CN114436894A

CN114436894A - Termite sodium crystal form and preparation method thereof

Info

Publication number: CN114436894A
Application number: CN202011217480.9A
Authority: CN
Inventors: 肖飞; 仇波; 张鹏
Original assignee: Cinkate Pharmaceutical Intermediates Co ltd
Current assignee: Cinkate Pharmaceutical Intermediates Co ltd
Priority date: 2020-11-04
Filing date: 2020-11-04
Publication date: 2022-05-06

Abstract

The invention relates to a terimide sodium crystal form and a preparation method thereof. In particular, the present invention provides crystalline form I, crystalline form II and crystalline form IV of the compound of formula a. The crystal form I, the crystal form II and the crystal form IV of the compound of the formula A have excellent stability.

Description

Termite sodium crystal form and preparation method thereof

Technical Field

The invention relates to the field of medicines, and in particular relates to a terimide sodium crystal form and a preparation method thereof.

Background

Leflunomide (leflunomide, LEF) is a small molecule inhibitor, which is approved by the national food and drug administration for marketing in 1999, and is indicated as adult rheumatoid arthritis. Leflunomide has stable curative effect, but the drug has relatively slow onset time and large individual difference; in the clinical application process, particularly when the pharmaceutical composition is used together with methotrexate, adverse drug reactions such as gastrointestinal reaction, liver dysfunction, alopecia and the like are common. Among them, hepatotoxicity is the most important reason for restricting the clinical application of leflunomide.

Teromit (Teriflumide, TER, CASC 108605-62-5) is a drug developed by SInofi-Iventis company, and the structural formula of Teromit is as follows:

terimide (timid)

Tiramite was approved by the FDA for marketing in 2012. The sodium teriflunomide is an effective active ingredient of leflunomide (leflunomide), and the pharmacological action of the sodium teriflunomide comprises the following components: inhibiting the de novo pyrimidine synthesis pathway; inhibiting the activity of tyrosine kinase, and blocking the cell inflammation signal conduction process; inhibit the activation of NF-kB and the expression of regulated genes, such as IL-1 and TNF-alpha; inhibiting lymphocyte proliferation and antibody production; inhibiting the expression of cell adhesion molecules and the transendothelial migration of peripheral blood mononuclear cells; inhibiting Dendritic Cell (DC) function; inhibiting viral replication, and the like. The tiramite is currently approved by the FDA in 2012 for marketing and the clinical indication is multiple sclerosis.

The termitimide sodium is a common form of termitimide, and the structural formula of the termitimide sodium is shown as follows:

sodium terimate

The current use of sodium toremifate for the treatment of autoimmune diseases has entered the second phase of clinical trials. Ternamide sodium has minimal hepatotoxicity and a maximal therapeutic window compared to leflunomide or teramimide. However, no crystal form of the terixamide sodium is reported so far.

However, since termitimide sodium is very hygroscopic and has low thermal stability, and the purity is easily decreased, thereby limiting the application of termitimide sodium, there is a need in the art to develop a method for improving the stability of termitimide sodium.

Disclosure of Invention

The invention aims to provide a crystal form I, a crystal form II and a crystal form IV of a compound shown in a formula A, wherein the crystal form I, the crystal form II and the crystal form IV of the compound shown in the formula A have excellent stability.

In a first aspect of the invention, there is provided a crystalline form I of a compound of formula A,

in another preferred embodiment, said compound of formula a has a form I having an X-ray powder diffraction pattern with characteristic peaks at 2 θ angles of 9.04 ± 0.2 °, 16.51 ± 0.2 °, 17.96 ± 0.2 °, 21.39 ± 0.2 °, 22.12 ± 0.2 °, 23.26 ± 0.2 °, 24.64 ± 0.2 °, 26.33 ± 0.2 °.

In another preferred embodiment, said compound of formula a has a form I having an X-ray powder diffraction pattern with characteristic peaks at 2 θ angles of 9.04 ± 0.2 °, 12.99 ± 0.2 °, 15.06 ± 0.2 °, 16.51 ± 0.2 °, 16.85 ± 0.2 °, 17.96 ± 0.2 °, 19.16 ± 0.2 °, 20.72 ± 0.2 °, 21.39 ± 0.2 °, 22.12 ± 0.2 °, 22.67 ± 0.2 °, 23.26 ± 0.2 °, 23.57 ± 0.2 °, 24.64 ± 0.2 °, 26.33 ± 0.2 °, 28.26 ± 0.2 °.

In another preferred embodiment, said crystalline form I of the compound of formula a has an X-ray powder diffraction pattern having characteristic peaks at 1 or more 2 Θ values selected from the group consisting of: 9.04 +/-0.2 degrees, 10.04 +/-0.2 degrees, 12.99 +/-0.2 degrees, 15.06 +/-0.2 degrees, 16.51 +/-0.2 degrees, 16.85 +/-0.2 degrees, 17.96 +/-0.2 degrees, 19.16 +/-0.2 degrees, 19.77 +/-0.2 degrees, 20.72 +/-0.2 degrees, 21.39 +/-0.2 degrees, 22.12 +/-0.2 degrees, 22.67 +/-0.2 degrees, 23.26 +/-0.2 degrees, 23.57 +/-0.2 degrees, 24.64 +/-0.2 degrees, 26.33 +/-0.2 degrees, 27.09 +/-0.2 degrees, 28.26 +/-0.2 degrees, 30.23 +/-0.2 degrees, 31.09 +/-0.2 degrees, 31.92 +/-0.2 degrees, 33.12 +/-0.2 degrees, 34.31 +/-0.2 degrees, 36.10 +/-0.2 degrees and 38.16 +/-0.2 degrees.

