CN115745913B

CN115745913B - Qu Faluo statin polymorphism and preparation method thereof

Info

Publication number: CN115745913B
Application number: CN202211131122.5A
Authority: CN
Inventors: 刘飞; 李先朝; 林成刚; 吴刚; 赵欣; 殷宪艳
Original assignee: Nanjing Minoway Medical Technology Co ltd
Current assignee: Nanjing Minoway Medical Technology Co ltd
Priority date: 2022-09-16
Filing date: 2022-09-16
Publication date: 2024-05-24
Anticipated expiration: 2042-09-16
Also published as: CN115745913A

Abstract

The invention provides a polymorphic form of a trefoil compound, a preparation method and application thereof, wherein the crystalline form II has excellent stability, is suitable for large-scale production, and is suitable for drug research and development and industrial application.

Description

Qu Faluo statin polymorphism and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a crystal form of a compound Qu Faluo tin and a preparation method thereof.

Background

Qu Faluo (Trifarotene) is a topical retinoid that selectively targets Retinoic Acid Receptor (RAR) gamma. On day 4 of 10 2019, the U.S. Food and Drug Administration (FDA) approved 0.005% Aklief (Trifarotene) face cream for topical treatment of acne. Trifarotene is the first retinoid molecule approved by the FDA in the united states for use in treating acne.

WO2021216628 discloses a crystalline form 1 of trefoil which is obtained by dissolving in methanol as solvent at 60 ℃ and cooling to room temperature, and crystallizing. CN202080085458.5 discloses various crystalline forms D to F of trefoil. Experiments prove that the crystal form result obtained by the method is poor in reproducibility or cannot be obtained.

In order to find a more stable form of trefoil, it is necessary to conduct a form screening study on Qu Faluo th of the compounds.

Disclosure of Invention

The invention aims to provide various crystal forms of trefoil, and a preparation method and application thereof.

In a first aspect of the present invention, there is provided a crystal of a trefoil compound represented by formula (I),

The crystals are selected from form I, form II, form III, form IV, or a combination thereof.

In one embodiment, the X-ray powder diffraction pattern of form I comprises 3 or more 2θ values selected from the group consisting of: 3.65.+ -. 0.1 °, 7.26.+ -. 0.1 °, 8.82.+ -. 0.1 °, 10.86.+ -. 0.1 °, 14.47.+ -. 0.1 °, 16.54.+ -. 0.1 °, 18.10.+ -. 0.1 °, 23.15.+ -. 0.1 ° and 24.19.+ -. 0.1 °.

In another embodiment, further, the crystalline form I has a 2θ value selected from the list shown in the following:

in another preferred embodiment, the X-ray powder diffraction (XRPD) pattern of form I is substantially as depicted in figure 1.

In another preferred embodiment, the DSC pattern of form I has an endothermic peak at a temperature in the range of about 260-262 ℃. The melting point of form I is about 261 ℃.

In another preferred embodiment, the DSC profile of form I is substantially as characterized in figure 2.

In one embodiment, the X-ray powder diffraction pattern of form II comprises 3 or more 2θ values selected from the group consisting of: 3.26.+ -. 0.1 °, 6.43.+ -. 0.1 °, 12.78.+ -. 0.1 °, 15.97.+ -. 0.1 °, 16.42.+ -. 0.1 °, 18.57.+ -. 0.1 °, 19.30.+ -. 0.1 °, 20.78.+ -. 0.1 °.

In another embodiment, further, the form II has a2θ value selected from the list shown in the following:

Sequence number	2θ	D value	Relative intensity	Sequence number	2θ	D value	Relative intensity
								1	3.26	27.11	100	7	17.86	4.96	1.3
2	6.43	13.74	2.0	8	18.10	4.90	1.1
								3	12.78	6.92	5.1	9	18.57	4.77	2.4
4	15.08	5.87	1.1	10	19.30	4.59	2.2
								5	15.97	5.55	5.5	11	20.78	4.27	1.6
6	16.42	5.39	3.6	12	21.49	4.13	1.1

In another preferred embodiment, the XRPD pattern of form II is substantially as characterized in figure 3.

