A crystalline pentacyclic triterpenoid and methods of making the same

Abstract

Provided are a crystalline form of a pentacyclic triterpenoid compound and a preparation method of the crystalline form, the pentacyclic triterpenoid compound being 3-O-cyclohexanecarbonyl-11-carbonyl-beta-boswellic acid, abbreviated as CKBA, the preparation method of the crystalline form being simple in operation, the crystalline form prepared being more stable under light conditions, less change in impurities, and the crystalline form prepared being higher in solubility in organic solvents, lower in hygroscopicity, and more conducive to development of a subsequent preparation process. Further provided are a pharmaceutical composition using the crystalline form as an active ingredient, and use of the crystalline form in preparation of a medicament for treating psoriasis.

Description

[0001] The present application claims priority to the prior application filed on April 25, 2021 with the China National Intellectual Property Office and with the patent application number 202110449743.7 and with the title "A crystalline of pentacyclic triterpenoid compound and a preparation method thereof". The entire contents of the aforementioned prior application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the technical field of pharmacy, and in particular relates to a crystalline of pentacyclic triterpenoid compound and a preparation method thereof. BACKGROUND

[0003] The pharmaceutically active compound involved in the present application is a pentacyclic triterpenoid compound, with the chemical name: 3-O-cyclohexanecarbonyl-11-carbonyl-β-boswellic acid, abbreviated as CKBA, and with the structural formula as follows:

[0004]

[0005] The compound achieves targeted treatment of psoriasis by selectively inhibiting the activation of the nucleic acid transcription factor NF-kappa B, regulating the expression of related cytokines and the differentiation of Th1 / 17.

[0006] Chinese patent CN104672293A discloses a preparation method of CKBA. The CKBA prepared by this method is in amorphous form. Chinese patent CN110818767A discloses a preparation method of 3-O-cyclohexanecarbonyl-11-carbonyl-β-boswellic acid or its analogues. The crude CKBA prepared by this method is dissolved in acetone, tetrahydrofuran, anhydrous methanol, anhydrous ethanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, water or a combination thereof to obtain fine CKBA. However, the fine CKBA is still in amorphous form. The amorphous substance prepared by the above two methods is unstable under light conditions and is prone to decomposition to generate impurities. Moreover, the amorphous compound has poor solubility in organic solvents, which is not conducive to the development of subsequent preparations. Therefore, there is a need in the art to obtain a crystalline compound with excellent physical and chemical properties suitable for application. SUMMARY

[0007] The present application provides a crystalline of a compound represented by formula (I),

[0008]

[0009] The crystalline is selected from a crystal form A, and the X-ray diffraction pattern of the crystal form A has diffraction peaks with 2θ angles of 6.139±0.2°, 7.315±0.2°, 10.553±0.2°, 14.319±0.2°, 15.459±0.2° and 17.749±0.2°.

[0010] In some embodiments, the crystalline form A of the compound of formula (I) has an X-ray diffraction pattern comprising peaks at diffraction angles 2Q of: 6.139±0.2°, 7.315±0.2°, 10.553±0.2°, 12.825±0.2°, 13.424±0.2°, 14.319±0.2°, 14.846±0.2°, 15.459±0.2°, 16.611±0.2°, 17.749±0.2°.

[0011] In some embodiments, the crystalline form A of the compound of formula (I) has an X-ray diffraction pattern comprising peaks at diffraction angles 2Q of: 6.139±0.2°, 7.315±0.2°, 8.830±0.2°, 10.553±0.2°, 12.062±0.2°, 12.825±0.2°, 13.424±0.2°, 14.319±0.2°, 14.846±0.2°, 15.459±0.2°, 15.737±0.2°, 16.611±0.2°, 17.749±0.2°, 19.089±0.2°, 21.631±0.2°, 22.131±0.2°.

[0012] In some embodiments, the crystalline form A of the compound of formula (I) has an X-ray diffraction pattern comprising peaks at diffraction angles 2Q as shown in Table 1.

