WO2020143781A1 - Crystal form of heterocyclic compound as crth2 receptor antagonist - Google Patents

Abstract

The present invention provides a crystalline form of the heterocyclic compound represented by formula A or a hydrate thereof, and preparation method and application thereof. The crystalline form of the compound of formula A or hydrate thereof is superior to its amorphous form in terms of solubility, hygroscopicity, and stability. Furthermore, the crystalline form also has better bioavailability than the amorphous form. In addition, its preparation method is simple, and therefore it has a higher practicality.

Description

Crystal forms of heterocyclic compounds as CRTH2 receptor antagonists

This application requires the priority of the prior application filed on January 10, 2019, with the patent application number 201910024247.X and the invention titled "Crystal Form of Heterocyclic Compound as CRTH2 Receptor Antagonist". The entire text of this application is incorporated into this application by reference.

Technical field

The present invention belongs to the technical field of pharmaceutical crystal forms, and specifically relates to the crystal forms of heterocyclic compounds as CRTH2 receptor antagonists.

Background technique

Prostaglandin D2 (PGD ₂ ) is a cyclooxygenase metabolite of arachidonic acid. It is released from mast cells and TH2 cells in response to immune challenge, and it has been suggested to play a role in different physiological events such as sleep and allergic reactions.

Receptors for PGD ₂ include "DP" receptors, chemoattractant receptor homologous molecules ("CRTH2") expressed on TH2 cells, and "FP" receptors. These receptors are G protein coupled receptors activated by PGD ₂ . CRTH2 receptor and its expression on different cells including human T helper cells, basophils and eosinophils have been expressed in Abe, etal., Gene227: 71-77, 1999, Nagata, etal., FEBSLetters459: 195-199, 1999 and Nagata, etal., The Journal of Immunology 162: 1278-1286, 1999, which describe CRTH2 receptors. Hirai, etal., J. Exp. Med. 193:255-261, 2001 proved that CRTH2 is a receptor for PGD ₂ .

Th2-polarization has been found in allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis (Romagnani S. Immunology Today, 18, 263-266, 1997; Hammad H. et al., Blood , 98, 1135-1141, 2001). Th2 cells regulate allergic diseases by producing Th2 cytokines, such as IL-4, IL-5, and IL-13 (Orissetal., J. Immunol., 162, 1999-2007, 1999; Violaetal., Blood, 91, 2223 -2230, 1998; Webbetal., J. Immunol., 165, 108-113, 2000; Dumont F. J., Exp. Opin. Ther. Pat., 12, 341-367, 2002). These Th2 cytokines directly or indirectly induce the migration, activation, priming and prolongation of effector cells such as eosinophils and basophils in allergic diseases (Sanzetal., J. Immunol., 160, 5637 -5645, 1998; Popeetal., J. AllergyClin. Immunol., 108, 594-601, 2001; Teran L.M., Clin. Exp. Allergy, 29, 287-290, 1999).

Therefore, antagonists that inhibit the binding of CRTH2 to PGD ₂ should be useful in the treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis.

Chinese invention patent application CN101896178B discloses a heterocyclic compound represented by the following formula I as a CRTH2 receptor antagonist.

Example 3 discloses compounds of the following structure:

It is known to those skilled in the art that although it is common for pharmaceutical compounds to have a crystalline form, whether a certain pharmaceutical compound can obtain a crystalline form often requires a lot of experiments and screening before it is possible to obtain the desired product. Moreover, the development of products with improved performance on this basis has become a further demand for a long time. Therefore, one of the important tasks of drug workers includes the discovery of stable crystalline forms of drugs. However, the solutions to these problems are rarely as simple as they look afterwards. An efficient drug development process must focus on a comprehensive consideration of product quality, repeatability, durability and cost-effectiveness.

Summary of the invention

To solve the above problems, the present invention provides the following technical solutions:

A crystalline form of a heterocyclic compound represented by formula A or its hydrate, which uses Cu-Kα radiation and X-ray powder diffraction expressed at an angle of 2θ at 11.1±0.2°, 11.4±0.2°, 17.9±0.2°, 22.6 There are characteristic peaks at ±0.2°, 24.4±0.2°,

Preferably, the crystal form uses Cu-Kα radiation, and the X-ray powder diffraction expressed at an angle of 2θ is 8.6±0.2°, 11.1±0.2°, 11.4±0.2°, 14.1±0.2°, 16.1±0.2°, 17.9± There are characteristic peaks at 0.2°, 20.9±0.2°, 22.6±0.2°, 24.4±0.2°, and 25.8±0.2°.

Also preferably, the crystalline form uses Cu-Kα radiation, and the X-ray powder diffraction expressed at a 2θ angle is 8.6±0.2°, 11.1±0.2°, 11.4±0.2°, 14.1±0.2°, 15.6±0.2°, 16.1 There are characteristic peaks at ±0.2°, 17.9±0.2°, 18.3±0.2°, 20.9±0.2°, 22.6±0.2°, 24.4±0.2°, 25.8±0.2°, 26.5±0.2°, 28.9±0.2°.

It is further preferred that the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 1.

More preferably, the crystal form has a DSC-TGA spectrum substantially as shown in FIG. 2.

According to the present invention, the crystal form of the heterocyclic compound represented by formula A is a hydrate, preferably a monohydrate. More preferably, the mass fraction of water in the hydrate is 4.2-5.2%, more preferably 4.5-5.0%.

The monohydrate is as follows:

Still more preferably, the crystal form is a single crystal, having the following single crystal parameters:

The invention also provides a method for preparing the crystalline form of the heterocyclic compound represented by formula A or its hydrate, which includes the following steps:

The compound represented by formula A is placed in a mixed solvent composed of a ketone solvent and water, heated and dissolved, and then cooled, and crystallized by stirring to obtain the crystal form of the heterocyclic compound represented by formula A or its hydrate

For the preparation of the heterocyclic compound represented by Formula A in the present invention, reference may be made to the methods described in Examples 3 and 4 of CN101896178B. For example, the racemic body of the heterocyclic compound represented by Formula A is eluted on a Chiralcel OJ-RH column (Chiralcel Technologies) with a methanol solution containing 0.05% trifluoroacetic acid, and the heterocyclic compound represented by Formula A is isolated.

According to the preparation method of the present invention, the ketone solvent is selected from acetone or methyl ethyl ketone.

According to the preparation method of the present invention, the volume ratio of the ketone solvent to water is (1-3):1, for example, 1:1.

According to the preparation method of the present invention, the heating temperature is 30 to 80°C, preferably 40 to 60°C.

The ability of the crystalline form of the heterocyclic compound represented by Formula A or its hydrate provided by the present invention to interact with prostaglandin receptors makes it possible to prevent or reverse the adverse symptoms caused by prostaglandins in mammals, especially human . Such mimicry or antagonism of the action of prostaglandins indicates that the compounds of the present invention and their pharmaceutical compositions can be used to treat, prevent or improve respiratory conditions, allergic conditions, pain, inflammatory conditions in mammals, especially humans , Mucus secretion disease (mucussecretiondisorder), bone disease, sleep disease (sleepdisorder), fertility disease, blood coagulation disease (blood coagulationdisorder), vision problems and immune and autoimmune diseases. In addition, this compound can also inhibit cell tumorigenic transformation and metastatic tumor growth, and thus can be used to treat various forms of cancer. The crystalline form of the heterocyclic compound represented by formula A or its hydrate can also be used to treat and/or prevent prostaglandin-mediated proliferative diseases, such as proliferative diseases that may occur in diabetic retinopathy and tumor angiogenesis. The crystalline form of the heterocyclic compound represented by Formula A or its hydrate can also inhibit prostanoid-induced smooth muscle contraction by antagonizing contractile prostanoids or simulated relaxing prostaglandins, and thus can It is used to treat dysmenorrhea, premature delivery and eosinophil-related diseases. More specifically, the crystalline form of the heterocyclic compound represented by Formula A or its hydrate is an antagonist of prostaglandin D2 receptor (CRTH2).

The present invention also provides a method of antagonizing the PGD ₂ receptor, including the CRTH2 receptor, which method comprises administering to a mammal in need thereof an effective amount of the crystalline form of the heterocyclic compound represented by Formula A or its hydrate.

Another aspect of the present invention provides a method of treating or preventing a prostaglandin-mediated disease, the method comprising administering to a mammalian patient in need of such treatment an amount that can effectively treat or prevent the prostaglandin-mediated disease A shows the crystalline form of the heterocyclic compound or its hydrate.

The crystal forms and compositions of the present invention can be used to treat prostaglandin-mediated diseases, including but not limited to allergic rhinitis, nasal congestion, runny nose, perennial rhinitis, rhinitis, asthma including allergic asthma, chronic obstructive pulmonary disease And other forms of pneumonia; sleep sickness and sleep-wake cycle disorder; dysmenorrhea and preterm labor associated with prostaglandin-induced smooth muscle contraction; eosinophil-related diseases; thrombosis; glaucoma and vision disorders; Occlusive vascular disease; congestive heart failure; diseases or conditions that require anticoagulant therapy, such as post-injury or post-operative treatment; inflammation; gangrene; Raynaud's disease; mucin secretion disorders including cell protection; pain and migraine; need Diseases that control bone formation and resorption, such as osteoporosis; shock; thermal regulation, including fever; and immune diseases or disorders that require immune regulation. More specifically, the diseases to be treated are diseases mediated by prostaglandin D2, such as nasal congestion, pulmonary congestion, and asthma including allergic asthma.

The present invention also provides a method of treating or preventing a prostaglandin-mediated disease, the method comprising administering to a mammalian patient in need of such treatment an amount of a heterocyclic compound represented by formula A that can effectively treat or prevent a prostaglandin-mediated disease Crystalline form, wherein the prostaglandin-mediated diseases are stuffy nose, rhinitis including allergic rhinitis and perennial rhinitis, and asthma including allergic asthma.

The present invention also provides a method of treating or preventing a prostaglandin D2-mediated disease, the method comprising administering to a mammalian patient in need of such treatment an heterocyclic ring of formula A in an amount effective to treat or prevent a prostaglandin D2-mediated disease The crystalline form of the compound or its hydrate, wherein the disease mediated by prostaglandin D2 is nasal congestion or asthma.

The present invention also provides a method of treating nasal congestion in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of the heterocyclic compound represented by Formula A or a hydrate thereof.

The present invention also provides a method of treating asthma, especially allergic asthma, in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of the heterocyclic compound represented by Formula A or a hydrate thereof.

Those skilled in the art will readily understand that the administration of the compounds disclosed herein can be mixed with pharmaceutically acceptable excipients well known in the art. Specifically, as a drug for systemic administration, it can be formulated into capsules, powders, pills, tablets, etc. suitable for oral or parenteral administration or inhalation.

In order to treat and prevent prostaglandin-mediated diseases, the crystalline form of the heterocyclic compound represented by formula A or its hydrate can be co-administered with other therapeutic agents. Therefore, another aspect of the present invention provides a pharmaceutical composition for treating prostaglandin-mediated diseases, which includes a therapeutically effective amount of the crystalline form of the heterocyclic compound represented by formula A or its hydrate and one or more Kinds of other therapeutic agents. Suitable therapeutic agents used in combination therapy with the crystalline form of the heterocyclic compound represented by Formula A or its hydrate include: (1) DP receptor antagonists, such as S-5751 or laropiprant; 2) Corticosteroids, such as triamcinolone (acetonide); (3) β-agonists, such as salmeterol, formoterol, terbutaline, isoprotonin (metaproterenol) and albuterol (albuterol), etc.; (4) Leukotriene modifiers, including leukotriene receptor antagonists or lipooxygenase inhibitors, such as montelukast, montelukast Zafirlukast, pranlukast or zileuton; (5) antihistamines, such as bromopheniramine, chlorpheniramine, dexchlorobenzene Dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, Methilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine ( pheniramine, pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine and Decarbonized ethoxyloratadine (descarboethoxyloratadine), etc.; (6) Decongestants, including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline , Ephinephrine, naphazoline, xylometazoline, propylhexedrine or levo-deso xyephedrine); (7) Antiitussive, including codeine, hydrocodone, caramiphen, carbetapentane or dextramethorphan; (8 ) Another prostaglandin ligand, including prostaglandin F agonists, such as latanoprost, misoprostol, enprostil, rioprostil, ornoprost Alcohol (omoprostol) or rosaprostol (rosaprostol); (9) diuretics; (10) non-steroidal anti-inflammatory agents (NSAIDs), such as propionic acid derivatives (alminoprofen (alminoprofen), benzoxolfen ( benoxaprofen), bucloxicacid, carprofen, fenbufen, fenbuprofen, fenoprofen, fluprofen, flurbiprofen, ibuprofen Ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pirprofen Pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, acemetacin) Alclofenac, clidanac, diclofenac, fenclofenac, fenclozicacid, fentiazac, furofenac, Ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zometaic acid ( zomepirac)), fenamicacid derivatives (flufenamicacid), meclofenamicacid, mefenamicacid, niflumicacid and tolfena micacid)), biphenyl carboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam), piroxicam , Sudoxicam (sudoxicam) and tenoxican (tenoxican), salicylic acids (acetylsalicylic acid, sulfasalazine) and pyrazolone (apazone), bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (11) cyclooxygenase-2 (COX-2) inhibitor , Such as celecoxib (celecoxib) and rofecoxib (rofecoxib); (12) type IV phosphodiesterase (PDE-IV) inhibitors, such as Ariflo, roflumilast (roflumilast); (13) Antagonists of chemokine receptors, especially CCR-I, CCR-2 and CCR-3; (14) cholesterol-lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin ) And pravastatin, fluvastatin, atorvastatin and other statins), chelating agents (cholestyramine and colestipol), niacin, non- Fenofibricacid derivatives (gembrozil, clofibrat, fenofibrate and benzafretate), and probucol; (15 ) Antidiabetic drugs, such as insulin, sulfonylureas, biguanides (metformin), α-glucosidase inhibitors (acarbose) and glitazones (troglitazone, pioglitazone ( pioglitazone), englitazone (englitazone) and rosiglitazone (rosiglitazone, etc.); (16) preparations of interferon beta (interferon beta-1a, interferon beta-1b); (17) anticholinergics, such as poison Muscarinic antagonists (ipratropiumbromide and tiotropiumbromide), and selective muscarinic M3 antagonists; (18) steroids, such as beclometha sone), methylprednisolone, betamethasone, prednisone, dexamethasone and hydrocortisone; (19) commonly used in the treatment of migraine Triptans, such as sumitriptan and rizatriptan; (20) alendronate and other osteoporosis treatment agents; (21) other compounds, For example, 5-aminosalicylic acid and its prodrugs, antimetabolites, such as azathioprine and 6-mercaptopurine, cytotoxic cancer chemotherapeutic agents, bradykinin (BK2) antagonists, such as FK-3657, TP Receptor antagonists, such as seratrodast, neurokinin antagonists (NK1/NK2), VLA-4 antagonists, for example in US 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96 /22966, WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206 described antagonists.

Beneficial effect

The present invention provides the crystal form of the compound of formula A or its hydrate. The inventor unexpectedly discovered that the crystalline form of the compound of formula A or its hydrate is superior to its amorphous form in terms of moisture absorption and stability. Moreover, the crystalline form also has better bioavailability than the amorphous form. In addition, the preparation method of the compound of formula A or its hydrate is simple, can be applied in industry, and has higher practicability.

BRIEF DESCRIPTION

FIG. 1 is an XRPD spectrum of the crystal form obtained in Example 1. FIG.

2 is a DSC-TGA spectrum of the crystal form obtained in Example 1. FIG.

3 is a three-dimensional structure diagram and cell diagram of the crystal form obtained in Example 1. FIG.

DSC-TGA test project instrument name and model: synchronous thermal analyzer (STA449F3) 20 ℃ to 350 ℃

XRPD testing project instrument name and model: AFC10/Saturn724+Rigaku X-ray diffraction analyzer

detailed description

The technical solution of the present invention will be further described in detail below with reference to specific embodiments. The following examples are merely illustrative for explaining and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by the scope of protection of the present invention.

Unless otherwise stated, the raw materials and reagents used in the following examples are all commercially available products, or can be prepared by known methods.

Example 1. Preparation of the crystalline form of the compound of formula A monohydrate

With reference to the methods described in Examples 3 and 4 of Patent Document CN101896178B, the racemic compound (0.500 g) of the heterocyclic compound of formula A was eluted on a Chiralcel OJ-RH column (Chiralcel Technologies) with methanol containing 0.05% TFA and collected The eluate was concentrated to dryness to obtain about 0.2 g of product, which was amorphous. Add acetone (2.5mL) and water (2.5mL) to the concentrate, heat and dissolve at 40-50°C, then drop to 0-10°C, stir and crystallize for 2 to 3h, and filter to obtain the crystalline form of the heterocyclic compound of formula A ( 0.156g), the yield was 31.2%. The XRPD detection results of the crystal form are shown in FIG. 1, and the DSC-TGA detection results are shown in FIG. 2. From the DSC chart of FIG. 2, it can be seen that the endothermic peaks appear at 86.4°C and 130.4°C, respectively, and the TGA loses weight. The graph shows a weight loss of 4.29%. The DSC-TGA pattern of the crystal form indicates that the crystal form is a monohydrate. 3 is a three-dimensional structure diagram and unit cell diagram of the obtained crystal form.

¹ H NMR (600 MHz, CD ₃ OD): 8.13-8.15 (m, 1H), 8.00-8.04 (m, 2H), 7.92-7.95 (m, 1H), 7.37-7.42 (m, 2H), 7.09-7.14 (m,1H), 4.50-4.55(m,1H), 4.38-4.42(m,1H), 3.91-3.97(m,1H), 3.61-3.71(m,2H), 3.17-3.23(m,1H) , 2.85-2.95 (m, 4H), 1.97-2.02 (m, 1H), 1.75-1.79 (m, 1H).

Test Example 1. Solubility test

The solubility of the crystal form obtained in Example 1 in different pH solutions was tested by the following test method:

1.1, the preparation of different pH media

pH1.0 medium: take 9.0mL of hydrochloric acid, dilute with water to 1000mL, shake well, then you get.

pH4.5 medium: take 6.80g of potassium dihydrogen phosphate (KH ₂ PO ₄ ), add appropriate amount of water to dissolve and dilute to 1000mL, adjust the pH value to 4.5 with phosphoric acid or sodium hydroxide, shake well, then you get.

pH6.8 medium: take 55.38g of disodium hydrogen phosphate (Na ₂ HPO ₄ · 12H ₂ O) and 4.77g of citric acid (C ₆ H ₈ O ₇ · H ₂ O), add appropriate amount of water to dissolve and dilute to 1000mL, Adjust the pH to 6.8 with phosphoric acid or sodium hydroxide, shake well, and you're done.

Pure water medium: purified water

1.2. Test method: Take a certain amount of the test sample (crystal form prepared in Example 1), add the medium with the corresponding pH one by one, and continue to shake until it reaches the saturation state, record the weight of the test sample and the amount of solvent, Calculate the concentration when dissolving the sample, and the test results show that the crystal form of the compound of formula A has good solubility in different pH.

Test Example 2 Humidity Test

The hygroscopicity test of the crystal form obtained in Example 1;

The test method is:

Inspection method: Chinese Pharmacopoeia method (Chinese Pharmacopoeia 2015 Edition Four General Rules 9103)

Test conditions:

Operating temperature: 25℃±1℃

Dryer humidity: 80%±2%RH.

Specific test operation: place the dried flat weighing bottle in a constant temperature dryer (place a saturated solution of ammonium chloride or ammonium sulfate in the lower part) for 24h, take 1 g of the crystal form obtained in Example 1 and lay it flat in the flat weighing bottle, open And put it in the desiccator together with the bottle cap for 24h.

sample name	Weight gain (%)	in conclusion
Crystal form	0.23	Slightly hygroscopic

From the above results, it can be seen that the crystalline form of the compound of formula A is slightly hygroscopic under high humidity conditions, indicating that the crystalline form of the compound of formula A has high stability.

Test Example 3. Stability test

Test process: Take an appropriate amount of the crystal form prepared in Example 1 and place it on a clean watch glass, open it, and place it under the conditions of light 4500lx±500lx, high temperature 60℃, high humidity 92.5%RH for 5 days and 10 days, respectively. Traits, related substances, and compare with the 0-day result to check the stability.

The relevant substance inspection methods are as follows:

Preparation of test product solution: Take about 10 mg of each test product, place in a 10 ml measuring bottle, add 50% acetonitrile to dissolve and dilute to the mark, shake well, and filter as the test product solution. Accurately measure 10μl of the sample solution, inject the sample according to the above chromatographic method, and calculate the maximum single impurity and total impurity according to the area normalization method. The test results show that the crystal form of the compound of formula A has good stability under high temperature and high humidity. The largest single impurity does not exceed 0.1%, while the total impurity does not exceed 0.4%. And the inventor found that the stability of the crystal form of the compound of formula A under light conditions is worse than the stability under high temperature and high humidity, but still has relatively good stability.

In the above, the embodiment of the present invention has been described. However, the present invention is not limited to the above-mentioned embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (10)

1. The crystalline form of the heterocyclic compound or its hydrate represented by formula A, characterized in that the crystalline form is used

   Cu-Kα radiation, X-ray powder diffraction expressed at a 2θ angle of 11.1±0.2°, 11.4±0.2°,

   There are characteristic peaks at 17.9±0.2°, 22.6±0.2°, 24.4±0.2°,

   
2. The crystalline form according to claim 1, wherein the crystalline form uses Cu-Kα radiation, and the X-ray powder diffraction expressed at an angle of 2θ is 8.6±0.2°, 11.1±0.2°, 11.4±0.2°, 14.1 There are characteristic peaks at ±0.2°, 16.1±0.2°, 17.9±0.2°, 20.9±0.2°, 22.6±0.2°, 24.4±0.2°, 25.8±0.2°.

   More preferably, the crystal form uses Cu-Kα radiation, and the X-ray powder diffraction expressed at an angle of 2θ is 8.6±0.2°, 11.1±0.2°, 11.4±0.2°, 14.1±0.2°, 15.6±0.2°, 16.1 There are characteristic peaks at ±0.2°, 17.9±0.2°, 18.3±0.2°, 20.9±0.2°, 22.6±0.2°, 24.4±0.2°, 25.8±0.2°, 26.5±0.2°, 28.9±0.2°.
3. The crystal form according to claim 1 or 2, wherein the crystal form of the heterocyclic compound represented by formula A is a hydrate, preferably a monohydrate. More preferably, the mass fraction of water in the hydrate is 4.2-5.2%, more preferably 4.5-5.0%.
4. The crystalline form according to any one of claims 1 to 3, wherein the crystalline form has an X-ray powder diffraction spectrum substantially as shown in FIG.
5. The crystalline form according to any one of claims 1 to 4, wherein the crystalline form is a single crystal and has the following single crystal parameters:

   
6. The method for preparing a crystal form according to any one of claims 1-5, comprising the following steps:

   Place the compound represented by formula A in a mixed solvent composed of ketone solvent and water, dissolve it after heating and cool down, stir and crystallize to obtain a crystal form

   
7. The preparation method according to claim 6, wherein the ketone solvent is selected from acetone or methyl ethyl ketone.
8. The preparation method according to claim 6 or 7, wherein the volume ratio of the ketone solvent to water is (1-3):1.
9. A pharmaceutical composition comprising the crystalline form of any one of claims 1-5.
10. Use of the crystal form according to any one of claims 1 to 5 in the preparation of a medicament for the treatment or prevention of CRTH2-mediated diseases.

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