In another preferred embodiment, the DSC pattern of form II has an endothermic peak in the range of about 257 to 260 ℃. The melting point of form II is about 259 ℃.

In another preferred embodiment, the DSC profile for form II is substantially as characterized in figure 4.

In another preferred embodiment, the TG of form II is substantially as characterized in figure 5.

In another preferred embodiment, the form II is an anhydrate form.

In one embodiment, the X-ray powder diffraction pattern of form III comprises 3 or more 2θ values selected from the group consisting of: 3.24+ -0.1 °, 8.77+ -0.1 °, 12.13+ -0.1 °, 13.88+ -0.1 °, 16.50+ -0.1 °, 18.08+ -0.1 °, 19.85+ -0.1 °, 23.15+ -0.1 °.

In another embodiment, further, the form III has a 2θ value selected from the list shown in the following:

Sequence number	2θ	D value	Relative intensity	Sequence number	2θ	D value	Relative intensity
								1	3.24	27.28	100	7	16.01	5.53	5.9
2	8.77	10.07	4.1	8	16.50	5.37	20.2
								3	12.13	7.29	4.2	9	18.08	4.90	7.4
4	12.86	6.88	3.5	10	19.85	4.47	4.2
								5	13.88	6.37	7.1	11	22.23	3.99	3.9
6	15.12	5.85	4.1	12	23.15	3.84	10.2

In another preferred embodiment, the XRPD pattern of form III is substantially as characterized in figure 6.

In another preferred embodiment, the DSC pattern of form III has an endothermic peak in the range of about 253-256 ℃. The melting point of form III is about 256 ℃.

In another preferred embodiment, the DSC profile of form III is substantially as characterized in figure 7.

In one embodiment, the X-ray powder diffraction pattern of form IV comprises 3 or more 2θ values selected from the group consisting of: 3.63+ -0.1 °, 8.77+ -0.1 °, 9.72+ -0.1 °, 13.00+ -0.1 °, 14.45+ -0.1 °, 16.50+ -0.1 °, 18.08+ -0.1 °, 22.16+ -0.1 °, 24.19+ -0.1 °.

In another embodiment, further, the form IV has a2θ value selected from the list shown in the following:

Sequence number	2θ	D value	Relative intensity	Sequence number	2θ	D value	Relative intensity
								1	3.63	24.32	100	7	14.45	6.12	19.0
2	8.77	10.07	19.1	8	15.46	5.73	11.8
								3	9.72	9.09	4.0	9	16.50	5.37	22.2
4	10.76	8.21	4.2	10	18.08	4.90	32.1
								5	13.00	6.81	42.5	11	22.16	4.01	46.8
6	13.63	6.49	6.4	12	24.19	3.68	62.1

In another preferred embodiment, the XRPD pattern of form IV is substantially as characterized in figure 8.

In another preferred embodiment, the DSC pattern of form IV has an endothermic peak in the range of about 245-252 ℃. The melting point of form IV is about 248.5 ℃.

In another preferred embodiment, the DSC profile of form IV is substantially as characterized in figure 9.

In a second aspect of the invention, there is provided a process for preparing form Luo Tingjing of koji, comprising: heating and dissolving the Qu Faluo th crude product in an organic solvent, cooling and crystallizing to obtain the Qu Faluo th crystal form II.

Preferably, the organic solvent is selected from methanol, isopropanol, n-propanol, ethyl acetate, isopropyl acetate, methyl isobutyl ketone.

Preferably, the weight-to-volume ratio of Qu Faluo th to organic solvent is 1g:10-100ml, preferably 1g:20-50ml.