In another preferred embodiment, said form I of the compound of formula a has an X-ray powder diffraction pattern having one or more characteristic peaks at 2 Θ values selected from the group consisting of:

in another preferred embodiment, the crystalline form I of the compound of formula a is a monohydrate.

In another preferred embodiment, said crystalline form I of the compound of formula a has X-ray powder diffraction characteristic peaks substantially as shown in figure 1.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) profile of said crystalline form I of the compound of formula a is substantially as shown in figure 2.

In another preferred embodiment, the thermogravimetric analysis (TGA) profile of the crystalline form I of the compound of formula a is substantially as shown in figure 3.

In another preferred embodiment, the nuclear magnetic resonance hydrogen spectrum of the crystalline form I of the compound of formula a (b¹HNMR) is substantially as shown in fig. 4.

In another preferred embodiment, said compound of formula a has a Differential Scanning Calorimetry (DSC) profile of form I having an endothermic peak at 163.9 ± 5 ℃ (preferably ± 4 ℃, ± 3 ℃, ± 2 ℃, ± 1 ℃ or ± 0.5 ℃).

In another preferred embodiment, the thermogravimetric analysis (TGA) profile of said crystalline form I of the compound of formula a has a weight loss of about 6.12 ± 1.0% (preferably ± 0.8%, ± 0.7%, ± 0.6%, or ± 0.5%) when heated to 160 ± 0.5 ℃.

In a second aspect of the invention, there is provided a process for preparing a crystalline form I of a compound of formula a according to the first aspect of the invention, said process comprising:

(i-1) dissolving the compound of the formula A in an alcohol-water solution, heating and refluxing, and filtering to obtain a filtrate;

(I-2) heating the filtrate until the filtrate is refluxed and dissolved to be clear, cooling, growing crystals, filtering, and drying the obtained solid to obtain the crystal form I of the compound shown in the formula A.

In another preferred example, in the step (i-1), the alcohol in the alcohol aqueous solution is a C1-C4 lower alcohol.

In another preferred embodiment, the C1-C4 lower alcohol is selected from the group consisting of: methanol, ethanol, propanol, butanol, or combinations thereof.

In another preferred embodiment, in the step (i-1), the volume fraction of the alcohol in the aqueous alcohol solution is 50 to 98 (v/v)%, preferably 70 to 98 (v/v)%, more preferably 80 to 98 (v/v)%, still more preferably 90 to 98 (v/v)%.

In another preferred example, in the step (i-1), the alcohol aqueous solution is 50-98 (v/v)% ethanol aqueous solution, preferably 70-98 (v/v)% ethanol aqueous solution, more preferably 80-98 (v/v)% ethanol aqueous solution, more preferably 90-98 (v/v)% ethanol aqueous solution.

In another preferred embodiment, in the step (i-1), the weight ratio of the aqueous alcohol solution to the compound of formula a is 0.8-3: 1, preferably 0.8-2: 1, more preferably 1.2 to 1.6: 1, optimally 1.35-1.45: 1.

in another preferred example, in the step (i-1), an adsorbent is added to the reflux liquid during the heating reflux.

In another preferred example, the adsorbent is activated carbon.

In another preferred embodiment, the weight ratio of said adsorbent to said compound of formula a is 1: 25-50, preferably 1: 30-45, more preferably 1: 32-42.

In another preferred embodiment, in the step (i-1), the heating and refluxing includes the steps of:

dissolving the compound of the formula A in an alcohol-water solution, heating until the mixture is refluxed and dissolved to be clear, adding an adsorbent, and continuously adding the adsorbent for refluxing for 0.5-2 h.

In another preferred example, in the step (i-2), the temperature reduction is natural temperature reduction.

In another preferred example, in the step (i-2), the temperature after the temperature reduction is 20 to 30 ℃, for example, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, preferably 20 to 25 ℃.

In another preferred embodiment, in the step (i-2), the temperature of the crystal growth is 20 to 30 ℃, for example, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, preferably 20 to 25 ℃.

In another preferred embodiment, in the step (i-2), the time for growing the crystals is 18-30h, and more preferably 20-22 h.

In another preferred embodiment, in the step (i-2), the drying temperature is 60 to 90 ℃, preferably 70 to 90 ℃, and more preferably 75 to 85 ℃.

In another preferred embodiment, in the step (i-2), the drying time is 20-24 h.

In a third aspect of the invention, there is provided a crystalline form II of the compound of formula a,

in another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form II of the compound of formula a has characteristic peaks at 2 θ angles of 6.98 ± 0.2 °, 9.31 ± 0.2 °, 12.30 ± 0.2 °, 13.9 ± 0.2 °, 18.90 ± 0.2 °.

In another preferred embodiment, said compound of formula a has an X-ray powder diffraction pattern having characteristic peaks at 2 θ angles of 6.98 ± 0.2 °, 9.31 ± 0.2 °, 12.30 ± 0.2 °, 13.9 ± 0.2 °, 18.90 ± 0.2 °, 26.4 ± 0.2 °, 28.0 ± 0.2 ° in crystalline form II.

In another preferred embodiment, said crystalline form II of the compound of formula a has an X-ray powder diffraction pattern having characteristic peaks at 1 or more 2 Θ values selected from the group consisting of: 6.98 +/-0.2 degrees, 9.31 +/-0.2 degrees, 12.30 +/-0.2 degrees, 13.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.2 +/-0.2 degrees, 24.6 +/-0.2 degrees, 25.2 +/-0.2 degrees, 26.4 +/-0.2 degrees, 28.0 +/-0.2 degrees, 31.8 +/-0.2 degrees, 33.0 +/-0.2 degrees and 36.4 +/-0.2 degrees.

In another preferred embodiment, said crystalline form II of the compound of formula a has an X-ray powder diffraction pattern having one or more characteristic peaks at 2 Θ values selected from the group consisting of:

in another preferred embodiment, the crystalline form II of the compound of formula a is an anhydrous crystalline form.

