Eutectic of p-aminosalicylic acid and proline as well as preparation method and application of eutectic

Abstract

The invention relates to the technical field of pharmaceutical co-crystals, in particular to a co-crystal of p-aminosalicylic acid and proline and a preparation method and application of the co-crystal, the molecular formula of the co-crystal is C7H7NO3. 2C5H9NO2, Mo-K alpha radiation is used, the co-crystal has characteristic peaks at 8.521 + / -0.2 degrees, 9.828 + / -0.2 degrees, 15.584 + / -0.2 degrees, 17.002 + / -0.2 degrees, 22.387 + / -0.2 degrees and 24.087 + / -0.2 degrees through powder X-ray diffraction represented by the angle of 2 theta, and the characteristic peaks are different from the characteristic peaks at the same time. The eutectic crystal provided by the invention not only has very high purity and crystallinity, but also has the solubility obviously higher than that of an existing crystal form, has a relatively high dissolution rate, can be kept stable for a long time without deterioration, effectively avoids the problem of deterioration of a single drug, and keeps relatively good medication safety.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical cocrystal, and particularly relates to a cocrystal of para - amino salicylic acid and proline, and its preparation method and use. Background Art

[0002] Para - amino salicylic acid (PASA) is a white crystalline powder with the molecular formula C7H7NO3. As a second - line drug for treating tuberculosis caused by Mycobacterium tuberculosis, it mainly inhibits Mycobacterium tuberculosis by competitively inhibiting folic acid synthesis, thereby exerting a therapeutic effect. However, the poor solubility of para - amino salicylic acid affects the bioavailability of the drug and limits its clinical application to a certain extent. At present, although there are various pharmaceutical methods for improving the physicochemical properties of para - amino salicylic acid, these methods have problems such as complex processes and high costs. Therefore, it is of great practical significance to find a simple method to improve the physicochemical properties of para - amino salicylic acid and enhance its bioavailability. Summary of the Invention

[0003] Therefore, the technical problem to be solved by the present invention is to overcome the problem of poor solubility of the existing para - amino salicylic acid.

[0004] To achieve the above object, the present invention provides a cocrystal of para - amino salicylic acid and proline, and the molecular formula of the cocrystal is C7H7NO3·2C5H9NO2.

[0005] Further, using Mo - Kα radiation, the powder X - ray diffraction of the cocrystal expressed in 2θ angle has characteristic peaks at 8.521±0.2°, 9.828±0.2°, 15.584±0.2°, 17.002±0.2°, 22.387±0.2°, 24.087±0.2°.

[0006] Further, using Mo - Kα radiation, the powder X - ray diffraction of the cocrystal expressed in 2θ angle also has characteristic peaks at one or more of 20.101±0.2°, 20.420±0.2°, 22.387±0.2°, 23.226±0.2°, 27.365±0.2°.

[0007] Further, the cocrystal has a PXRD pattern substantially as Figure 3 -C shown.

[0008] Further, the cocrystal is in the orthorhombic crystal system, the space group is Pbca, and the unit cell parameters are: α = 89.80 to 90.20°, β = 89.80 to 90.20°, γ = 89.80 to 90.20°; and / or, the eutectic has an endothermic peak in the differential scanning calorimetry curve DSC, and the corresponding temperature range is 145.50 to 149.53 °C.

[0009] The present invention also provides a preparation method of the eutectic of para-aminosalicylic acid and proline as described in any one of the above, including the following steps: dissolving the para-aminosalicylic acid raw material and proline with methanol and water in a volume ratio of 100 to 500:1 (such as 125 to 200:1, 200 to 500:1), filtering to obtain a solution, placing the solution at a temperature below 28 °C for static crystallization, collecting the solid, and thus obtaining the eutectic.

[0010] Further, the volume ratio of methanol to water is 120 to 200:1.

[0011] Further, the molar ratio of the para-aminosalicylic acid raw material to proline is 1:1.8 to 2.8, preferably 1:1.9 to 2.2.

[0012] Further, the ratio of the total mass of the para-aminosalicylic acid raw material and proline to the total volume of methanol and water is 4 to 26:1, preferably 4 to 8:1; wherein, the ratio of mass to volume is mg / mL.

[0013] Further, the dissolution is carried out by the method of heating and stirring;

[0014] Preferably, the temperature of heating and stirring is 35 to 42 °C, more preferably 38 to 41 °C;

[0015] Preferably, the heating method is water bath heating;

[0016] Preferably, the time of heating and stirring is 0.5 to 2.5 h, more preferably 0.5 to 2 h (such as 0.5 to 1 h, 1 to 2 h).

[0017] Further, the temperature of the static crystallization is 4 to 28 °C, preferably 24 to 28 °C.

[0018] Further, the time of static crystallization is 20 min to 72 h (for example, static crystallization at 4 °C for 20 - 30 min, static crystallization at 24 - 28 °C for 48 - 72 h).