Preferably, the dissolution is carried out under heating conditions and the heating temperature is 40 ℃ to 100 ℃, preferably 60 ℃ to 80 ℃.

Preferably, the cooling crystallization is performed at room temperature or below, e.g., 0-25 ℃, e.g., 0-10 ℃.

Preferably, the crystallization further comprises a filtering and drying step. For example, vacuum drying at 40 ℃.

Or the invention provides a method for preparing the yeast Luo Tingjing type II, which comprises the following steps: and dissolving Qu Faluo th in a benign solvent, and adding a poor solvent for crystallization to obtain the crystal form II.

Preferably, the benign solvent is selected from ethyl acetate, isopropyl acetate; the poor solvent is selected from n-heptane and acetonitrile.

The crystals produced according to the present invention have a purity of greater than 95%, preferably greater than 97%, more preferably greater than 99%, most preferably greater than 99.5%.

In a third aspect of the invention there is provided a pharmaceutical composition comprising any one or more of the form Luo Tingjing of the present invention, particularly form II of Qu Faluo, and any pharmaceutically acceptable carrier.

In a fourth aspect of the invention, there is provided the use of any one or more of the form Luo Tingjing of the koji (especially form II) or the pharmaceutical composition of the invention in the manufacture of a medicament for the prevention and treatment of skin disorders.

Skin diseases in the present invention include:

-skin disorders associated with keratosis involving cell differentiation and proliferation;

ichthyosis, ichthyosis-like disorders, follicular keratosis, palmoplantar keratosis, leukoplakia and leukoplakia disorders, and lichen (of the oral cavity) of the skin or mucous;

-dermatological disorders with an inflammatory immune allergic component, with or without a cell proliferation disorder;

-skin disorders caused by exposure to ultraviolet radiation, photo-induced or chronological skin ageing, or actinic pigmentation and keratosis;

-conditions associated with chronological or actinic skin ageing;

Benign or malignant hyperplasia of the skin or epidermis of viral origin or of non-viral origin;

proliferation inducible by ultraviolet light;

Pre-cancerous skin lesions;

-an immune skin disorder;

-immune bullous disease;

-collagen disease;

-dermatological disorders with an immune component;

-an ophthalmic disease;

-macula and/or skin atrophy of the epidermis induced by local or systemic corticosteroids, or any other form of skin atrophy;

-skin diseases of viral origin;

-conditions associated with chronological or actinic skin ageing;

-disorders of sebum function;

-cicatrisation disorders or elongation marks; or (b)

-A pigmentation disorder.

Wherein the skin disorder associated with keratosis involving cell differentiation and proliferation is selected from acne vulgaris, acne, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne, and secondary acne such as solar acne, acne associated with drug treatment or occupational acne.

Wherein the dermatological disorder with an inflammatory immune allergic component, with or without a cell proliferative disorder, is selected from all forms of psoriasis, whether psoriasis of the skin, mucous or nails, psoriatic rheumatism, skin specific reactivity, such as eczema, or respiratory specific reactivity, or gingival hypertrophy.

The various crystal forms of the trefoil comprise the crystal form I, the crystal form II, the crystal form III and the crystal form IV, wherein the crystal form II has good stability, and the preparation method is simple and easy to operate, is suitable for large-scale production, and has good industrial application value.

Drawings

FIG. 1 is an XRPD pattern for form I of method Luo Tingjing of the present invention;

FIG. 2 is a DSC chart of form I of koji method Luo Tingjing of the invention;

FIG. 3 is an XRPD pattern for form II of method Luo Tingjing of the present invention;

FIG. 4 is a DSC chart of form II of koji method Luo Tingjing of the invention;

FIG. 5 is a TG pattern of form Luo Tingjing of the present invention;

FIG. 6 is an XRPD pattern for form III of method Luo Tingjing of the present invention;

FIG. 7 is a DSC chart of form III of the present invention, form Luo Tingjing;

FIG. 8 is an XRPD pattern for form IV of method Luo Tingjing of the invention;

FIG. 9 is a DSC chart of form Luo Tingjing of the present invention.

