 15°C at a rate of 0.1°C / min to 0.5°C / min.

10. A sheet-like L-tryptophan / 2,3-pyridinedicarboxylic acid cocrystal, characterized in that: The flaky L-tryptophan / 2,3-pyridinedicarboxylic acid eutectic is prepared by the preparation process of any one of claims 1 to 9.

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