[0019] Further, the preparation method includes the following steps: mixing the para-aminosalicylic acid raw material and proline according to a molar ratio of 1:1.9 to 2.2, adding methanol and water with a volume ratio of 100 to 500:1, heating and stirring in a water bath at 38 to 41 °C for 0.5 to 2 h and then filtering, allowing the filtrate to stand for crystallization at 24 to 28 °C, and collecting the solid for 48 to 72 h, thus obtaining the eutectic.

[0020] Further, the filtration is hot filtration.

[0021] The present invention also provides a pharmaceutical composition, comprising any of the cocrystals of para - aminosalicylic acid and proline or any of the cocrystals of para - aminosalicylic acid and proline prepared by the preparation method, and pharmaceutically acceptable excipients.

[0022] The present invention also provides the use of any of the cocrystals of para - aminosalicylic acid and proline or any of the cocrystals of para - aminosalicylic acid and proline prepared by the preparation method or the pharmaceutical composition in the preparation of a drug for treating diseases, preferably in the preparation of an antituberculosis drug.

[0023] The technical solution of the present invention has the following advantages:

[0024] 1. The cocrystal of para - aminosalicylic acid and proline provided by the present invention has a molecular formula of C7H7NO3·2C5H9NO2. This cocrystal not only has high purity and crystallinity, but also the solubility of the cocrystal is significantly higher than that of the existing crystal forms, with a high dissolution rate, which is beneficial to improving the bioavailability of para - aminosalicylic acid. In addition, since there are no solvent molecules in the cocrystal structure, it can remain stable even after being placed at room temperature for a long time, effectively avoiding the problem of deterioration of single drugs and maintaining good drug safety.

[0025] 2. The preparation method of the cocrystal of para - aminosalicylic acid and proline provided by the present invention uses methanol and water with a volume ratio of 100 - 500:1 to dissolve the para - aminosalicylic acid raw material and proline, filters to obtain a solution, and places the solution at a temperature below 28°C for static crystallization, and collects the solid to obtain the cocrystal. By using methanol and water with the above - mentioned specific volume ratio as solvents and combining the control of the crystallization temperature, a large amount of cocrystal solids can be precipitated, preparing para - aminosalicylic acid - proline cocrystals with higher purity and yield. Moreover, this process is simple, has good reproducibility, is easy to operate, has a high yield and purity, and is low in cost, suitable for large - scale production. The solubility of the cocrystal prepared according to this method is higher than that of the existing crystal forms, and it can effectively inhibit the decarboxylation degradation of the drug itself, improving the stability during storage.

[0026] 3. The preparation method of the cocrystal of para - aminosalicylic acid and proline provided by the present invention optimizes the synthesis method by screening suitable feeding ratios, solvent ratios, water - bath heating temperatures and times, crystallization temperatures and other conditions, prepares para - aminosalicylic acid - proline cocrystals with higher purity and yield, and accurately analyzes its molecular structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0028] Figure 1 The ORTEP structure diagram of the co-crystal of para-aminosalicylic acid and proline.

[0029] Figure 2 The hydrogen bond diagram of the co-crystal of para-aminosalicylic acid and proline.

[0030] Figure 3 The comparison of the PXRD spectra of para-aminosalicylic acid raw material, proline and the co-crystal of para-aminosalicylic acid and proline (abbreviated as drug co-crystal) obtained in Example 1.

[0031] Figure 4 The comparison of the PXRD spectra of the software-simulated PXRD spectrum and the co-crystal of para-aminosalicylic acid and proline (abbreviated as drug co-crystal) obtained in Example 1.

[0032] Figure 5 The TG-DSC curve of the co-crystal of para-aminosalicylic acid and proline obtained in Example 1.

[0033] Figure 6 The PXRD spectra of the co-crystals of para-aminosalicylic acid and proline obtained in different examples.

[0034] Figure 7 The comparison of the dissolution rates of the co-crystal of para-aminosalicylic acid and proline obtained in Example 1 and para-aminosalicylic acid raw material in the buffer solution. Specific Embodiments

[0035] The following embodiments are provided to better further understand the present invention, which is not limited to the best embodiment, and does not limit the content and protection scope of the present invention. Any product obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior art features and being the same as or similar to the present invention falls within the protection scope of the present invention.

[0036] In the specification and claims of the present application, compounds are named according to their chemical structural formulas. When representing the same compound, if the naming of the compound does not conform to the chemical structural formula, the chemical structural formula or chemical reaction formula shall prevail. In the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, the definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of the terms provided in the present application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in the present application shall prevail.

[0037] The term powder X-ray diffraction (PXRD) is a technique that uses X-rays to diffract powder samples and can analyze the structure, composition, and physical properties of crystalline materials. An X-ray diffractometer uses the diffraction principle to accurately determine the crystal structure of a substance, analyze the texture and stress of a material, and perform phase analysis, including qualitative and quantitative analysis. For crystalline materials, when the crystal to be measured is at different angles to the incident beam, those crystal planes that satisfy Bragg diffraction will be detected, which are manifested as diffraction peaks with different diffraction intensities on the PXRD pattern. For amorphous materials, since their structure does not have the long-range order of atomic arrangement in the crystal structure but only has short-range order within a few atoms, the PXRD pattern of amorphous materials is some diffuse scattering hump peaks. The abscissa 2Theta / degree of the PXRD pattern is 2θ / °.