FIG. 10 is an XRPD pattern for form II of koji Luo Tingjing prepared by a different method.

Detailed Description

The present invention will be described in detail with reference to examples. It should be understood that the methods in the examples are for illustrative purposes only and are not to be construed as limiting the invention in any way. Modifications and improvements made on the basis of the present invention fall within the scope of the claimed invention without departing from the spirit of the invention.

According to the result of the rough solubility of Qu Faluo th and the characteristics of the compound, the invention adopts a suspension stirring method, a slow volatilization method and an antisolvent addition method to carry out polymorphism screening experiments on Qu Faluo th. The material of the trefoil used in the examples is mixed crystals. Of course, any other crude product of trefoil may be used.

The testing method comprises the following steps:

XRPD (X-ray powder diffraction) method: instrument model: bruk D8 advanceX-ray diffractometer; the testing method comprises the following steps: about 10-20 mg of sample is used for XRPD detection; the detailed XRPD parameters are as follows: light pipe: cu, kα, Light pipe voltage: 40kV, light pipe current: 40mA; scanning range: 3-45deg; step diameter: 0.02deg; step size: 0.12 seconds.

DSC (differential scanning calorimetry) method: instrument model: METTLER TOLEDO DSC3+ differential scanning calorimeter; the testing method comprises the following steps: taking a sample (3-5 mg) and placing the sample into a DSC aluminum pot for testing; the detailed DSC parameters are as follows: temperature range: 25-300 ℃; rate of temperature rise: 10 ℃/min; nitrogen purge gas: 50ml/min.

TG (thermogravimetric analysis) method: instrument model: U.S. TA TGA550; the testing method comprises the following steps: taking a sample (5-10 mg) and placing the sample in a TGA platinum pot for testing; the detailed TGA parameters are as follows: temperature range: 30-300 ℃; rate of temperature rise: 10 ℃/min; nitrogen purge gas: 25ml/min.

Table 1 below shows the definition and range of hygroscopicity of the drug at 25 ℃ + -1 ℃,80% + -2% RH balance for the drug in Chinese pharmacopoeia 2020 edition.

TABLE 1

Deliquescence of	Absorb sufficient moisture to form a liquid
		Has very good moisture permeability	The weight gain of the wet-induced hair is not less than 15 percent
Having moisture-permeability	The weight gain of the wet-induced weight is less than 15 percent but not less than 2 percent
		Slightly moisture-absorbing property	The weight gain of the wet-drawing is less than 2 percent but not less than 0.2 percent
No or almost no hygroscopicity	The weight gain of the wet-induced weight is less than 0.2 percent

EXAMPLE 1 preparation of Curve Luo Tingjing form I

Method 1-1 (suspension stirring method): 1ml of 2-methyltetrahydrofuran was added to the flask, followed by 184.2mg Qu Faluo of statin to bring the system into suspension. The suspension of Qu Faluo th and 2-methyltetrahydrofuran was stirred at room temperature for fourteen days. And then taking the suspension for centrifugal separation to obtain a solid product. The product was dried in vacuo at 40 ℃ to give a white solid which was detected as form I of the koji method Luo Tingjing.

Method 1-2 (heating cooling method): about 30mg of trefoil was added to the flask, followed by 2ml of methanol, and heated for dissolution. Filtering the solution after the solution is cleared by a PTFE filter membrane with the thickness of 0.22 mu m, standing the obtained filtrate at room temperature or in the environment of 2-8 ℃ for crystallization, collecting the separated product, and vacuum drying the product at the temperature of 40 ℃ to obtain white solid, and detecting the white solid as the type I of the koji method Luo Tingjing.