[0013] In some embodiments, the crystalline form A of the compound of formula (I) has an X-ray diffraction pattern substantially as shown in Figure 1

[0014] In some embodiments, the crystalline form A has a differential scanning calorimetry curve with an endothermic peak at 237.56±2℃.

[0015] In some embodiments, the present application provides a preparation method of a crystalline of a compound of formula (I), which is selected from the crystalline form A, the preparation method comprising: dissolving the compound of formula (I) in cyclohexane, warming to 65-80℃, stirring until the solid is dissolved, cooling to room temperature, continuing to stir, suction filtering, and drying to obtain the crystalline form A.

[0016] In some embodiments, the cooling to room temperature is natural cooling to room temperature.

[0017] In some embodiments, the volume (mL) of the solvent is 3-15 times, preferably 3-12 times, more preferably 3-5 times of the mass (g) of the compound.

[0018] In some embodiments, the warming is to 70-80℃.

[0019] ​In some embodiments, the present application provides a crystalline form of the compound of formula (I),

[0020]

[0021] The crystalline form is selected from the group consisting of Form B, wherein the X-ray diffraction pattern of the Form B has diffraction peaks at 2θ angles of 10.692±0.2°, 12.026±0.2°, 12.940±0.2°, 13.402±0.2°, 14.430±0.2°.

[0022] In some embodiments, the X-ray diffraction pattern of the Form B has diffraction peaks at 2θ angles of 8.583±0.2°, 10.207±0.2°, 10.692±0.2°, 12.026±0.2°, 12.601±0.2°, 12.940±0.2°, 13.402±0.2°, 13.782±0.2°, 13.991±0.2°, 14.430±0.2°, 15.392±0.2°, 18.035±0.2°.

[0023] In some embodiments, the X-ray diffraction pattern of the Form B has diffraction peaks at 2θ angles of 8.583±0.2°, 10.207±0.2°, 10.692±0.2°, 12.026±0.2°, 12.601±0.2°, 12.292±0.2°, 12.940±0.2°, 13.402±0.2°, 13.782±0.2°, 13.991±0.2°, 14.430±0.2°, 15.392±0.2°, 16.823±0.2°, 17.391±0.2°, 18.035±0.2°, 28.049±0.2°.

[0024] In some embodiments, the X-ray diffraction pattern of the Form B has diffraction peaks at 2θ angles as shown in Table 2.

[0025] In some embodiments, the X-ray diffraction pattern of the Form B is substantially as shown in Figure 5 .

[0026] In some embodiments, the Form B has a differential scanning calorimetry curve with an endothermic peak at 167.80±2℃.

[0027] In some embodiments, the present application provides a preparation method of a crystalline form of the compound of formula (I), wherein the crystalline form is selected from the group consisting of Form B, and the preparation method of the Form B comprises: dissolving the compound of formula (I) in acetonitrile, warming to 65-80℃, stirring until the solid is dissolved, cooling to room temperature, continuing to stir, and drying to obtain the Form B.

[0028] In some embodiments, the volume of the solvent (mL) is 3-15 times, preferably 5-15 times, more preferably 8-12 times the mass of the compound (g).

[0029] In some embodiments, the temperature is raised to 70-80°C.

[0030] In some embodiments, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as described above in crystal form A and / or crystal form B, and one or more pharmaceutically acceptable carriers or excipients.

[0031] In some embodiments, the present application also provides the use of the compound of formula (I) as described above in crystal form A and / or crystal form B in the manufacture of a medicament for the treatment of psoriasis.

[0032] In another aspect, the present application provides a method of treating psoriasis in a mammal, preferably a human, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of the compound of formula (I) as described above in crystal form A and / or crystal form B, or a pharmaceutical composition thereof.

[0033] In another aspect, the present application also provides the use of the compound of formula (I) as described above in crystal form A and / or crystal form B in the prevention or treatment of psoriasis.

