Topiroxostat malonate crystal form A

Abstract

The invention relates to the field of medicine crystal forms, in particular to a topiroxostat malonate crystal form A. In the salt structure, the molar ratio of topiroxostat cations to malonic acid anions is 1: 1. The topiroxostat malonate crystal form A prepared by the invention has relatively high solubility, relatively high release speed and relatively high moisture stability, and has application value in development of medicines for treating gout and hyperuricemia. Meanwhile, the salt forming reaction time is short, and the process time is greatly shortened.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical crystal forms, and particularly relates to a salt synthesized by topiroxostat and malonic acid and a crystal form thereof, a preparation method and application in treating gout and hyperuricemia. BACKGROUND

[0002] Topiroxostat (formula II), chemical name: 4-[5-(pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile, is developed by Sankyo Co., Ltd. and Fuji Pharmaceutical Co., Ltd. of Japan, and approved by the Japanese Pharmaceutical and Medical Device Management Bureau in June 2013 for the treatment of gout and hyperuricemia.

[0003]

[0004] Fuji Pharmaceutical Co., Ltd. of Japan discloses crystal form I, crystal form II and monohydrate of topiroxostat in patent WO2014014515. The solubility of crystal form I, which is the preferred crystal form of the preparation, is slightly large, and there is a disadvantage of low solubility (only 6.2 μg / mL in water). It is found in the development process that crystal form I has the problems of poor dissolution performance and poor moisture stability, so it is necessary to develop a solid form with good dissolution and dissolution, not easy to absorb moisture, simple preparation, suitable for process production.

[0005] CN104961730A reports a new crystal form III, which has advantages in thermal stability and moisture stability. CN105693699A discloses a new crystal form A with good crystal form stability and low moisture absorption. CN114656448A reports a topiroxostat sulfamate co-crystal, CN114685451A discloses a maleic acid topiroxostat dihydrate co-crystal, and CN114685452A reports a topiroxostat-salicylic acid-acetic acid ternary co-crystal. The three co-crystals have improved stability and solubility. As can be seen from the above examples, there is still room for further exploration in the solubility and stability of topiroxostat free base. Salting is a common strategy to modify the properties of drugs, especially the dissolution and dissolution performance. Salt-type drugs are very common in marketed drugs. Therefore, constructing topiroxostat salt is a favorable means to cope with its performance defects, but according to literature and patent research, there is no report on organic crystal salt of topiroxostat. SUMMARY

[0006] The present application aims to provide a topiroxostat malate crystal form A. The topiroxostat malate crystal form A has good solubility and dissolution rate, and also exhibits better humidity stability, which makes up for the defects of topiroxostat crystal form I and has good application value. In addition, the active proton in the structure of the topiroxostat malate crystal form A is located on the triazole ring of the topiroxostat cation, which is different from the disclosed topiroxostat crystal form I (CSD refcode: KUQGOW), crystal form II (CSD refcode: KUQGOW01) and monohydrate (Powder Diffraction, 2022, 37, 166-170).

[0007] The present application provides a topiroxostat malate crystal form A, wherein the molar ratio of the topiroxostat cation to the malate anion is 1:1, and the structure is shown in formula (I).

[0008]

[0009] Further, the topiroxostat malate crystal form A provided by the present application has characteristic peaks at 2θ angles of 11.2±0.2°, 17.6±0.2°, 19.0±0.2°, 25.4±0.2° and 27.8±0.2° in the powder X-ray diffraction spectrum.

[0010] Further, the topiroxostat malate crystal form A provided by the present application has characteristic peaks at 2θ angles of 11.2±0.2°, 13.8±0.2°, 14.0±0.2°, 15.5±0.2°, 17.6±0.2°, 19.0±0.2°, 23.7±0.2°, 25.4±0.2°, 27.8±0.2° and 28.4±0.2° in the powder X-ray diffraction spectrum.

[0011] Further, the topiroxostat malate crystal form A provided by the present application has characteristic peaks at 2θ angles of 11.2±0.2°, 13.8±0.2°, 14.0±0.2°, 15.5±0.2°, 17.6±0.2°, 19.0±0.2°, 23.7±0.2°, 25.4±0.2°, 27.8±0.2° and 28.4±0.2° in the powder X-ray diffraction spectrum.

[0012] Further, the topiroxostat malate crystal form A provided by the present application has endothermic peaks at 183.6℃±5℃ and 330.6℃±5℃ in the differential scanning calorimetry curve.