Methods 1 to 3 (heating and cooling method): about 30mg of trefoil was added to the flask, followed by 1.5ml of acetone, and heated for dissolution. Filtering the solution after the solution is cleared by a PTFE filter membrane with the thickness of 0.22 mu m, standing the obtained filtrate at room temperature or in the environment of 2-8 ℃ for crystallization, collecting the separated product, and vacuum drying the product at the temperature of 40 ℃ to obtain long rod-shaped crystals, and detecting the long rod-shaped crystals as the type I of the koji method Luo Tingjing.

The XRPD pattern of the resulting form I is shown in fig. 1, and the diffraction angle data is substantially as shown in table 2 below. The DSC pattern of form I is substantially as shown in FIG. 2.

TABLE 2 XRPD data for form I

Sequence number	2θ	D value	Relative intensity	Sequence number	2θ	D value	Relative intensity
								1	3.20	27.60	17.8	7	14.47	6.12	9.7
2	3.65	24.18	100	8	16.54	5.36	11.1
								3	7.26	12.17	2.2	9	18.10	4.90	21.3
4	8.82	10.02	1.7	10	22.18	4.00	11.2
								5	10.86	8.14	2.9	11	23.15	3.84	42.0
6	13.00	6.81	5.0	12	24.19	3.68	19.5

DSC results of form I show that there is an endothermic peak in the range of 260-262 ℃, the single strong endothermic peak occurring at about 260.7 ℃ is its melting peak, while no other thermal phenomena are found on the spectrum.

EXAMPLE 2 preparation of Curve Luo Tingjing form II

Method 2-1 (volatilization method): about 30mg of trefoil was added to the flask, followed by 6ml of acetone, and dissolved at room temperature. The solution after the solution was filtered through a 0.22 μm PTFE filter, the resulting filtrate was transferred to a flask, and the flask was sealed with a Parafilm sealer, and three small holes were punched. The flask was then left to evaporate slowly at room temperature. When the product is separated out, the product is collected and dried in vacuum at 40 ℃ to obtain white solid, and the white solid is detected as the koji method Luo Tingjing type II.

Method 2-2 (heating and cooling method): about 30mg of trefoil was added to the flask, followed by 1.5ml of isopropanol, and heated for dissolution. Filtering the solution after the solution is cleared by a PTFE filter membrane with the thickness of 0.22 mu m, standing the obtained filtrate at room temperature or in the environment of 2-8 ℃ for crystallization, collecting the separated product, and vacuum drying the product at the temperature of 40 ℃ to obtain white solid, and detecting the white solid as the type II of the koji method Luo Tingjing.

Method 2-3 (antisolvent addition method): about 400mg of the trefoil compound was weighed into a flask, and 8ml of tetrahydrofuran solvent was added thereto for ultrasonic dissolution. The solution after the solution is dissolved is filtered by a PTFE filter membrane with the diameter of 0.22 mu m to obtain clear liquid. 2 parts of 1ml solution are respectively added into 2 flasks, 2ml of acetonitrile or 2ml of n-heptane serving as a poor solvent are added, the mixture is placed at room temperature for standing crystallization, the separated samples are collected and then are placed at 40 ℃ for vacuum drying, so that white solid is obtained, and the white solid is detected as the type II of the koji method Luo Tingjing.

The XRPD pattern of the resulting form II is shown in fig. 3, and the diffraction angle data is substantially as shown in table 3 below. The DSC pattern of form II is substantially as shown in FIG. 4. The TG profile of form II is substantially as shown in figure 5.

TABLE 3 XRPD data for form II

DSC results of form II show that there is an endothermic peak in the range of 257-260℃and a single strong endothermic peak occurring at about 258.6 ℃is its melting peak, while no other thermal phenomena are found on the spectrum.

The TG result of the crystal form II shows that the crystal form II has no thermal weightlessness process, which indicates that the crystal form II is an anhydrous crystal form.