In another preferred embodiment, the crystalline form II of the compound of formula a has X-ray powder diffraction characteristic peaks substantially as shown in figure 5.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) profile of said crystalline form II of the compound of formula a is substantially as shown in figure 6.

In another preferred embodiment, the thermogravimetric analysis (TGA) profile of the crystalline form II of the compound of formula a is substantially as shown in figure 7.

In another preferred embodiment, the nmr hydrogen spectrum of the crystalline form II of the compound of formula a: (¹HNMR) is substantially as shown in fig. 8.

In another preferred embodiment, said compound of formula a has a Differential Scanning Calorimetry (DSC) profile of form II with an endothermic peak at 287.5 ± 5 ℃ (preferably ± 4 ℃, ± 3 ℃, ± 2 ℃, ± 1 ℃ or ± 0.5 ℃).

In another preferred embodiment, the thermogravimetric analysis (TGA) profile of said crystalline form II of the compound of formula a has a weight loss of about 0.75% (preferably ± 0.4%, ± 0.2% or ± 0.1%) when heated to 200 ± 0.5 ℃.

In a fourth aspect of the present invention, there is provided a process for preparing a crystalline form II of the compound of formula a according to the third aspect of the present invention, wherein the process comprises:

(ii-1) mixing the crystal form I of the compound of the formula A as claimed in claim 1 with a solvent, and heating for reaction to obtain a reaction solution;

(II-2) cooling the reaction solution, filtering, and drying the obtained solid to obtain the crystal form II of the compound in the formula A.

In another preferred embodiment, said crystalline form I of the compound of formula a is prepared according to the process of claim 2.

In another preferred embodiment, in the step (ii-1), the solvent is selected from the group consisting of: ethyl acetate, anisole, 2-methyltetrahydrofuran, n-heptane, or combinations thereof.

In another preferred example, in the step (ii-1), the solvent is a mixture of ethyl acetate and anisole.

In another preferred embodiment, the volume ratio of ethyl acetate to anisole is 1:5-40, preferably 1:10-30, more preferably 1: 15-25.

In another preferred embodiment, in the step (ii-1), the mass-to-volume ratio (g: mL) of the crystalline form I of the compound of formula a to the solvent is 1:30 to 90, preferably 1:40 to 80, and more preferably 1:50 to 60.

In another preferred embodiment, in the step (ii-1), the heating temperature is 40-60 ℃, preferably 45-55 ℃.

In another preferred embodiment, in the step (ii-1), the reaction time is 4 to 7 days, such as 4 days, 5 days, 6 days or 7 days.

In another preferred embodiment, in the step (ii-2), the temperature after temperature reduction is 10-30 ℃, preferably 15-25 ℃.

In another preferred embodiment, in the step (ii-2), the drying temperature is 60 to 90 ℃, preferably 70 to 90 ℃, and more preferably 75 to 85 ℃.

In another preferred embodiment, in the step (ii-2), the drying time is 20-24 h.

In a fifth aspect of the invention, there is provided a crystalline form III of the compound of formula a,

in another preferred embodiment, said compound of formula a has a form III having an X-ray powder diffraction pattern with characteristic peaks at 2 Θ angles of 8.46 ± 0.2 °, 10.5 ± 0.2 °, 13.7 ± 0.2 °, 18.7 ± 0.2 °, 25.0 ± 0.2 °, 26.5 ± 0.2 °, 27.2 ± 0.2 °, 28.7 ± 0.2 °.

In another preferred embodiment, said compound of formula a has a form III having an X-ray powder diffraction pattern with characteristic peaks at 2 Θ angles of 8.46 ± 0.2 °, 10.5 ± 0.2 °, 13.7 ± 0.2 °, 17.1 ± 0.2 °, 18.7 ± 0.2 °, 19.9 ± 0.2 °, 20.3 ± 0.2 °, 21.6 ± 0.2 °, 25.0 ± 0.2 °, 26.5 ± 0.2 °, 27.2 ± 0.2 °, 28.7 ± 0.2 °.

In another preferred embodiment, said compound of formula a has a form III having an X-ray powder diffraction pattern with characteristic peaks at 1 or more 2 Θ values selected from the group consisting of 8.46 ± 0.2 °, 10.5 ± 0.2 °, 13.7 ± 0.2 °, 16.6 ± 0.2 °, 17.1 ± 0.2 °, 18.7 ± 0.2 °, 19.5 ± 0.2 °, 19.9 ± 0.2 °, 20.3 ± 0.2 °, 21.3 ± 0.2 °, 21.6 ± 0.2 °, 25.0 ± 0.2 °, 26.0 ± 0.2 °, 26.5 ± 0.2 °, 27.2 ± 0.2 °, 28.7 ± 0.2 °, 31.1 ± 0.2 °.

In another preferred embodiment, said form III of the compound of formula a has an X-ray powder diffraction pattern having one or more characteristic peaks at 2 Θ values selected from the group consisting of:

in another preferred embodiment, the crystalline form III of the compound of formula a is a tetrahydrate.

In another preferred embodiment, said form III of the compound of formula a has X-ray powder diffraction characteristic peaks substantially as shown in figure 9.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) profile of form III of the compound of formula a is substantially as shown in figure 10.

In another preferred embodiment, the thermogravimetric analysis (TGA) profile of the crystalline form III of the compound of formula a is substantially as shown in figure 11.

In another preferred embodiment, said compound of formula a has a Differential Scanning Calorimetry (DSC) profile of form III with two endothermic peaks at 89.8 ± 5 ℃ (preferably ± 4 ℃, ± 3 ℃, ± 2 ℃, ± 1 ℃ or ± 0.5 ℃) and 113.3 ± 5 ℃ (preferably ± 4 ℃, ± 3 ℃, ± 2 ℃, ± 1 ℃ or ± 0.5 ℃).