[0034] In another aspect, the present application also provides the compound of formula (I) as described above in crystal form A and / or crystal form B, or a pharmaceutical composition thereof, for use in the prevention or treatment of psoriasis.

[0035] Terminology definitions and explanations

[0036] For the same crystal form of the same compound, the peak positions of the XRD pattern have a similarity in the whole, and the relative intensity error can be large. It should also be noted that in the identification of mixtures, the loss of some diffraction lines due to factors such as content reduction can occur, at which time, it is not necessary to rely on all the diffraction peaks observed in a high-purity sample, and even one diffraction peak can be characteristic of a given crystal.

[0037] The "2-theta or 2-theta angle" described herein refers to the diffraction angle, theta, is the Bragg angle, in ° or degrees. The 2-theta values allow for a range of error. Typically, the range of error is indicated by "±". For example, 5.921 ± 0.2° 2-theta means within the range of 6.121 to 5.721. Depending on sample preparation techniques, calibration techniques applied to the instrument, human manipulation bias, etc., one of skill in the art recognizes that a suitable range of error for XRD diffraction angles (2-theta) can be ± 0.20°, ± 0.15°, ± 0.10°, ± 0.05° or less. The term "substantially the same" or "substantially as shown" when used to describe an XRD pattern means a pattern that includes at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the diffraction peaks within a standard deviation of ± 0.2° 2-theta.

[0038] One of skill in the art recognizes that the measured data for a DSC profile for a given crystalline form of the same compound will vary within the range of error. The single peak peak value (in degrees Celsius) allows for a range of error. Typically, the range of error is indicated by "±". For the same crystalline form of the same compound, the thermal transition temperature and melting point error is typically within about ± 2°C in successive analyses. For example, a peak value of "140.96 ± 2°C" means within the range of 142.96 to 138.96. Depending on sample preparation techniques, calibration techniques applied to the instrument, human manipulation bias, etc.

[0039] Room temperature as described herein means 20 ± 5.0°C.

[0040] The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats a particular disease, condition, or disorder, (ii) delays or reduces the symptoms of a particular disease, condition, or disorder, or (iii) delays onset of a particular disease, condition, or disorder as described herein. The amount of a compound of the present application that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as an initial guess, and adjusted as necessary, based on the knowledge of the practitioner and the disclosure herein.

[0041] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The pharmaceutical compositions of the present application can be prepared by combining a compound of the present application or a pharmaceutically acceptable salt or solvate thereof with a suitable pharmaceutically acceptable carrier or excipient, and formulated into a solid, semi-solid, liquid, or gaseous dosage form, such as a paste, emulsion, gel, etc.

[0042] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as the conventional mixing, dissolving, granulating, emulsifying, dring, etc.

[0043] The pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound.

[0044] The excipient refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the compound. Examples of excipients include (but are not limited to) calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0045] Advantages of the present application:

[0046] The crystal form A and the crystal form B of the compound represented by formula (I) prepared by the present application are more stable under light conditions than the CKBA amorphous substance disclosed in patents CN104672293A and CN110818767A, have small impurity changes, and have higher solubility in organic solvents than the crystal form A and the crystal form B prepared.

[0047] In addition, the crystal form A and the crystal form B provided by the present application are almost non-hygroscopic, meet the requirements of bioavailability and drug efficacy, simplify the drug post-processing process, are not easily affected by humidity, have not strict requirements on storage conditions, and are convenient for long-term storage. BRIEF DESCRIPTION OF DRAWINGS

[0048] Figure 1 is the XRD pattern of the crystal form A of the compound of formula (I).

[0049] Figure 2 is the DSC pattern of the crystal form A of the compound of formula (I).

[0050] Figure 3 is the TG pattern of the crystal form A of the compound of formula (I).

[0051] Figure 4 is the DVS pattern of the crystal form A of the compound of formula (I).

[0052] Figure 5 is the XRD pattern of the crystal form B of the compound of formula (I).

[0053] Figure 6 is the DSC pattern of the crystal form B of the compound of formula (I).

[0054] Figure 7 is the TG pattern of the crystal form B of the compound of formula (I).

[0055] Figure 8is a DVS pattern of Form B of the compound of Formula (I).

[0056] Figure 9 is a DVS pattern of amorphous of the compound of Formula (I) in the prior art. DETAILED DESCRIPTION

[0057] The application will be described in detail below with reference to the embodiments. However, the application is not limited to the embodiments. The embodiments of the present application are only exemplary and do not constitute any limitation on the scope of the present application. Those skilled in the art should understand that the details and forms of the technical solutions of the present application can be modified or replaced without departing from the spirit and scope of the present application, and such modifications and replacements fall within the protection scope of the present application.

[0058] Example 1: Preparation of CKBA amorphous

[0059] Referring to CN104672293A Example 1, 3-O-cyclohexanecarbonyl-11-carbonyl-β-boswellic acid was prepared, i.e. CKBA amorphous substance was obtained.

[0060] Example 2: Preparation of CKBA Form A

[0061] 0.3 g of CKBA amorphous sample was placed in a 5 ml reaction bottle, 0.9 ml of cyclohexane was added, and the temperature was raised to 70°C, and stirred for 1 h, and the solid was dissolved, and then naturally reduced to room temperature and stirred for 3 hours. Filtration, the filter cake was vacuum dried at 40°C for 4 h, and 0.27 g of white solid was obtained.

[0062] Example 3: Preparation of CKBA Form A

[0063] 22 g of CKBA amorphous sample was placed in a 250 ml reaction bottle, 66 ml of cyclohexane was added, and the temperature was raised to 80°C, and stirred for 1 h, and the solid was dissolved, and then naturally reduced to room temperature and stirred for 36 hours. Filtration, the filter cake was vacuum dried at 40°C for 4 h, and 19.7 g of white solid was obtained.

[0064] Example 4: Preparation of CKBA Form B

[0065] 0.3 g of CKBA amorphous sample was placed in a 5 ml reaction bottle, 3.6 ml of acetonitrile was added, and the temperature was raised to 70°C, and stirred for 0.5 h, and the solid was dissolved, and then naturally reduced to room temperature and stirred for 3 hours. Filtration, the filter cake was vacuum dried at 40°C for 4 h, and 0.27 g of white solid was obtained.

[0066] Experimental Example 1

[0067] Method and results:

[0068] XRD (X-ray diffraction): instrument model: Bruker D8 Focus, Cu-Ka ray, scanning range: 3-40 degrees, scanning speed: 5 degrees / min, step length: 0.12° / step.

[0069] TG (thermogravimetric analysis): instrument model: TA TGA55, temperature range: 30-350℃, temperature rising rate: 10℃ / min.

[0070] DSC (differential scanning calorimetry): instrument model: TA DSC2500, temperature range: 30-300℃, temperature rising rate: 10℃ / min.

[0071] The crystals obtained in Example 2 and Example 4 were analyzed by the above method, respectively.

[0072] The X-ray diffraction pattern of the crystal form A is shown in Figure 1 The position of the diffraction peak (2θ) is shown in Table 1.

[0073] Table 1

[0074] No. 2Θ (°) No. 2Θ (°) 1 6.139 19 22.131 2 7.315 20 22.854 3 8.830 21 23.441 4 10.553 22 24.863 5 12.062 23 25.457 6 12.328 24 26.836 7 12.825 25 27.422 8 13.424 26 28.347 9 14.319 27 28.758 10 14.846 28 29.664 11 15.459 29 29.970 12 15.737 30 31.031 13 16.611 31 32.196 14 17.749 32 35.521 15 18.664 33 35.931 16 19.089 34 37.400 17 20.089 35 37.928 18 21.631 36 39.431

[0075] Table 2

[0076] No. 2Θ (°) No. 2Θ (°) 1 7.706 24 21.598 2 8.583 25 22.405 3 10.207 26 22.784 4 10.692 27 23.177

[0077] 5 11.043 28 23.704 6 12.026 29 24.033 7 12.292 30 25.046 8 12.601 31 25.578 9 12.940 32 25.885 10 13.402 33 26.519 11 13.782 34 28.049 12 13.991 35 29.142 13 14.430 36 30.571 14 15.392 37 31.552 15 16.823 38 32.281 16 16.898 39 33.465 17 17.391 40 34.127 18 18.035 41 34.895 19 18.124 42 35.567 20 18.689 43 36.816 21 19.473 44 37.260 22 20.448 45 38.276 23 20.879

[0078] The DSC pattern of the crystal form A is shown in Figure 2 and the differential scanning heat curve thereof has an endothermic peak at 237.56±2℃. The DSC pattern of the crystal form B is shown in Figure 6 and the differential scanning heat curve thereof has an endothermic peak at 167.80±2℃.

[0079] The TG of the crystal form A and the crystal form B is shown in Figure 3 and Figure 7 It can be seen from the figures that the crystal form A and the crystal form B do not contain crystalline water and crystalline solvent.

[0080] Determination of stability in experimental example 2

[0081] Determination method: according to the “Guiding Principles for Stability Test of Raw Materials and Preparations” in the fourth part of the “People’s Republic of China Pharmacopoeia” 2015 edition, the samples obtained in the examples were placed at high temperature 60℃ for 10 days, high humidity 92.5% for 10 days, and light 4500 lux for 11 days, and the change of related substances was observed.

[0082] Related substance detection method:

[0083] Phenylsilane bonded silica gel as the filler (Waters XBridge Phenyl 4.6mm x 150mm, 3.5μm), 0.1% phosphoric acid solution as mobile phase A, acetonitrile as mobile phase B, linear gradient elution was carried out according to the following table; the column temperature was 40℃; the flow rate was 1.0ml per minute; the detection wavelength was 250nm, the injection volume was 20μl.

[0084] Gradient elution conditions are as follows:

[0085]

[0086] The results are shown in Table 3:

[0087] Table 3

[0088]

[0089] The results show that under high temperature and high humidity conditions, the CKBA crystal form and amorphous impurities do not change, under light conditions, the CKBA crystal form A impurity does not change, and although the CKBA crystal form B impurity increases, compared with the CKBA amorphous, the change of impurities is small.

[0090] Determination of solubility in experimental example 3

[0091] Detection method: 1g of the sample of example 1, example 2 and example 4 was weighed and placed in a certain capacity of methanol (or propylene glycol) at 25℃±2℃, and shaken vigorously for 30s every 5min, and the dissolution within 30min was observed. If there was no visible solute particles or droplets, it was considered to be completely dissolved.

[0092] Very soluble system refers to 1g(ml) of solute can be dissolved in less than 1ml of solvent;

[0093] Easily soluble system refers to 1g(ml) of solute can be dissolved in 1-10ml of solvent;

[0094] Soluble system refers to 1g(ml) of solute can be dissolved in 10-30ml of solvent;

[0095] Slightly soluble system refers to 1g(ml) of solute can be dissolved in 30-100ml of solvent;

[0096] Slightly soluble system refers to 1g(ml) of solute can be dissolved in 30-100ml of solvent;

[0097] Very slightly soluble system refers to 1g(ml) of solute can be dissolved in 1000-10000ml of solvent;

[0098] Almost insoluble or insoluble system refers to 1g(ml) of solute cannot be completely dissolved in 10000ml of solvent.

[0099] The determination results are shown in Table 4:

[0100] Table 4

[0101] Test substance Solubility in methanol Solubility in propylene glycol CKBA Form A Very soluble -- CKBA Form B Soluble Slightly soluble CKBA amorphous Soluble Very slightly soluble

[0102] “--” indicates that no test is performed

[0103] The results show that, compared with CKBA amorphous, the solubility of CKBA crystal form A and CKBA crystal form B in methanol is obviously improved, and the solubility of CKBA crystal form B in propylene glycol is higher. For a liposoluble drug, improving its solubility in a solvent is more conducive to preparation.

[0104] Determination of hygroscopicity

[0105] About 10 mg of the samples of Example 1, Example 2 and Example 4 of the present application are tested for hygroscopicity by using a dynamic water adsorption instrument (instrument model: DVS Intrinsic).

[0106] The experimental results are shown in Table 5. The DVS graph of the hygroscopicity experiment is as follows: Figure 4 、 Figure 8 and Figure 9 .

[0107] Table 5

[0108] Test substance Weight gain at 80% relative humidity (%) CKBA Form A 0.01 CKBA Form B 0.13 CKBA amorphous 0.58

[0109] The results show that CKBA amorphous has hygroscopicity, while the crystal form A and the crystal form B of the compound of formula (I) of the present application have almost no hygroscopicity under 80% relative humidity, indicating that the crystal form A and the crystal form B are not easily affected by humidity, and the requirements for storage conditions are not harsh, and long-term storage is facilitated. Therefore, the crystal form A and the crystal form B of CKBA of the present application have wider application value.

[0110] The above is only a preferred embodiment of the present application, and does not limit the present application in any form. Any person skilled in the art, without departing from the technical solution of the present application, according to the technical essence of the present application, any simple modification, equivalent replacement and improvement of the above embodiment, etc. still belongs to the protection scope of the technical solution of the present application.

Claims

1. A crystal of a compound of formula (I), characterized in that: the crystal is Form A, and the X-ray diffraction pattern of the Form A has diffraction peaks at 2θ angles as shown in the following numbers 1-36: the Form A is prepared by dissolving the compound of formula (I) in cyclohexane, heating to 65-80℃, stirring until the solid is dissolved, cooling to room temperature, continuing to stir, suction filtration, and drying.

2. The crystalline compound of formula (I) according to claim 1, characterized in that: the Form A has an endothermic peak at 237.56±2℃ in the differential scanning calorimetry curve.

3. A process for the preparation of a crystalline form of a compound of formula (I) as claimed in any one of claims 1-2, characterized in that: the crystal is Form A, and the Form A is prepared by dissolving the compound of formula (I) in cyclohexane, heating to 65-80℃, stirring until the solid is dissolved, cooling to room temperature, continuing to stir, suction filtration, and drying.

4. The process for the preparation of crystalline compounds of formula (I) according to claim 3, characterized in that: the cooling to room temperature is natural cooling to room temperature. 5.A crystal of a compound of formula (I), characterized in that: the crystal is Form B, and the X-ray diffraction pattern of the Form B has diffraction peaks at 2θ angles as shown in the following numbers 1-36: the Form B is prepared by dissolving the compound of formula (I) in acetonitrile, heating to 65-80℃, stirring until the solid is dissolved, cooling to room temperature, continuing to stir, suction filtration, and drying.

6. The crystalline compound of formula (I) according to claim 5, characterized in that: the Form B has an endothermic peak at 167.80±2℃ in the differential scanning calorimetry curve.

7. A process for the preparation of a crystalline form of a compound of formula (I) as claimed in any one of claims 5-6, characterized in that: the crystal is Form B, and the Form B is prepared by dissolving the compound of formula (I) in acetonitrile, heating to 65-80℃, stirring until the solid is dissolved, cooling to room temperature, continuing to stir, suction filtration, and drying. 8.A pharmaceutical composition comprising a therapeutically effective amount of the crystal of the compound of formula (I) according to any one of claims 1-7, and one or more pharmaceutically acceptable carriers or excipients. 9.Use of the crystal of the compound of formula (I) according to any one of claims 1-7 or the pharmaceutical composition of claim 8 in the preparation of a medicament for treating psoriasis.

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