EXAMPLE 3 preparation of Curve Luo Tingjing form III

Method 3-1 (suspension stirring method): to the flask was added 1ml of purified water, followed by 41.7mg Qu Faluo of statin to bring the system to suspension. The suspension of Qu Faluo th and purified water was stirred at room temperature for fourteen days. And then taking the suspension for centrifugal separation to obtain a solid product. The product was dried in vacuo at 40 ℃ to give a white solid, which was detected as form III of the koji method Luo Tingjing.

Method 3-2 (suspension stirring method): to the flask was added 1ml of n-heptane followed by 50.4mg Qu Faluo of the statin to bring the system to suspension. The suspension of Qu Faluo th and n-heptane was stirred at room temperature for fourteen days. And then taking the suspension for centrifugal separation to obtain a solid product. The product was dried in vacuo at 40 ℃ to give a white solid, which was detected as form III of the koji method Luo Tingjing.

The XRPD pattern of the resulting form III is shown in fig. 6, and the diffraction angle data is substantially as shown in table 4 below. The DSC pattern of form III is substantially as shown in FIG. 7.

TABLE 4 XRPD data for form III

DSC results of form III show that there is an endothermic peak in the range of 253-256 ℃, the single strong endothermic peak occurring at about 255.9 ℃ is its melting peak, while no other thermal phenomena are found on the spectrum.

EXAMPLE 4 preparation of Curve Luo Tingjing type IV

Method 4-1 (suspension stirring method): to the flask was added 1ml of n-propanol or 1ml of ethyl acetate, followed by 54mg of Qu Faluo th-e-amine to bring the system into suspension. The suspension of Qu Faluo th and n-propanol or ethyl acetate was stirred at room temperature for three days. And then taking the suspension for centrifugal separation to obtain a solid product. The product was dried in vacuo at 40 ℃ to give a white solid which was detected as form IV of the koji method Luo Tingjing.

Method 4-2 (volatilization): about 30mg of trefoil was added to the flask, followed by 6ml of ethyl acetate, and dissolved at room temperature. The solution after the solution was filtered through a 0.22 μm PTFE filter, the resulting filtrate was transferred to a flask, and the flask was sealed with a Parafilm sealer, and three small holes were punched. The flask was then left to evaporate slowly at room temperature. When the product is separated out, the product is collected and dried in vacuum at 40 ℃ to obtain a pale yellow solid, and the pale yellow solid is detected as the type IV of the koji method Luo Tingjing.

The XRPD pattern of the resulting form IV is shown in fig. 8, and the diffraction angle data is substantially as shown in table 5 below. The DSC pattern of form IV is substantially as shown in FIG. 9.

TABLE 5 XRPD data for form IV

DSC results of form IV show that there is an endothermic peak in the range of 245-252 ℃, the single strong endothermic peak occurring at about 248.5 ℃ is its melting peak, while no other thermal phenomena are found on the spectrum.

Example 5 preparation of crystalline form

5.1 Amplified preparation of form I

According to the method for preparing the crystal form I in the ginseng test example 1, the crystal form I is difficult to produce in an amplified manner, and the prepared white solid is the crystal form II.

The specific method comprises the following steps:

500mg of trefoil is weighed into a flask, 30ml of methanol solvent is added, and the mixture is heated for dissolution. Filtering the solution after the solution is cleared by a PTFE filter membrane with the thickness of 0.22 mu m to obtain clear solution, and standing and crystallizing the clear solution at room temperature. After about 12 hours, solid is separated out, filtered, and the filter cake is leached by methanol, and the obtained wet product is dried in vacuum at 40 ℃ to obtain white solid. XRPD results showed that the resulting form was form ii.

500Mg of trefoil is weighed into a flask, 25ml of acetone solvent is added, and the mixture is heated for dissolution. Filtering the solution after the solution is cleared by a PTFE filter membrane with the thickness of 0.22 mu m to obtain clear solution, and standing and crystallizing the clear solution at room temperature. After about 12 hours, solid is separated out, filtered, the filter cake is rinsed by acetone, and the obtained wet product is dried in vacuum at 40 ℃ to obtain white solid. XRPD results showed the compound obtained to be form ii (fig. 10, 1).