[0038] The "2θ angle" as described in the present invention refers to the X-ray diffraction analysis based on Bragg's formula (Bragg's formula is 2dsinθ = nλ), where "θ" refers to the grazing angle or Bragg angle, which is the complementary angle of the incident angle, and "2θ" refers to the diffraction angle, the same as 2-Theta or 2Theta; "d" refers to the interplanar spacing between two adjacent crystal planes in the crystal lattice, in units; "λ" refers to the wavelength of the X-ray; "n" is any positive integer and is correspondingly called the nth-order diffraction. In the PXRD pattern, the abscissa corresponding to the powder diffraction peak is the 2θ angle, and the error range of the peak position 2θ angle is ±0.3°, preferably ±0.2°. When determining the crystal form of the present invention by X-ray diffraction, sometimes due to the measuring instrument or measuring conditions, there will be a slight measuring error for the measured peak. Therefore, when determining the crystal structure, this error should be taken into account. Therefore, the applicant considered the error range (±0.2) when determining the 2θ angle. "Substantially as shown in the figure" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 99% of the peaks in the pattern are shown in the figure.

[0039] Differential scanning calorimetry (DSC) is a thermal analysis method. Under programmed temperature control, the relationship between the power difference (such as in the form of heat) input to the sample and the reference and temperature is measured. The curve recorded by the differential scanning calorimeter is called the DSC curve. With the heat absorption or heat release rate of the sample, that is, the heat flow rate dH / dt (unit: millijoule per second) or the heat flow Heat flow (unit: W / g) as the ordinate and temperature T or time t as the abscissa, various thermodynamic and kinetic parameters can be measured, such as specific heat capacity, heat of reaction, heat of transition, phase diagram, reaction rate, crystallization rate, crystallinity of polymers, sample purity, etc.

[0040] Aiming at the problems of low solubility, poor stability, and poor reproducibility in the existing para - aminosalicylic acid, on the one hand, the present invention provides a co - crystal of para - aminosalicylic acid and proline, and the molecular formula of the co - crystal is C7H7NO3·2C5H9NO2. This co - crystal has good chemical stability, high solubility, and effectively avoids the problems of poor reproducibility and solvent residue through the formation of the co - crystal.

[0041] Among them, proline (Proline, PRO) is a white crystalline powder, easily soluble in water. Its molecular structure contains a rigid five - membered ring skeleton. Proline contains both a carboxyl group that can act as a hydrogen - bond donor and an amino group that can act as a hydrogen - bond acceptor, and can form a new co - crystal with para - aminosalicylic acid through non - covalent interactions such as hydrogen bonds. Figure 1 Figure 1 is the ORTEP structure diagram of the co - crystal of para - aminosalicylic acid and proline. Figure 2 Figure 2 is the hydrogen - bond diagram of the co - crystal of para - aminosalicylic acid and proline.

[0042] From Figure 1 and Figure 2 it can be seen that the co - crystal of para - aminosalicylic acid and proline has a basic structural unit composed of one para - aminosalicylic acid molecule and two proline molecules, and the molecular formula of the co - crystal is C7H7NO3·2C5H9NO2. Among them, the hydroxyl group in the para - aminosalicylic acid molecule acts as a hydrogen - bond donor to form an intramolecular hydrogen bond with the carbonyl group in the carboxyl group. In addition, proline forms zwitterions. The - COO - group in the L - proline structure acts as a hydrogen - bond acceptor to form an intermolecular hydrogen bond with the carboxyl group in the para - aminosalicylic acid molecule. The - COO - group in the D - proline structure acts as a hydrogen - bond acceptor to form an intermolecular hydrogen bond with the amino group in the para - aminosalicylic acid molecule. The basic structural units are alternately connected through the N - H···O hydrogen - bond interaction between prolines to form an infinitely extended chain - like structure. And the chains are stacked into a tight two - dimensional planar structure through the N - H···O hydrogen - bond interaction between prolines.

[0043] In certain specific embodiments, using Mo-Kα radiation, the powder X-ray diffraction of the eutectic represented by the 2θ angle has characteristic peaks at 8.521±0.2°, 9.828±0.2°, 15.584±0.2°, 17.002±0.2°, 22.387±0.2°, and 24.087±0.2°.

[0044] In certain specific embodiments, using Mo-Kα radiation, the powder X-ray diffraction of the eutectic represented by the 2θ angle also has characteristic peaks at one or more of 20.101±0.2°, 20.420±0.2°, 22.387±0.2°, 23.226±0.2°, and 27.365±0.2°.

[0045] In certain specific embodiments, the molecular formula of the eutectic is C7H7NO3·2C5H9NO2. That is to say, the molar ratio of p-aminosalicylic acid molecules to proline molecules in the eutectic is 1:2.