[0013] The present application also relates to a method for preparing the topiroxostat malate crystal form A, which comprises adding topiroxostat and malic acid into a mixed organic solvent, stirring for a certain period of time, centrifuging, filtering and drying, and the obtained solid is the topiroxostat malate crystal form A.

[0014] The present application also relates to a method for preparing the topiroxostat malate crystal form A, which comprises adding topiroxostat and malic acid into a mixed organic solvent, stirring for a certain period of time, centrifuging, filtering and drying, and the obtained solid is the topiroxostat malate crystal form A.

[0015] Further, the molar ratio of topiroxostat to malonic acid is 1: (1.3-2.5), preferably 1:2.

[0016] Further, the mixed solvent comprises a good solvent and an anti-solvent. The good solvent comprises acetonitrile, acetone, 2-butanone, ethyl acetate and isopropyl acetate; and the anti-solvent comprises n-hexane, n-heptane, n-octane and n-nonane. The volume of the good solvent to the total volume of the mixed solvent is less than 20%.

[0017] Further, the mass-volume ratio of the total solid of topiroxostat and malonic acid to the mixed solvent is 15-25 mg:mL.

[0018] Further, the stirring time is 12-25 min, preferably 20 min; the drying method is vacuum drying; and the drying temperature is 15-60℃.

[0019] The present application relates to the use of topiroxostat malonate crystal form A in the preparation of a product for treating gout and hyperuricemia.

[0020] The present application has the following beneficial effects:

[0021] 1. Compared with the preferred topiroxostat crystal form I, the topiroxostat malonate crystal form A prepared by the present application has higher solubility and dissolution rate, and better bioavailability.

[0022] 2. Compared with the preferred topiroxostat crystal form I, the topiroxostat malonate crystal form A prepared by the present application has higher moisture stability, which is beneficial for drug storage.

[0023] 3. As a drug salting method, the salting reaction time of the present application is short (about 20 min), which is beneficial for shortening the process time. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 The powder X-ray diffraction pattern of topiroxostat malonate crystal form A obtained in Example 1.

[0025] Figure 2 The single crystal structure diagram of topiroxostat malonate crystal form A obtained in Example 6.

[0026] Figure 3 The differential scanning calorimetry diagram of topiroxostat malonate crystal form A obtained in Example 1.

[0027] Figure 4 The powder X-ray diffraction test comparison diagram of topiroxostat crystal form I and topiroxostat malonate crystal form A before and after placing in high humidity for accelerated stability.

[0028] Figure 5 Concentration-time plots for intrinsic dissolution rate test of topiroxostat Form I and topiroxostat malonate Form A. DETAILED DESCRIPTION

[0029] The application is further described in conjunction with the following examples, which are not intended to limit the application. Any addition, substitution, or alteration of equivalents based on the disclosure of the application is within the scope of the application.

[0030] The abbreviations used in the present application are explained as follows:

[0031] XRD: X-ray diffraction

[0032] The data were collected using a D8 Advance X-ray powder diffractometer produced by Bruker, Germany. The instrument was equipped with a LynxEye detector, with Cu-Ka radiation source, and the tube current and voltage of the X-ray generator were 40 mA and 40 kV, respectively. The data were collected at room temperature, with a 2Q range of 3°-40°, a step size of 0.02°, and a residence time of 0.1 s. In the powder XRD patterns of the present application, the error of the 2Q diffraction angle was ±0.2°.

[0033] The single crystal XRD test described in the present application was performed by collecting data using a Pilatus 2M detector produced by DECTRIS, Switzerland, through a synchrotron radiation generated ray source The data were collected at 100 K. The single crystal structure was resolved using OLEX2 software. The molecular model was initially determined using the Intrinsic phasing method in the SHELXT program, and then refined using the full-matrix least squares method in SHELXL. The active hydrogen atoms connected to N or O atoms were confirmed by difference Fourier maps, while the active hydrogen atoms connected to carbon atoms were placed at their geometrically reasonable positions. All non-hydrogen atoms were anisotropically refined. 2

[0034] DSC: differential scanning calorimetry

[0035] The DSC test described in the present application was performed by collecting data using a Discovery DSC 250 differential scanning calorimeter produced by TA, USA. 3-5 mg of the sample was packed in a punched aluminum crucible, and heated from 30°C to the end of the test at a temperature increase rate of 10°C min –1 under a N2flow of 50 mL min –1 .

[0036] Example 1: Preparation of topiroxostat malonate Form A

[0037] ​24.8 mg of topiprestat and 20.8 mg of malonic acid were weighed and added to 2.2 mL of acetonitrile-n-octane (3 / 19, v / v) solution, and magnetically stirred for 20 min. The suspension was separated by centrifugation, the supernatant was discarded, and the remaining powder was placed in a vacuum drying oven for 12 h to obtain the final sample powder. The obtained sample was subjected to powder XRD using Cu-Kα rays. The diffraction angles, interplanar spacings, and relative intensities are shown in Table 1. The X-ray powder diffraction pattern is basically as follows: Figure 1 As shown.

[0038] Table 1. Diffraction angles, interplanar spacings, and relative intensities of topitasta malonate crystal form A.

[0039]

[0040]

[0041]

[0042] Example 2: Preparation of Topiprostine Malonate Crystal Form A

[0043] 24.8 mg of topiprestat and 17.7 mg of malonic acid were weighed and added to 2.1 mL of acetonitrile-n-octane (1 / 9, v / v) solution, and the mixture was magnetically stirred for 20 min. The suspension was separated by centrifugation, the supernatant was discarded, and the remaining powder was dried in a vacuum drying oven to obtain the final sample powder. The obtained sample was subjected to Cu-Ka X-ray powder diffraction, and its X-ray powder diffraction pattern was basically consistent with that of Example 1.

[0044] Example 3: Preparation of Topiprostine Malonate Crystal Form A

[0045] 24.8 mg of topiprestat and 20.8 mg of malonic acid were weighed and added to 2 mL of acetonitrile-n-octane (1 / 9, v / v) solution, and the mixture was magnetically stirred for 20 min. The suspension was separated by centrifugation, the supernatant was discarded, and the remaining powder was dried in a vacuum drying oven to obtain the final sample powder. The obtained sample was subjected to Cu-Ka X-ray powder diffraction, and its X-ray powder diffraction pattern was basically consistent with that of Example 1.

[0046] Example 4: Preparation of Topiprostine Malonate Crystal Form A

[0047] 24.8 mg of topiprestat and 20.8 mg of malonic acid were weighed and added to 2 mL of acetone-n-octane (1 / 9, v / v) solution, and the mixture was magnetically stirred for 20 min. The suspension was separated by centrifugation, the supernatant was discarded, and the remaining powder was dried in a vacuum drying oven to obtain the final sample powder. The obtained sample was subjected to Cu-Ka X-ray powder diffraction, and its X-ray powder diffraction pattern was basically consistent with that of Example 1.

[0048] Example 5: Preparation of Topipseltathione Malonate Crystal Form A

[0049] 24.8 mg of topiprestat and 20.8 mg of malonic acid were weighed and added to 2.2 mL of acetonitrile-n-heptane (3 / 19, v / v) solution, and the mixture was magnetically stirred for 20 min. The suspension was separated by centrifugation, the supernatant was discarded, and the remaining powder was dried in a vacuum drying oven to obtain the final sample powder. The obtained sample was subjected to Cu-Ka X-ray powder diffraction, and its X-ray powder diffraction pattern was basically consistent with that of Example 1.

[0050] Example 6: Preparation of Topixstat Malonate Crystal Form A Single Crystal

[0051] 3.5 mg of topiprostine and 50 mg of malonic acid were added to a mixed solution of acetonitrile, 1,4-dioxane, and methanol (3 / 3 / 2, v / v / v). The mixture was heated to 50 °C until the solid was completely dissolved. The solution was filtered through a 0.22 μm PTFE membrane and then slowly evaporated in a 50 °C water bath. Colorless needle-like crystals were harvested after 12 days. The crystallographic data and structural refinement parameters are shown in Table 2. The asymmetric unit structure is shown below. Figure 2 As shown, the H atom on the cationic triazole ring of topipusta is located on N3, as shown in formula (I).

[0052] Table 2. Crystallographic data and structural refinement parameters of topipsestat malonate crystal form A.

[0053]

[0054] Experimental Example 1: Investigation of Moisture Stability

[0055] To investigate the stability of the topipirostat malonate crystal form A prepared in this invention, topipirostat malonate crystal form A and topipirostat crystal form I prepared in Example 1 were placed at 25°C and 75% relative humidity for 14 days. Samples were taken for powder XRD testing, and the results were compared with those obtained on day 0. Specific results are as follows: Figure 4 As shown.

[0056] from Figure 4It can be seen that after being placed in a high humidity environment for 14 days, topirostat malonate crystal form A did not undergo crystal transformation, while topirostat crystal form I underwent crystal transformation under high humidity. In summary, the topirostat malonate crystal form A prepared in this invention has good moisture stability.

[0057] Experimental Example 2: Investigation of Apparent Equilibrium Solubility

[0058] In the apparent equilibrium solubility experiment, 24.8 mg of topipirostat crystal form I and 35.2 mg of topipirostat malonate crystal form A powder were added to 5 mL of solvent and magnetically stirred at 400 rpm for 3 days at 37 ± 0.2 °C. 3 mL of the suspension was filtered through a 0.22 μm MCE membrane filter and used to test the topipirostat concentration. Apparent equilibrium solubility was determined in phosphate buffer solution (pH 6.8, simulating intestinal fluid) and hydrochloric acid aqueous solution (pH 1.2, simulating gastric fluid). Each experiment was performed three times to eliminate randomness.

[0059] The concentrations are shown in Table 3. At pH 6.8 and 1.2, the concentrations of topiramate in crystal form I were 0.00375 and 0.336 mg / mL, respectively. -1 The concentration of topiramate malonate in crystal form A was significantly increased to 0.0533 and 0.660 mg / mL. -1 This indicates that topipsestat malonate crystal form A has a greater solubility advantage.

[0060] Table 3. Results of Apparent Equilibrium Solubility Test

[0061]

[0062] Experimental Example 3: Investigation of Intrinsic Dissolution Rate

[0063] Intrinsic dissolution rate (IDR) tests were conducted using a paddle dissolution apparatus. A 100 mg sample was subjected to a pressure of 200 MPa for 1 min to form a sample disc (Φ = 10 mm). The disc was then sealed with a sealing film, exposing only one surface to the solvent. The solvent volume was 100 mL, the temperature was maintained at 37 ± 0.2 °C, and the paddle rotation speed was 150 rpm. At specified time points (10, 20, 30, 40, 50, 60, 80, 100, and 120 minutes), 1 mL of solution was drawn for concentration testing. The intrinsic dissolution rate (IDR) was determined in a phosphate buffer solution at pH 6.8 and an aqueous hydrochloric acid solution at pH 1.2. Each experiment was performed three times to eliminate randomness.

[0064] like Figure 5As shown in Table 4, under pH 6.8 and pH 1.2 conditions, topirostat malonate form A has a greater slope and a faster dissolution rate compared to topirostat form I. This indicates that topirostat malonate form A has the advantage of faster dissolution.

[0065] Table 4 Intrinsic dissolution rate results

[0066]

[0067] In summary, the topipsestat malonate crystal form A prepared by this invention has excellent moisture stability, solubility, dissolution properties and a relatively fast salt formation reaction rate.

[0068] It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds and their preparation methods without departing from the spirit or scope of the invention. Therefore, the scope of protection of the present invention covers various modifications and variations made to this application, as long as the modifications or variations are within the scope of the claims and their equivalent embodiments.

Claims

1. A topicasta malonate crystal form A having the structure of formula (I), characterized in that, In crystal form A, the molar ratio of topipsestat cation to malonate anion is 1:

1.

2. In the topipirostat malonate crystal form A as described in claim 1, the H on the topipirostat cationic triazole ring is located on N3.

3. The topixistat malonate crystal form A as described in claim 1, characterized in that, The powder X-ray diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 11.2±0.2°, 17.6±0.2°, 19.0±0.2°, 25.4±0.2° and 27.8±0.2°.

4. The topixistat malonate crystal form A as described in claim 1, characterized in that, The powder X-ray diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 11.2±0.2°, 13.8±0.2°, 14.0±0.2°, 15.5±0.2°, 17.6±0.2°, 19.0±0.2°, 23.7±0.2°, 25.4±0.2°, 27.8±0.2°, and 28.4±0.2°.

5. The topixistat malonate crystal form A as described in claim 1, characterized in that, When its single crystal structure was tested at 100K, the cell parameters were a=3.82240(10), b=27.7674(7), c=14.5811(3), α=90°, β=95.963(2)°, γ=90°, and the space group was P21 / n.

6. The topixistat malonate crystal form A as described in claim 1, characterized in that, The differential scanning calorimetry curves show endothermic peaks at 183.6℃±5℃ and 330.6℃±5℃.

7. The use of topipsestat malonate crystal form A as described in any one of claims 1 to 6 in the preparation of products for treating gout and hyperuricemia.

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