5.2 Preparation of Crystal form II by amplification

The inventors refer to the method of example 2 to prepare form II, and the results show that form II can be produced in a large scale, and the white solid prepared is form II.

The specific method comprises the following steps:

5g of trefoil is weighed and added into a flask, 100ml of isopropanol solvent is added, and the mixture is heated and stirred for dissolution. Transferring to room temperature, stirring and crystallizing for 12 hours, precipitating a large amount of solids, filtering, leaching the filter cake with isopropanol, and vacuum drying the wet product at 40 ℃ to obtain white solids. XRPD results showed the compound obtained to be form ii.

5.3 Preparation of Crystal form II by amplification

According to the method for preparing the crystal form III in the invention, the crystal form III cannot be produced in an amplified manner, and the prepared white solid is the crystal form II.

The specific method comprises the following steps:

400mg of the trefoil compound was weighed into a flask, 10ml of purified water was added thereto, and stirred and beaten at room temperature. After 14 days, the mixture was filtered, and the filter cake was rinsed with purified water to give a wet product which was dried in vacuo at 40℃to give a white solid. XRPD results showed the compound obtained to be form ii.

500Mg of the trefoil compound was weighed into a flask, 10ml of n-heptane solvent was added thereto, and stirred and beaten at room temperature. After 14 days, the mixture was filtered, and the filter cake was rinsed with n-heptane to give a wet product which was dried under vacuum at 40℃to give a white solid. XRPD results showed the compound obtained to be form ii (fig. 10, 2).

5.4 Preparation of Crystal form IV by amplification

The inventors refer to the method of example 4 to prepare form IV, which shows that form IV cannot be produced in large scale, and the prepared white solids are all form II.

The specific method comprises the following steps:

400mg of the trefoil compound was weighed into a flask, 10ml of n-propanol solvent was added thereto, and stirred and beaten at room temperature. After 3 days, the mixture was filtered, and the filter cake was rinsed with n-propanol to give a wet product which was dried in vacuo at 40℃to give a white solid. XRPD results showed the compound obtained to be form ii (fig. 10, 3).

500Mg of the trefoil compound was weighed into a flask, 10ml of ethyl acetate solvent was added thereto, and stirred and beaten at room temperature. After 3 days, the mixture was filtered, and the filter cake was rinsed with ethyl acetate to give a wet product which was dried in vacuo at 40℃to give a white solid. XRPD results showed the compound obtained to be form ii.

The amplification experiments show that the crystal forms I, III and IV are difficult to prepare in a large scale, and the crystal form II is obtained in the amplification production process. The patterns of form II prepared by the different methods are consistent, with the XRPD patterns substantially as shown in figure 3.

Example 6 stability study of Curve Luo Tingjing type II

6.1 Research on thermodynamic stability of form II

About 50mg of form II of koji method Luo Tingjing was placed in 12 to 12 flasks, and 1ml of each of the corresponding solvents shown in Table 6 below was added to form a suspension, and the suspension was sealed and stirred at room temperature for three days. Sampling and centrifugal separation are carried out after three days, liquid phase is discarded, and solid phase is dried in vacuum at 40 ℃ to obtain a sample. DSC is measured on the dried sample, and the change in crystal form is judged from the DSC result. The experimental results are shown in Table 6.

TABLE 6 thermodynamic stability study of form II

Analysis of results: the thermodynamic stability research of the crystal form II shows that the crystal form II generates partial phase change in the ethanol solvent to form a mixed crystal form of the crystal form II and the crystal form III; partial phase change occurs in ethyl acetate to form a mixed crystal form of a crystal form II, a crystal form III and a crystal form IV; remains stable to form ii in most other solvents. In summary, the thermodynamic stability of form ii is good.