[0046] In certain specific embodiments, the eutectic is in the orthorhombic crystal system, the space group is Pbca, and the unit cell parameters are: α = 89.80 - 90.20°, β = 89.80 - 90.20°, γ = 89.80 - 90.20°.

[0047] In certain specific embodiments, the eutectic has an endothermic peak in the differential scanning calorimetry curve DSC, and the corresponding temperature range is 145.50 - 149.53°C. Its peak value is 147.51°C.

[0048] On the other hand, the present invention provides a method for preparing a eutectic of p-aminosalicylic acid and proline, including the following steps: dissolving p-aminosalicylic acid raw material medicine and proline in methanol and water with a volume ratio of 100 - 500:1, filtering to obtain a solution, placing the solution at a temperature below 28°C for static crystallization, and collecting the solid to obtain the eutectic.

[0049] In order to improve the yield of the eutectic, in certain specific embodiments, the volume ratio of methanol to water is 120 - 200:1.

[0050] In order to improve the yield of the eutectic, in certain specific embodiments, the molar ratio of the p-aminosalicylic acid raw material medicine to proline is 1:1.8 - 2.8, preferably 1:1.9 - 2.2.

[0051] In certain specific embodiments, the ratio of the total mass of the p-aminosalicylic acid raw material medicine and proline to the total volume of methanol and water is 4 - 26:1, preferably 4 - 8:1; wherein, the mass-to-volume ratio relationship is mg / mL.

[0052] In some specific embodiments, the dissolution is carried out by heating and stirring;

[0053] Preferably, the temperature of heating and stirring is 35 - 42 °C, more preferably 38 - 41 °C;

[0054] Preferably, the heating method is water bath heating;

[0055] Preferably, the time of heating and stirring is 0.5 - 2.5 h, more preferably 0.5 - 2 h.

[0056] In order to improve the yield of the eutectic, in some specific embodiments, the temperature of static crystallization is 4 - 28 °C, preferably 24 - 28 °C.

[0057] In some specific embodiments, the time of static crystallization is 20 min - 72 h (for example, static crystallization for 20 - 30 min at 4 °C and static crystallization for 48 - 72 h at 24 - 28 °C).

[0058] In some specific embodiments, the preparation method of the eutectic comprises the following steps: mixing para - aminosalicylic acid raw material medicine and proline according to a molar ratio of 1:1.9 - 2.2, adding methanol and water with a volume ratio of 100 - 500:1, heating and stirring in a water bath at 38 - 41 °C for 0.5 - 2 h, then filtering, and allowing the filtrate to crystallize statically at 24 - 28 °C for 48 - 72 h, collecting the solid to obtain the eutectic.

[0059] On the other hand, the present invention provides a pharmaceutical composition comprising the eutectic of para - aminosalicylic acid and proline as described above or the eutectic of para - aminosalicylic acid and proline prepared by the above - mentioned preparation method, and pharmaceutically acceptable excipients.

[0060] Among them, the types of the pharmaceutically acceptable excipients are not limited in the present invention and can be conventional solvents, fillers, binders, disintegrants, preservatives, solubilizers, etc. in the art.

[0061] The preparation method of the pharmaceutical composition in this study can be as follows: using standard or conventional techniques to combine the eutectic with pharmaceutically acceptable excipients to prepare a usable dosage form, such as tablets, granules, injections, oral liquids, etc.

[0062] On the other hand, the present invention provides the use of the eutectic of para - aminosalicylic acid and proline as described in any one of the above, or the eutectic of para - aminosalicylic acid and proline prepared by the preparation method as described in any one of the above, or the pharmaceutical composition for the preparation of a drug for treating diseases, preferably for the preparation of an anti - tuberculosis drug.

[0063] In the following embodiments of the present invention, the active pharmaceutical ingredient is para-aminosalicylic acid provided by Shanghai Macklin Biochemical Co., Ltd., with a chemical purity of 98%. Proline is proline raw material provided by Shanghai Macklin Biochemical Co., Ltd., with a chemical purity of 99%.

[0064] Example 1

[0065] This example provides a method for preparing a co-crystal of para-aminosalicylic acid and proline, which includes the following steps: Add 30.6 mg of para-aminosalicylic acid and 46.2 mg of proline into a round-bottom flask, and add 10 mL of methanol and 50 μL of deionized water to the flask. Stir well at 40 °C in a water bath for 60 min. After filtration, a light brown transparent solution is obtained. Crystallize by static precipitation at a controlled temperature of 24 - 28 °C for 48 hours. Collect the solid phase to obtain the co-crystal of para-aminosalicylic acid and proline, with a yield of 91.35%.

[0066] The co-crystal was characterized by powder X-ray diffraction (PXRD diffraction) and thermogravimetry-differential scanning calorimetry (TGA-DSC) respectively to further confirm the formation of the co-crystal.

[0067] ① Powder X-ray diffraction (PXRD diffraction)

[0068] Powder X-ray diffraction was performed on the co-crystal, para-aminosalicylic acid, and proline respectively. The measurement conditions are as follows:

[0069] Cu target Ka, Mo-Kα target tube voltage 40 kV, tube current 10 mA, scanning speed 2° / min, measured by a D8 type powder X-ray diffractometer of BRUKER Company, Germany.

[0070] The PXRD diffraction pattern of the above co-crystal is as shown in Figure 3 -C. The powder X-ray diffraction of the co-crystal expressed in 2θ angle has characteristic peaks at 8.521 ± 0.2°, 9.828 ± 0.2°, 15.584 ± 0.2°, 17.002 ± 0.2°, 22.387 ± 0.2°, 24.087 ± 0.2°, and also has characteristic peaks at one or more of 20.101 ± 0.2°, 20.420 ± 0.2°, 22.387 ± 0.2°, 23.226 ± 0.2°, 27.365 ± 0.2°. The specific X-ray diffraction positions of the co-crystal are shown in Table 1. Combining the PXRD diffraction patterns (3-A and 3-B) of para-aminosalicylic acid raw material and proline and Tables 2 - 3, it can be seen by comparing the obtained co-crystal of para-aminosalicylic acid and proline with the two raw materials that the positions and intensities of the characteristic diffraction peaks have changed significantly, indicating the generation of a new phase. The product is the co-crystal of para-aminosalicylic acid and proline.

[0071] Table 1 X-ray Diffraction Results of the Eutectic

[0072]

[0073]

[0074] Table 2 X-ray Diffraction Results of p-Aminosalicylic Acid

[0075]

[0076] Table 3 X-ray Diffraction Results of Proline

[0077]

[0078] ② TGA-DSC Measurement

[0079] The eutectic was used for TGA-DSC measurement, and the measurement conditions were as follows:

[0080] Measured by Netzsch STA 409PC synchronous thermal analyzer, the TGA curve and DSC curve of the eutectic are as Figure 5 shown. It can be seen from the figure that the obtained eutectic is a homogeneous phase with a melting point of 147.51 °C.

[0081] Example 2

[0082] This example provides a preparation method of the eutectic of p-aminosalicylic acid and proline, which is basically the same as that in Example 1, except that in this example, the volume of deionized water is adjusted to 100 μL, and the other process conditions and operations are the same as those in Example 1. Finally, the yield of the eutectic of p-aminosalicylic acid and proline is 88.35%. The measured PXRD pattern is shown in Figure 6 shown, which is basically the same as that in Figure 3 -C in Example 1.

[0083] Example 3

[0084] This example provides a preparation method of the eutectic of p-aminosalicylic acid and proline, which is basically the same as that in Example 1, except that in this example, the mass of proline is adjusted to 64.4 mg of proline, and the other process conditions and operations are the same as those in Example 1. Finally, the yield of the eutectic of p-aminosalicylic acid and proline is 90.18%. The measured PXRD pattern is shown in Figure 6 shown, which is basically the same as that in Figure 3 -C in Example 1.

[0085] Example 4

[0086] This example provides a method for preparing the cocrystal of para - aminosalicylic acid and proline, which is basically the same as Example 1. The only difference is that in this example, it is fully stirred in a 35 °C water bath, and the rest of the process conditions and operations are the same as those in Example 1. Finally, the yield of the cocrystal of para - aminosalicylic acid and proline is 90.05%. The measured PXRD pattern is shown in Figure 6 as shown, which is basically the same as Figure 3 -C in Example 1.

[0087] Example 5

[0088] This example provides a method for preparing the cocrystal of para - aminosalicylic acid and proline, which is basically the same as Example 1. The only difference is that the stirring time is adjusted to 150 min, and the rest of the process conditions and operations are the same as those in Example 1. Finally, the yield of the cocrystal of para - aminosalicylic acid and proline is 89.63%. The measured PXRD pattern is shown in Figure 6 as shown, which is basically the same as Figure 3 -C in Example 1.

[0089] Example 6

[0090] This example provides a method for preparing the cocrystal of para - aminosalicylic acid and proline, which is basically the same as Example 1. The only difference is that the static crystallization time is adjusted to 72 hours, and the rest of the process conditions and operations are the same as those in Example 1. Finally, the yield of the cocrystal of para - aminosalicylic acid and proline is 86.64%. The measured PXRD pattern is shown in Figure 6 as shown, which is basically the same as Figure 3 -C in Example 1.

[0091] Example 7

[0092] This example provides a method for preparing the cocrystal of para - aminosalicylic acid and proline, including the following steps: Place 300 mg of para - aminosalicylic acid raw material and 460 mg of proline in a round - bottom flask, add a mixed solution of 30 mL of methanol and 150 μL of deionized water to the mixed powder, heat and stir in a 40 °C water bath for 60 min, filter while it is hot, and let the filtrate stand in a 4 °C refrigerator. After cooling to 4 °C (the cooling time is 20 min), a solid phase precipitates. Collect the solid phase to obtain the cocrystal of para - aminosalicylic acid and proline, with a yield of 90.3%. The measured PXRD pattern is shown in Figure 6 as shown, which is basically the same as Figure 3 -C in Example 1.

[0093] The cocrystal of para - aminosalicylic acid and proline prepared from Example 7 is a light - brown crystalline crystal cluster and has good chemical stability. Since there are no solvent molecules in the drug cocrystal structure, it can remain stable at room temperature for a long time without any deterioration phenomenon.

[0094] Comparative Examples 1 - 2

[0095] The preparation method of Comparative Example 1 was basically the same as that of Example 1, except that the type of solvent was different. In this comparative example, 10 mL of ethanol was used instead of "10 mL of methanol and 50 μL of deionized water" in Example 1. The results showed that no solid precipitated after standing at 24 - 28°C for 48 hours; after re - cooling to 4°C and standing for crystallization for 48 hours, no solid was still observed to precipitate.

[0096] The preparation method of Comparative Example 2 was basically the same as that of Comparative Example 1, except that the relevant experimental conditions were adjusted. Specifically: the stirring time under water bath was adjusted to 30 min, and the standing crystallization time for both times was adjusted to 72 h, and no crystals precipitated.

[0097] Comparative Examples 3 - 4

[0098] The preparation method of Comparative Example 3 was basically the same as that of Example 1, except that the type of solvent was different. In this comparative example, 10 mL of acetone was used instead of "10 mL of methanol and 50 μL of deionized water" in Example 1. The results showed that no solid precipitated after standing at 24 - 28°C for 48 hours; after re - cooling to 4°C and standing for crystallization for 48 hours, no solid was still observed to precipitate.

[0099] The preparation method of Comparative Example 4 was basically the same as that of Comparative Example 3, except that the relevant experimental conditions were adjusted. Specifically: the stirring time under water bath was adjusted to 30 min, and the standing crystallization time for both times was adjusted to 72 h, and no crystals precipitated.

[0100] Comparative Examples 5 - 6

[0101] The preparation method of Comparative Example 5 was basically the same as that of Example 1, except that the type of solvent was different. In this comparative example, 10 mL of acetonitrile was used instead of "10 mL of methanol and 50 μL of deionized water" in Example 1. The results showed that no solid precipitated after standing at 24 - 28°C for 48 hours; after re - cooling to 4°C and standing for crystallization for 48 hours, no solid was still observed to precipitate.

[0102] The preparation method of Comparative Example 6 was basically the same as that of Comparative Example 5, except that the relevant experimental conditions were adjusted. Specifically: the stirring time under water bath was adjusted to 30 min, and the standing crystallization time for both times was adjusted to 72 h, and no crystals precipitated.

[0103] Comparative Examples 7 - 8

[0104] The preparation method of Comparative Example 7 was basically the same as that of Example 1, except that the type of solvent was different. In this comparative example, 10 mL of methanol was used instead of "10 mL of methanol and 50 μL of deionized water" in Example 1. The results showed that no solid was precipitated after standing at 24 - 28 °C for 48 hours; after cooling back to 4 °C and standing for crystallization for 48 hours, no solid was still observed to precipitate.

[0105] The preparation method of Comparative Example 8 was basically the same as that of Comparative Example 7, except that the relevant experimental conditions were adjusted. Specifically, the stirring time under water bath was adjusted to 30 min, and the standing crystallization time for both times was adjusted to 72 h, and no crystals were precipitated.

[0106] Comparative Examples 9 - 10

[0107] The preparation method of Comparative Example 9 was basically the same as that of Example 1, except that the amount of water was different. In this comparative example, the amount of deionized water was adjusted to 500 μL. The results showed that no solid was precipitated after standing at 24 - 28 °C for 48 hours; after cooling back to 4 °C and standing for crystallization for 48 hours, no solid was still observed to precipitate.

[0108] The preparation method of Comparative Example 10 was basically the same as that of Comparative Example 9, except that the relevant experimental conditions were adjusted. Specifically, the stirring time under water bath was adjusted to 30 min, and the standing crystallization time for both times was adjusted to 72 h, and no crystals were precipitated.

[0109] Comparative Examples 11 - 12

[0110] The preparation method of Comparative Example 11 was basically the same as that of Example 2, except that the temperature of standing crystallization was adjusted from "24 - 28 °C" to "30 - 35 °C". The results showed that no solid was precipitated after standing at 30 - 35 °C for 48 hours; after cooling back to 4 °C and standing for crystallization for 48 hours, no solid was still observed to precipitate.

[0111] The preparation method of Comparative Example 12 was basically the same as that of Comparative Example 11, except that the relevant experimental conditions were adjusted. Specifically, the stirring time under water bath was adjusted to 30 min, and the standing crystallization time for both times was adjusted to 72 h, and no crystals were precipitated.

[0112] Comparative Examples 13 - 14

[0113] The preparation method of Comparative Example 13 was basically the same as that of Example 1, except that the type of solvent was different. In this comparative example, "0.5 mL of acetone" was used instead of "50 μL of deionized water" in Example 1. The results showed that no solid was precipitated after standing at 24 - 28 °C for 48 hours; after cooling back to 4 °C and standing for crystallization for 48 hours, no solid was still observed to precipitate.

[0114] The preparation method of Comparative Example 14 was basically the same as that of Comparative Example 13, except that the relevant experimental conditions were adjusted. Specifically, the stirring time under water bath was adjusted to 30 min, and the standing and crystallization times for both times were adjusted to 72 h, and no crystals were precipitated.

[0115] Comparative Example 15

[0116] 30.6 mg of p-aminoproline and 46.2 mg of arginine were added to a round-bottom flask, and 10 mL of methanol and 50 μL of deionized water were added to the flask. The mixture was stirred thoroughly at 40 °C in a water bath for 60 min. After filtration, a light brown transparent solution was obtained. The solution was allowed to stand and crystallize at 24 - 28 °C for 48 hours, and then the solvent was evaporated to obtain an oily substance. The morphology of this sample was difficult to be characterized in the solid state, so it was not considered.

[0117] Comparative Example 16

[0118] 30.6 mg of p-aminoproline and 46.2 mg of serine were added to a round-bottom flask, and 10 mL of methanol and 50 μL of deionized water were added to the flask. The mixture was stirred thoroughly at 40 °C in a water bath for 60 min. After filtration, a light brown transparent solution was obtained. The solution was allowed to stand and crystallize at 24 - 28 °C for 48 hours, and then the solvent was evaporated to obtain an oily substance. The morphology of this sample was difficult to be characterized in the solid state, so it was not considered.

[0119] Experimental Example 1

[0120] Determination of the intrinsic dissolution rate (IDR) of the eutectic of aminosalicylic acid and proline prepared in Example 1: The IDR of the eutectic sample of p-aminosalicylic acid and proline and the p-aminosalicylic acid API were measured by the Rotating disk method in a pH 7.4 phosphate buffer medium. The experimental parameters included: drug dosage 100 mg; die area: 0.5 cm 2 , pressure: 35 MPa, maintained for 1 min; rotation speed: 80 rpm; volume of dissolution medium: 400 mL.

[0121] The results are shown in the appendix Figure 7 , and it can be seen from this figure that the IDR value of the eutectic of p-aminosalicylic acid and proline is 10.8 mg·min -1 ·cm -2 , which is higher than the IDR value of p-aminosalicylic acid of 3.71 mg·min -1 ·cm -2 , indicating that the drug eutectic in this study can improve the dissolution properties of p-aminosalicylic acid. The research results provide a scientific basis for improving the bioavailability and efficacy of p-aminosalicylic acid.

[0122] Experimental Example 2

[0123] Method for preparing single crystal: The co-crystals of p-aminosalicylic acid and proline prepared in Examples 1-6 are all light brown long strip crystals, and a single crystal sample is selected from the co-crystal of p-aminosalicylic acid and proline prepared in Example 1 as the test sample.

[0124] Test: Test using an Xcalibur Eos diffractometer from Agilent Corporation. The test conditions are as follows: Scanning with Mo-Kα rays monochromatized by a graphite monochromator, and the scanning mode is ω scanning. Set the current and voltage required for the diffraction experiment to 40 mA and 50 kV to obtain crystal data.

[0125] The results show that the molecular formula of the co-crystal of p-aminosalicylic acid and proline in this example is [C7H7NO3·2C5H9NO2], and the basic structural unit is composed of one p-aminosalicylic acid molecule and two proline molecules. The co-crystal of p-aminosalicylic acid and proline belongs to the orthorhombic crystal system, the space group is Pbca, and the unit cell parameters are: α = 90.000°, β = 90.000°, γ = 90.000°.

[0126] The theoretical spectrum of the co-crystal of p-aminosalicylic acid and proline simulated by Mercury software using the crystal data obtained from the X-ray single crystal diffraction experiment. And it is compared with the PXRD diffraction pattern.

[0127] As Figure 4 shown, its characteristic diffraction peaks appear at 8.521°, 9.828°, 15.584°, 17.002°, 20.101°, 20.420°, 22.38°, 23.226°, 24.087°, 27.365°. The powder diffraction peaks are sharp and coincide with the diffraction peaks of the theoretical spectrum of the co-crystal sample of p-aminosalicylic acid and proline, indicating that the prepared co-crystal of p-aminosalicylic acid and proline has high crystallinity and purity.

[0128] Comparison of the results of yield and purity in Experimental Example 3

[0129] The purity and crystallinity of the co-crystals prepared in Examples 1-7 were measured by PXRD and DSC analysis respectively. The results are shown in the following table. The PXRD measurement conditions are as follows:

[0130] Cu target Ka, Mo-Kα target tube voltage 40 kV, tube current 10 mA, scanning speed 2° / min, measured by a D8 type powder X-ray diffractometer from BRUKER Corporation in Germany.

[0131] Measured by a Netzsch STA 409PC synchronous thermal analyzer, under nitrogen protection, heating rate 10 / min.

[0132] Table 4 Yield, purity and crystallinity

[0133] Yield / % Purity / % Crystallinity Example 1 91.35 99.74 99.82 Example 2 88.35 99.58 99.48 Example 3 90.18 99.55 99.24 Example 4 90.05 99.32 99.35 Example 5 89.63 99.67 99.28 Example 6 86.64 99.38 99.53 Example 7 90.30 99.76 99.58

[0134] As shown in the results of Table 4, the eutectic provided by this application has high purity and crystallinity, and the preparation method of this application has a high yield.

[0135] Obviously, the above embodiments are merely examples for clear illustration and not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation manners here. And the obvious changes or modifications derived therefrom are still within the protection scope of this invention.

Claims

1. A cocrystal of para - aminosalicylic acid and proline, characterized in that, The molecular formula of the eutectic is C7H7NO3·2C5H9NO2.

2. The cocrystal of para-aminosalicylic acid and proline according to claim 1, characterized in that, Using Mo-Kα radiation, the powder X-ray diffraction of the eutectic expressed in 2θ angle has characteristic peaks at 8.521±0.2°, 9.828±0.2°, 15.584±0.2°, 17.002±0.2°, 22.387±0.2°, 24.087±0.2°.

3. The cocrystal of para-aminosalicylic acid and proline according to claim 2, wherein Using Mo-Kα radiation, the powder X-ray diffraction of the eutectic expressed in 2θ angle also has characteristic peaks at one or more of 20.101±0.2°, 20.420±0.2°, 22.387±0.2°, 23.226±0.2°, 27.365±0.2°.

4. The co-crystal of para-aminosalicylic acid and proline according to any one of claims 1-3, characterized in that, The eutectic is orthorhombic, with the space group Pbca and the unit cell parameters as follows: α = 89.80 - 90.20°, β = 89.80 - 90.20°, γ = 89.80 - 90.20°; and / or, there is an endothermic peak in the differential scanning calorimetry (DSC) curve of the eutectic, and the corresponding temperature range is 145.50 - 149.53 °C.

5. A method for preparing the eutectic of para-aminosalicylic acid and proline according to any one of claims 1-4, characterized in that, It includes the following steps: Dissolve p-aminosalicylic acid raw material and proline with methanol and water in a volume ratio of 100-500:1, filter to obtain a solution, place the solution at a temperature below 28°C for static crystallization, collect the solid, and thus obtain the eutectic.

6. The preparation method of the eutectic of para-aminosalicylic acid and proline according to claim 5, characterized in that, The volume ratio of methanol to water is 120-200:

1.

7. The preparation method of the eutectic of para-aminosalicylic acid and proline according to claim 5 or 6, characterized in that, The molar ratio of the p-aminosalicylic acid raw material to proline is 1:1.8-2.8, preferably 1:1.9-2.

2.

8. The preparation method of the eutectic of para-aminosalicylic acid and proline according to any one of claims 5-7, characterized in that, The ratio of the total mass of the p-aminosalicylic acid raw material to proline to the total volume of methanol and water is 4-26:1, preferably 4-8:1; wherein, the mass-to-volume ratio relationship is mg / mL.

9. The preparation method of the eutectic of para-aminosalicylic acid and proline according to any one of claims 5-8, characterized in that, Use the method of heating and stirring for dissolution; Preferably, the temperature of heating and stirring is 35-42°C, more preferably 38-41°C; Preferably, the heating method is water bath heating; Preferably, the time of heating and stirring is 0.5-2.5 h, more preferably 0.5-2 h.

10. The preparation method of the eutectic of para-aminosalicylic acid and proline according to any one of claims 5-9, characterized in that, The temperature of the static crystallization is 4-28°C, preferably 24-28°C.

11. The preparation method of the eutectic of para-aminosalicylic acid and proline according to any one of claims 5-10, characterized in that, The time of static crystallization is 20 min-72 h.

12. The preparation method of the eutectic of para-aminosalicylic acid and proline according to any one of claims 5-11, characterized in that, The preparation method of the eutectic includes the following steps: Mix p-aminosalicylic acid raw material and proline according to a molar ratio of 1:1.9-2.2, add methanol and water in a volume ratio of 100-500:1, heat and stir in a water bath at 38-41°C for 0.5-2 h and then filter, let the filtrate stand for crystallization at 24-28°C for 48-72 h, collect the solid, and thus obtain the eutectic.

13. A pharmaceutical composition, characterized in that, It includes the eutectic of p-aminosalicylic acid and proline described in any one of claims 1-4 or the eutectic of p-aminosalicylic acid and proline prepared by the preparation method described in any one of claims 5-11, and pharmaceutically acceptable excipients.

14. Use of the eutectic of p-aminosalicylic acid and proline described in any one of claims 1-4 or the eutectic of p-aminosalicylic acid and proline prepared by the preparation method described in any one of claims 5-12 or the pharmaceutical composition described in claim 13 for the preparation of a drug for treating a disease, preferably for the preparation of an antituberculosis drug.

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