In another preferred embodiment, the thermogravimetric analysis (TGA) profile of said crystalline form III of the compound of formula a has a weight loss of about 18.91% (preferably ± 2%, ± 1% or ± 0.5%) when heated to 130 ± 0.5 ℃.

In a sixth aspect of the invention, there is provided a process for preparing form III of a compound of formula a according to the fifth aspect of the invention, said process comprising:

(III-1) standing crystalline form I of the compound of formula a according to claim 1 to obtain crystalline form III of the compound of formula a;

wherein the temperature of the placing is 20-60 ℃, preferably 30-50 ℃, more preferably 35-45 ℃, and most preferably 40 ℃;

the relative humidity of the placement is 20-80%, preferably 60-80%, more preferably 70-80%, most preferably 75%.

In another preferred embodiment, the standing time is 5 to 9 days, preferably 6 to 8 days, more preferably 7 days.

In a seventh aspect of the invention, there is provided a crystalline form IV of the compound of formula a,

in another preferred embodiment, said compound of formula a has a form IV having an X-ray powder diffraction pattern with characteristic peaks at 2 Θ angles of 8.49 ± 0.2 °, 13.81 ± 0.2 °, 14.12 ± 0.2 °, 18.74 ± 0.2 °, 25.11 ± 0.2 °, 26.52 ± 0.2 °, 27.31 ± 0.2 °, 28.75 ± 0.2 °.

In another preferred embodiment, said compound of formula a has a characteristic peak at a 2 θ angle of 3.62 ± 0.2 °, 8.49 ± 0.2 °, 10.62 ± 0.2 °, 13.81 ± 0.2 °, 14.12 ± 0.2 °, 17.18 ± 0.2 °, 18.74 ± 0.2 °, 20.01 ± 0.2 °, 21.21 ± 0.2 °, 21.66 ± 0.2 °, 25.11 ± 0.2 °, 26.06 ± 0.2 °, 26.52 ± 0.2 °, 27.31 ± 0.2 °, 28.75 ± 0.2 ° in the form IV of X-ray powder diffraction pattern.

In another preferred embodiment, said form IV of the compound of formula a has an X-ray powder diffraction pattern having characteristic peaks at 1 or more 2 Θ values selected from the group consisting of: 3.62 +/-0.2 °, 8.49 +/-0.2 °, 10.62 +/-0.2 °, 11.83 +/-0.2 °, 13.81 +/-0.2 °, 14.12 +/-0.2 °, 16.71 +/-0.2 °, 17.18 +/-0.2 °, 18.74 +/-0.2 °, 19.58 +/-0.2 °, 20.01 +/-0.2 °, 20.44 +/-0.2 °, 21.21 +/-0.2 °, 21.66 +/-0.2 °, 22.31 +/-0.2 °, 23.65 +/-0.2 °, 24.17 +/-0.2 °, 25.11 +/-0.2 °, 26.06 +/-0.2 °, 26.52 +/-0.2 °, 27.31 +/-0.2 °, 28.75 +/-0.2 °, 30.41 +/-0.2 °, 31.16 +/-0.2 °, 32.62 +/-0.2 °, 34.08 +/-0.2 °, 35.83 +/-0.2 °, 36.88 ± 0.2 °.

In another preferred embodiment, said form IV of the compound of formula a has an X-ray powder diffraction pattern having one or more characteristic peaks at 2 Θ values selected from the group consisting of:

in another preferred embodiment, the crystalline form IV of the compound of formula a is an anhydrous crystalline form.

In another preferred embodiment, said form IV of the compound of formula a has X-ray powder diffraction characteristic peaks substantially as shown in figure 12.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) profile of form IV of the compound of formula a is substantially as shown in figure 13.

In another preferred embodiment, the thermogravimetric analysis (TGA) profile of the crystalline form IV of the compound of formula a is substantially as shown in figure 14.

In another preferred embodiment, the nuclear magnetic resonance hydrogen spectrum of the crystalline form IV of the compound of formula a (b¹HNMR) is substantially as shown in fig. 15.

In another preferred embodiment, in a Differential Scanning Calorimetry (DSC) chart of said form IV of the compound of formula a, form IV of the compound of formula a has no endothermic peak prior to decomposition.

In another preferred embodiment, the thermogravimetric analysis (TGA) profile of said crystalline form IV of the compound of formula a has a weight loss of about 0.44% (preferably ± 0.4% or ± 0.2%) when heated to 150 ± 0.5 ℃.

In an eighth aspect of the present invention there is provided a process for the preparation of form IV of a compound of formula a as described in the seventh aspect of the present invention, said process comprising:

(IV-1) dissolving the compound of the formula A in an organic solvent, heating, stirring, cooling, filtering to obtain a solid, and drying to obtain the crystal form IV of the compound of the formula A.

In another preferred embodiment, in the step (iv-1), the organic solvent comprises toluene.

In another preferred embodiment, in the step (iv-1), the weight/volume ratio (g: ml) of the compound of formula A to the organic solvent is 1:20 to 40, preferably 1:25 to 35.

In another preferred embodiment, in the step (iv-1), the heating temperature is 70 to 90 ℃, preferably 75 to 85 ℃.

In another preferred embodiment, in the step (iv-1), the stirring time is 15 to 25 hours, preferably 18 to 22 hours.

In another preferred embodiment, in the step (iv-1), the temperature after the temperature reduction is 15 to 25 ℃, preferably 18 to 22 ℃.

In another preferred embodiment, in the step (iv-1), the drying temperature is 70 to 90 ℃, preferably 75 to 85 ℃.

In another preferred embodiment, in the step (iv-1), the drying time is 15 to 25 hours, preferably 20 to 24 hours.

In a ninth aspect, the present invention provides a pharmaceutical composition comprising form I of the compound a according to the first aspect of the present invention, form II of the compound a according to the third aspect of the present invention, form III of the compound a according to the fifth aspect of the present invention and/or form IV of the compound a according to the seventh aspect of the present invention; and a pharmaceutically acceptable carrier.

In a tenth aspect of the present invention, there is provided a use of crystalline form I of compound a according to the first aspect of the present invention, crystalline form II of compound a according to the third aspect of the present invention, crystalline form III of compound a according to the fifth aspect of the present invention and/or crystalline form IV of compound a according to the seventh aspect of the present invention in the manufacture of a medicament for the prophylaxis and/or treatment of an autoimmune disease.

In another preferred embodiment, the autoimmune disease is selected from the group consisting of: multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, or a combination thereof.

In an eleventh aspect of the present invention, there is provided a method for the treatment, prophylaxis and/or treatment of an autoimmune disease, said method comprising the steps of: administering to a subject in need thereof a crystalline form I of a compound according to the first aspect of the invention, a crystalline form II of a compound according to the third aspect of the invention, a crystalline form III of a compound according to the fifth aspect of the invention and/or a crystalline form IV of a compound according to the seventh aspect of the invention.

In another preferred embodiment, the subject is a human or non-human mammal.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1: an XRPD pattern of crystalline form I of tiramite sodium.

FIG. 2: a DSC profile of crystalline form I of tiramite sodium.

FIG. 3: a TGA profile of crystalline form I of tiramitripter sodium.

FIG. 4: crystal form I of tiramite sodium¹HNMR atlas.

FIG. 5: an XRPD pattern of crystalline form II of tiramite sodium.

FIG. 6: a DSC profile of crystalline form II of tiramite sodium.

FIG. 7 is a schematic view of: a TGA profile of crystalline form II of tiramite sodium.

FIG. 8: crystal form II of tiramite sodium¹H NMR spectrum.

FIG. 9: an XRPD pattern of tiramite sodium form III.

FIG. 10: a DSC profile of crystalline form III of tiramite sodium.

FIG. 11: a TGA profile of crystalline form III of tiramite sodium.

FIG. 12: an XRPD pattern of crystalline form IV of tiramite sodium.

FIG. 13: a DSC profile of crystalline form IV of tiramite sodium.

FIG. 14 is a schematic view of: a TGA profile of crystalline form IV of tiramitript sodium.

FIG. 15: crystal form IV of tiramite sodium¹H NMR spectrum.

Detailed Description

The inventor conducts extensive and intensive research and unexpectedly develops the crystal forms I, II, III and IV of the tiramister sodium for the first time. The crystal forms I, II, III and IV of the tiramister sodium have excellent thermal stability, so that the stability of the tiramister sodium in the processes of pharmacy, storage, transportation and the like is improved, and the application of the tiramister sodium is improved. On this basis, the inventors have completed the present invention.

Term(s) for

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the terms "comprising," "including," and "containing" are used interchangeably and include not only open-ended definitions, but also semi-closed and closed-ended definitions. In other words, the term includes "consisting of … …", "consisting essentially of … …".

As used herein, the terms "crystalline form I of the compound of formula a", "tiramitript sodium crystalline form I" and "crystalline form I" are used interchangeably.

As used herein, the terms "crystalline form II of the compound of formula a", "terremimide sodium form II" and "form II" are used interchangeably.

As used herein, the terms "form III of the compound of formula a", "tiramitript sodium form III" and "form III" are used interchangeably.

As used herein, the terms "form IV of the compound of formula a", "tiramitript sodium form IV" and "form IV" are used interchangeably.

Crystal form I and preparation method thereof

The present invention provides a crystalline form I of a compound of formula a:

typically, the X-ray powder diffraction pattern of the crystal form I of the compound of the formula A has characteristic peaks at 2 theta angles of 9.04 +/-0.2 degrees, 16.51 +/-0.2 degrees, 17.96 +/-0.2 degrees, 21.39 +/-0.2 degrees, 22.12 +/-0.2 degrees, 23.26 +/-0.2 degrees, 24.64 +/-0.2 degrees and 26.33 +/-0.2 degrees.

Typically, said crystalline form I of the compound of formula a has an X-ray powder diffraction pattern having characteristic peaks at 1 or more 2 Θ values selected from the group consisting of: 9.04 +/-0.2 degrees, 10.04 +/-0.2 degrees, 12.99 +/-0.2 degrees, 15.06 +/-0.2 degrees, 16.51 +/-0.2 degrees, 16.85 +/-0.2 degrees, 17.96 +/-0.2 degrees, 19.16 +/-0.2 degrees, 19.77 +/-0.2 degrees, 20.72 +/-0.2 degrees, 21.39 +/-0.2 degrees, 22.12 +/-0.2 degrees, 22.67 +/-0.2 degrees, 23.26 +/-0.2 degrees, 23.57 +/-0.2 degrees, 24.64 +/-0.2 degrees, 26.33 +/-0.2 degrees, 27.09 +/-0.2 degrees, 28.26 +/-0.2 degrees, 30.23 +/-0.2 degrees, 31.09 +/-0.2 degrees, 31.92 +/-0.2 degrees, 33.12 +/-0.2 degrees, 34.31 +/-0.2 degrees, 36.10 +/-0.2 degrees and 38.16 +/-0.2 degrees.

The present invention also provides a process for the preparation of a crystalline form I of the compound of formula a according to the invention, which process comprises:

in another preferred embodiment, in the step (i-1), the heating and refluxing step includes the steps of:

Crystal form II and preparation method thereof

The present invention provides a crystalline form II of a compound of formula a:

typically, the X-ray powder diffraction pattern of the crystal form II of the compound of the formula A has characteristic peaks at 2 theta angles of 6.98 +/-0.2 degrees, 9.31 +/-0.2 degrees, 12.30 +/-0.2 degrees, 13.9 +/-0.2 degrees and 18.90 +/-0.2 degrees.

Typically, said crystalline form II of the compound of formula a has an X-ray powder diffraction pattern having characteristic peaks at 1 or more 2 Θ values selected from the group consisting of: 6.98 +/-0.2 degrees, 9.31 +/-0.2 degrees, 12.30 +/-0.2 degrees, 13.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.2 +/-0.2 degrees, 24.6 +/-0.2 degrees, 25.2 +/-0.2 degrees, 26.4 +/-0.2 degrees, 28.0 +/-0.2 degrees, 31.8 +/-0.2 degrees, 33.0 +/-0.2 degrees and 36.4 +/-0.2 degrees.

The present invention also provides a process for preparing crystalline form II of the compound of formula a according to the present invention, said process comprising:

(ii-1) mixing the crystal form I of the compound shown in the formula A with a solvent, and heating for reaction to obtain a reaction solution;

Crystal form III and preparation method thereof

The present invention provides a crystalline form III of a compound of formula a:

typically, the X-ray powder diffraction pattern of the crystalline form III of the compound of formula a has characteristic peaks at 2 θ angles of 8.46 ± 0.2 °, 10.5 ± 0.2 °, 13.7 ± 0.2 °, 18.7 ± 0.2 °, 25.0 ± 0.2 °, 26.5 ± 0.2 °, 27.2 ± 0.2 °, and 28.7 ± 0.2 °.

Typically, said compound of formula a form III has an X-ray powder diffraction pattern with characteristic peaks at 1 or more 2 Θ values selected from 8.46 ± 0.2 °, 10.5 ± 0.2 °, 13.7 ± 0.2 °, 16.6 ± 0.2 °, 17.1 ± 0.2 °, 18.7 ± 0.2 °, 19.5 ± 0.2 °, 19.9 ± 0.2 °, 20.3 ± 0.2 °, 21.3 ± 0.2 °, 21.6 ± 0.2 °, 25.0 ± 0.2 °, 26.0 ± 0.2 °, 26.5 ± 0.2 °, 27.2 ± 0.2 °, 28.7 ± 0.2 °, 31.1 ± 0.2 °.

The present invention also provides a process for preparing crystalline form III of the compound of formula a according to the present invention, said process comprising:

Crystal form III and preparation method thereof

The present invention provides a crystalline form IV of a compound of formula a:

typically, the X-ray powder diffraction pattern of form IV of the compound of formula a has characteristic peaks at 2 Θ angles of 8.49 ± 0.2 °, 13.81 ± 0.2 °, 14.12 ± 0.2 °, 18.74 ± 0.2 °, 25.11 ± 0.2 °, 26.52 ± 0.2 °, 27.31 ± 0.2 °, and 28.75 ± 0.2 °.

Typically, said form IV of the compound of formula a has an X-ray powder diffraction pattern having characteristic peaks at 1 or more 2 Θ values selected from the group consisting of: 3.62 +/-0.2 °, 8.49 +/-0.2 °, 10.62 +/-0.2 °, 11.83 +/-0.2 °, 13.81 +/-0.2 °, 14.12 +/-0.2 °, 16.71 +/-0.2 °, 17.18 +/-0.2 °, 18.74 +/-0.2 °, 19.58 +/-0.2 °, 20.01 +/-0.2 °, 20.44 +/-0.2 °, 21.21 +/-0.2 °, 21.66 +/-0.2 °, 22.31 +/-0.2 °, 23.65 +/-0.2 °, 24.17 +/-0.2 °, 25.11 +/-0.2 °, 26.06 +/-0.2 °, 26.52 +/-0.2 °, 27.31 +/-0.2 °, 28.75 +/-0.2 °, 30.41 +/-0.2 °, 31.16 +/-0.2 °, 32.62 +/-0.2 °, 34.08 +/-0.2 °, 35.83 +/-0.2 °, 36.88 ± 0.2 °.

The present invention also provides a process for preparing crystalline form IV of the compound of formula a according to the present invention, said process comprising:

Pharmaceutical composition

The invention also provides a pharmaceutical composition comprising the crystal form I of the compound shown in the formula A, the crystal form II of the compound shown in the formula A, the crystal form III of the compound shown in the formula A and/or the crystal form IV of the compound shown in the formula A; and a pharmaceutically acceptable carrier.

In a preferred embodiment of the present invention, the dosage form of the pharmaceutical composition is a solid preparation, a liquid preparation or a semisolid preparation.

In a preferred embodiment of the invention, the dosage form of the pharmaceutical composition is oral preparation, injection preparation or external preparation or preparation.

In a preferred embodiment of the present invention, the pharmaceutical composition is in the form of tablet, injection or infusion solution.

The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid, semi-solid, liquid or gel fillers which are suitable for human or animal use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant that the components of the pharmaceutical composition and the active ingredient of the drug are blended with each other and not significantly detract from the efficacy of the drug.

It is to be understood that, in the present invention, the carrier is not particularly limited and may be selected from materials commonly used in the art, or prepared by a conventional method, or commercially available. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tween), wetting agents (e.g., sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavors, stabilizers, antioxidants, preservatives, bacteriostats, pyrogen-free water, etc.

Typically, liquid dosage forms may contain, in addition to the active pharmaceutical ingredient, inert diluents commonly employed in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents and the like

The pharmaceutical preparation should be compatible with the mode of administration. The agents of the invention may also be used with (including before, during or after) other co-therapeutic agents. In using the pharmaceutical composition or formulation, a safe and effective amount of the drug, typically at least about 10 micrograms/kg body weight, and in most cases no more than about 8 mg/kg body weight, preferably from about 10 micrograms/kg body weight to about 1 mg/kg body weight, is administered to a subject in need thereof (e.g., a human or non-human mammal). Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

Use of

The invention also provides application of the crystal form I of the compound shown in the formula A, the crystal form II of the compound shown in the formula A, the crystal form III of the compound shown in the formula A and/or the crystal form IV of the compound shown in the formula A, which are disclosed by the invention, in preventing and/or treating autoimmune diseases.

In another preferred embodiment, the autoimmune disease includes (but is not limited to): multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, or a combination thereof.

The present invention also provides a method for the treatment, prevention and/or treatment of an autoimmune disease, said method comprising the steps of: administering to a subject in need thereof a crystalline form I of the compound of formula a, a crystalline form II of the compound of formula a, a crystalline form III of the compound of formula a, and/or a crystalline form IV of the compound of formula a as described herein.

In another preferred embodiment, the subject is a human or non-human mammal.

The main advantages of the invention include:

the invention develops the crystal form I, the crystal form II and the crystal form IV of the compound shown in the formula A, wherein the crystal form I, the crystal form II and the crystal form IV of the compound shown in the formula A have excellent stability under high-temperature and high-humidity conditions, can be stably stored for a long time, and the chemical purity cannot be reduced.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Examples

Examples 1-4 crystalline forms I, II, III and IV of tiramite sodium were prepared, respectively, and XRPD (X-ray powder diffraction), TGA (thermogravimetric analysis) and DSC (differential scanning calorimetry) measurements of the forms were as follows:

XRPD (X-ray powder diffraction) was collected on an X-ray powder diffraction analyzer model PINILyticIL EmpyreIn and X' Pert3, with the scanning parameters shown in Table 1:

TABLE 1 XRPD test parameters

TGA (thermogravimetric analysis) was collected on a TI Q5000/Discovery 5500 thermogravimetric analyzer; DSC (differential scanning calorimetry) was taken on a TI Q2000/Discovery 2500 differential scanning calorimeter. TGA and DSC test parameters are as in table 2:

TABLE 2 TGA and DSC test parameters

Example 1: preparation of teriparatide sodium crystal form I

The preparation method of the crystal form I of the tiramite sodium comprises the following steps:

adding 47.7g of sodium teriummate into a reaction bottle, adding 66.3g of 95% ethanol, and heating to reflux to dissolve the sodium tauummate while stirring; then adding 1.26g of active carbon, continuously stirring and refluxing for 1h, and filtering while the solution is hot; and after the filtrate is stirred again, refluxed and dissolved to be clear, the heating and the stirring are turned off, the temperature is naturally and slowly reduced to 27 ℃ in a standing state, and the crystal is grown for 21 hours at the temperature of 27 ℃. Filtering, and drying the solid by blowing at 80 ℃ for 22.5h to obtain 30.55g of white solid sodium teriummate crystal form I with the yield of 64%.

Characterization of crystal form I of tiramite sodium:

the XRPD pattern of the tiramite sodium crystal form I is shown in figure 1 (the XRPD pattern characteristics are shown in table 3), the DSC pattern is shown in figure 2, the TGA pattern is shown in figure 3, and the XRPD pattern is shown in figure 3¹The H NMR spectrum is shown in FIG. 4. From the TGA plot in figure 3, it can be seen that form I has a weight loss of 6.12% when heated to 160 ℃, from figure 2The DSC chart in (1) shows that the crystal form I has an endothermic peak at 163.9 ℃ (peak temperature) before decomposition. From FIG. 4¹H NMR showed no significant solvent residue in the form I sample. According to the above results, it is presumed that form I is a monohydrate.

TABLE 3 XRPD pattern characterization of crystalline form I of sodium teriumide

Example 2: preparation of teriparatide sodium crystal form II

The preparation method of the crystal form II of the tiramite sodium comprises the following steps:

3.0g of terimido sodium crystal form I prepared according to the procedure of example 1 was added to a reaction flask, 168mL of a mixed solvent ethyl acetate: anisole 1:20(v/v) was added, and the reaction was stirred at 50 ℃ for 5 days. After the heating was turned off, the temperature was lowered to room temperature (20 ℃ C.) with stirring, and filtered. The solid is dried by air blast for 20-24h at the temperature of 80 ℃ to obtain 2.7g of white solid sodium teriummate crystal form II with the yield of 90%.

Characterization of crystal form II of tiramite sodium:

the XRPD pattern of the tylimilide sodium crystal form II is shown in figure 5 (the XRPD pattern characteristics are shown in table 4), the DSC pattern is shown in figure 6, the TGA pattern is shown in figure 7, and the XRPD pattern is shown in figure 4¹The H NMR spectrum is shown in FIG. 8. As can be seen from the TGA plot in fig. 7, the crystalline form II sample heated to 200 ℃ had a 0.72% weight loss, and from the DSC plot in fig. 6, an endothermic peak at 287.5 ℃ (peak temperature) prior to decomposition of the sample was seen. From FIG. 8¹H NMR results showed no significant solvent residue in the form II sample. And (4) combining the experimental results to judge that the crystal form II is an anhydrous crystal form.

TABLE 4 XRPD pattern characterization of crystalline form II of sodium teriumide

Example 3: preparation of teriparatide sodium crystal form III

The preparation method of the crystal form III of the tiramite sodium comprises the following steps:

1.5g of the crystalline form I of tiramite sodium prepared according to the procedure in example 1 were added to a petri dish and placed in a constant temperature and humidity cabinet at 40 ℃ and 75% RH for one week. To obtain 1.7g of white solid sodium tiramite crystal form III.

Characterization of crystal form III of tiramite sodium:

the XRPD pattern of the tiramitripter sodium crystal form III is shown in figure 9 (the XRPD pattern characteristics are shown in table 5), the DSC pattern is shown in figure 10, and the TGA pattern is shown in figure 11. From the TGA plot in fig. 11, it can be seen that there is a 18.91% weight loss of the crystalline form III sample upon heating to 130 ℃, and from the DSC plot in fig. 10, it can be seen that there are endothermic peaks at both 89.8 ℃ and 113.3 ℃ (peak temperature), resulting from sample dehydration. And (4) integrating the preparation and characterization results of the crystal form III, and judging that the crystal form III is a tetrahydrate.

TABLE 5 XRPD pattern characterization of crystalline form III of sodium teriumide

Example 4: preparation of teriparatide sodium crystal form IV

The preparation method of the crystal form IV of the tiramite sodium comprises the following steps:

5g of sodium teriummate is put into a reaction bottle, 150mL of toluene is added, the temperature is increased to 80 ℃, the temperature is kept and the stirring is carried out for 20h, and the temperature is reduced to room temperature (20 ℃) under the stirring. Filtering, and vacuum drying the solid at 80 ℃ for 22h to obtain 4.65g of white solid sodium tiramite crystal form IV with the yield of 93%.

Characterization of crystal form IV of tiramite sodium:

the XRPD pattern of the tiramitripter sodium crystal form IV is shown in figure 12 (the XRPD pattern characteristics are shown in table 6), the DSC pattern is shown in figure 13, the TGA pattern is shown in figure 14, and the TGA pattern is shown in figure¹The H NMR spectrum is shown in FIG. 15. As can be seen from the TGA plot in fig. 14, form IV had a 0.44% weight loss upon heating to 150 ℃, and as can be seen from the DSC plot in fig. 13, the sample had no endothermic peak prior to decomposition. And (4) integrating the preparation and characterization results of the crystal form IV, and judging that the crystal form IV is an anhydrous crystal form.

Table 6 XRPD pattern characterization of crystalline form IV of terixamide sodium

Comparative example 1

In order to evaluate the solid state stability of the crystal form iii of tiramite sodium, appropriate amounts of samples were weighed respectively and examined under different conditions, and then the solid samples under different conditions were evaluated for physical and chemical stability by XRPD and HPLC tests, respectively, and the evaluation results are summarized in table 7. The stability study results show that: 1) no crystal form transformation occurs under all test conditions; 2) the chemical purity of the sample did not decrease under all the test conditions.

TABLE 7 summary of solid state stability evaluation results for form III

*: the initial purity of the form II sample was 100%.

Amorphous sodium teriflunomide is very easy to absorb water and is easy to have reduced purity, and table 7 shows that crystal form iii of teriflunomide can stably exist for a long time under high-temperature conditions, and the chemical purity cannot be reduced. In addition, compared with amorphous tiramite sodium, the tiramite sodium crystal form compound has obvious advantages, for example, the preparation process is easier to control, and the obtained product has better state, uniformity and stability, and is more beneficial to controlling the mixing uniformity of preparation products and the like.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A crystalline form I of a compound of formula A,

the X-ray powder diffraction pattern of the crystal form I of the compound of the formula A has characteristic peaks when the 2 theta angle is 9.04 +/-0.2 degrees, 16.51 +/-0.2 degrees, 17.96 +/-0.2 degrees, 21.39 +/-0.2 degrees, 22.12 +/-0.2 degrees, 23.26 +/-0.2 degrees, 24.64 +/-0.2 degrees and 26.33 +/-0.2 degrees.

2. A process for preparing the crystalline form I of the compound of formula a of claim 1, comprising:

3. A crystalline form II of a compound of formula A,

the X-ray powder diffraction pattern of the crystal form II of the compound shown in the formula A has characteristic peaks at 2 theta angles of 6.98 +/-0.2 degrees, 9.31 +/-0.2 degrees, 12.30 +/-0.2 degrees, 13.9 +/-0.2 degrees and 18.90 +/-0.2 degrees.

4. A process for preparing the crystalline form II of the compound of formula a of claim 3, comprising:

5. A crystalline form III of a compound of formula A,

the X-ray powder diffraction pattern of the crystal form III of the compound shown in the formula A has characteristic peaks at 2 theta angles of 8.46 +/-0.2 degrees, 10.5 +/-0.2 degrees, 13.7 +/-0.2 degrees, 18.7 +/-0.2 degrees, 25.0 +/-0.2 degrees, 26.5 +/-0.2 degrees, 27.2 +/-0.2 degrees and 28.7 +/-0.2 degrees.

6. A process for preparing the crystalline form III of the compound of formula a of claim 5, comprising:

7. A crystalline form IV of a compound of formula A,

the X-ray powder diffraction pattern of the crystal form IV of the compound shown in the formula A has characteristic peaks at 2 theta angles of 8.49 +/-0.2 degrees, 13.81 +/-0.2 degrees, 14.12 +/-0.2 degrees, 18.74 +/-0.2 degrees, 25.11 +/-0.2 degrees, 26.52 +/-0.2 degrees, 27.31 +/-0.2 degrees and 28.75 +/-0.2 degrees.

8. A process for preparing form IV of the compound of formula a according to claim 7, comprising:

9. A pharmaceutical composition comprising form I of compound a according to claim 1, form II of compound a according to claim 3, form III of compound a according to claim 5 and/or form IV of compound a according to claim 7; and a pharmaceutically acceptable carrier.

10. Use of the crystalline form I of the compound a of claim 1, the crystalline form II of the compound a of claim 3, the crystalline form III of the compound a of claim 5, and/or the crystalline form IV of the compound a of claim 7 in the manufacture of a medicament for the prophylaxis and/or treatment of an autoimmune disease.