6.2 Physical and chemical stability study of form II

The Qu Faluo-tin form ii samples were left open and flat to examine the physical stability of the samples at high temperature (60 ℃), high humidity (RH 92.5%) and light, and samples were taken at 0, 10 and 30 days for DSC and XRPD measurements to evaluate physical stability, and samples were taken for HPLC measurements to evaluate chemical stability. The results are shown in Table 7.

TABLE 7 results of physicochemical stability of Qu Faluo Tine Crystal form II

Experimental results: qu Faluo the form II was left under high temperature (60 ℃), high humidity (RH 92.5%) and light conditions for a period of 30 days with a DSC pattern and XRPD pattern consistent with those of 0 days. The Qu Faluo shows that the crystal form II of the statin is unchanged and has good physical stability. In addition, qu Faluo of the Qu Faluo type I crystal form II is placed for 30 days under the conditions of high temperature (60 ℃), high humidity (RH 92.5%) and illumination, and related substances have no obvious change, so that the chemical stability of the Qu Faluo type I crystal form I is good.

In summary, the inventors performed polymorphic screening by the trefoil compound to obtain Qu Faluo statin Qu Faluo form i, form ii, form iii and form iv. Polymorphic forms of a compound may exhibit different melting points, hygroscopicity, stability, bioavailability, etc., which are important factors affecting drug development. The Qu Faluo-containing compound is anhydrous, the melting point is about 257-260 ℃, the moisture absorption performance is not caused, and the research on the mutual conversion among the crystal forms and the stability research test prove that the crystal form II provided by the invention is the most stable crystal form, is suitable for subsequent drug development research, can be amplified and prepared, and is suitable for industrial production and application.

Based on the above disclosure, a person skilled in the art may change the technical solution and the method of the present invention, where the changes all belong to the protection scope of the present invention without departing from the spirit of the present invention.

Claims

1. A crystal of Qu Faluo th compound of formula (I),

The crystal is a crystal form II; the method is characterized in that: the X-ray powder diffraction pattern of form II includes the following 2θ values: 3.26.+ -. 0.1 °, 6.43.+ -. 0.1 °, 12.78.+ -. 0.1 °, 15.97.+ -. 0.1 °, 16.42.+ -. 0.1 °, 18.57.+ -. 0.1 °, 19.30.+ -. 0.1 °, 20.78.+ -. 0.1 °.

2. The crystal of claim 1, wherein the X-ray powder diffraction pattern of form II is characterized in figure 3.

3. The crystal of claim 1, wherein the DSC profile of form II is characterized as shown in figure 4.

4. The crystal of claim 1, wherein the DSC profile of form II has an endothermic peak at a temperature in the range of 257-260 ℃.

5. The crystal of claim 1, wherein the TG of form II is characterized as in fig. 5.

6. The crystal of claim 1, wherein the melting point of form II is 259 ℃.

7. The crystal of claim 1, wherein form II is an anhydrate.

8. A method for preparing the crystal according to claim 1, wherein the Qu Faluo crude product of the statin is heated and dissolved in an organic solvent, cooled and crystallized to obtain the Qu Faluo statin crystal form II; the organic solvent is isopropanol.

9. A pharmaceutical composition comprising the Qu Faluo statin crystals of any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

10. Use of Qu Faluo statin crystals according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for the prevention and/or treatment of dermatological disorders.

11. The use according to claim 10, wherein the dermatological condition is: skin disorders associated with keratosis involving cell differentiation and proliferation.

12. The use according to claim 10, wherein the dermatological condition is: skin disorders caused by exposure to ultraviolet radiation, photo-induced or chronological skin aging, or actinic pigmentation and keratosis.

13. The use according to claim 10, wherein the dermatological condition is: conditions associated with chronological or actinic skin aging.

14. The use according to claim 10, wherein the dermatological condition is selected from the group consisting of acne vulgaris, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata.