CN115745913A

CN115745913A - Polymorphic form of trefavudine and preparation method thereof

Info

Publication number: CN115745913A
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: 2023-03-07

Abstract

The invention provides a polymorphic form of a trexarotene compound, and a preparation method and application thereof, wherein the crystal form II has excellent stability, is suitable for mass production, and is suitable for drug research and development and industrial application.

Description

Polymorphic form of trefavudine and preparation method thereof

Technical Field

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

Background

Trafagotine (Trifarotene) is a topical retinoid that selectively targets Retinoic Acid Receptor (RAR) γ. On day 4 of 2019, 10 months, 0.005% Aklief (Trifarotene) cream was approved by the U.S. Food and Drug Administration (FDA) for topical treatment of acne. Trifarotene is the first retinoid molecule to obtain U.S. FDA approval for the treatment of acne.

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

In order to find more stable forms of trefariptin, it is necessary to perform crystal form screening studies on the trefariptin compound.

Disclosure of Invention

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

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

the crystal is selected from crystal form I, crystal form II, crystal form III, crystal form IV or combination thereof.

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

In another embodiment, further the crystalline form I has 2 Θ values selected from the following table:

in another preferred embodiment, the form I has an X-ray powder diffraction (XRPD) pattern substantially as characterized in figure 1.

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

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

In one embodiment, the crystalline form II has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 3.26 +/-0.1 degrees, 6.43 +/-0.1 degrees, 12.78 +/-0.1 degrees, 15.97 +/-0.1 degrees, 16.42 +/-0.1 degrees, 18.57 +/-0.1 degrees, 19.30 +/-0.1 degrees and 20.78 +/-0.1 degrees.

In another embodiment, further the crystalline form II has 2 Θ values selected from the following table:

serial number	2θ	d value	Relative strength	Serial number	2θ	d value	Relative strength
								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 chart of the crystal form II has an endothermic peak at a temperature ranging from about 257 to 260 ℃. The melting point of form II is about 259 ℃.

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

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

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

In one embodiment, the crystalline form III has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 3.24 +/-0.1 degrees, 8.77 +/-0.1 degrees, 12.13 +/-0.1 degrees, 13.88 +/-0.1 degrees, 16.50 +/-0.1 degrees, 18.08 +/-0.1 degrees, 19.85 +/-0.1 degrees and 23.15 +/-0.1 degrees.

In another embodiment, further the crystalline form III has 2 Θ values selected from the following table:

serial number	2θ	d value	Relative strength	Serial number	2θ	d value	Relative strength
								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 diagram of the crystal form III has an endothermic peak in the range of about 253 to 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 form IV has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 3.63 +/-0.1 degrees, 8.77 +/-0.1 degrees, 9.72 +/-0.1 degrees, 13.00 +/-0.1 degrees, 14.45 +/-0.1 degrees, 16.50 +/-0.1 degrees, 18.08 +/-0.1 degrees, 22.16 +/-0.1 degrees and 24.19 +/-0.1 degrees.

In another embodiment, further the form IV has 2 Θ values selected from the following table:

serial number	2θ	d value	Relative strength	Serial number	2θ	d value	Relative strength
								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 diagram of form IV has an endothermic peak in the range of about 245 to 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 present invention, there is provided a process for preparing crystalline form II of treprostinil comprising: and heating and dissolving the crude product of trefariptin in an organic solvent, and cooling and crystallizing to obtain a trefariptin crystal form II.

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

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

Preferably, the dissolution is carried out under heating at a temperature of 40 ℃ to 100 ℃, preferably 60 ℃ to 80 ℃.

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

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

Alternatively, the invention provides a method for preparing crystal form II of trefluvastatin, which comprises the following steps: and dissolving the trefavudine 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 prepared according to the present invention are more than 95% pure, preferably more than 97% pure, more preferably more than 99% pure, and most preferably more than 99.5% pure.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising any one or more of the crystalline forms of trefariptin, especially crystalline form II of trefariptin, as described herein, together with any pharmaceutically acceptable carrier.

In a fourth aspect of the invention, there is provided the use of any one or more of the crystalline forms of trefariptin (especially crystalline form II) described herein or the pharmaceutical composition described herein for the preparation of a medicament for the prevention and treatment of skin diseases.

Skin diseases in the present invention include:

-skin diseases associated with keratinization disorders involving cell differentiation and proliferation;

-ichthyosis, ichthyosiform disorders, follicular keratosis, palmoplantar keratosis, vitiligo and vitiligo disorders, and licheniasis (of the oral cavity) of the skin or mucous;

-dermatological diseases with an inflammatory immunoallergic component, with or without cell proliferative disorders;

-skin diseases caused by exposure to ultraviolet radiation, light-induced or chronological skin aging, or actinic pigmentation and keratosis;

-pathologies associated with chronological or actinic skin aging;

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

-proliferation inducible by uv light;

-precancerous skin lesions;

-an immune skin disease;

-immune bullous disease;

-collagen diseases;

-skin diseases with an immunological component;

-an ophthalmic disease;

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

-skin diseases of viral origin;

-pathologies associated with chronological or actinic skin ageing;

-a disorder of sebum function;

-cicatrization disorders or elongated marks; or

-pigmentation disorders.

Wherein the dermatological disorders associated with keratinization disorders involving cell differentiation and proliferation are selected from the group consisting of acne vulgaris, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne, and secondary acne such as solar acne, acne associated with drug therapy or occupational acne.

Wherein said dermatological diseases with an inflammatory immunoallergic component, with or without cell proliferative disorders, are selected from all forms of psoriasis, whether of the skin, mucous or nails, psoriatic rheumatism, cutaneous atopy, such as eczema, or respiratory atopy, or gingival hypertrophy.

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

Drawings

Figure 1 is an XRPD pattern of crystalline form I of trefaropentin according to the invention;

figure 2 is a DSC profile of crystalline form I of trefariptin according to the invention;

figure 3 is an XRPD pattern of crystalline form II of treprostinil according to the invention;

FIG. 4 is a DSC spectrum of crystalline form II of trefaropentin of the present invention;

FIG. 5 is a TG map of crystalline form II of treprostinil of the present invention;

figure 6 is an XRPD pattern of crystalline form III of treprostinil according to the invention;

figure 7 is a DSC profile of crystalline form III of treprostinil according to the invention;

figure 8 is an XRPD pattern of crystalline form IV of treprostinil of the invention;

figure 9 is a DSC profile of crystalline form IV of treprostinil according to the invention.

Figure 10 is an XRPD pattern of crystalline form II of treprostinil prepared by different methods.

Detailed Description

The present invention will be described in detail below with reference to examples. It should be understood that the methods in the examples are for illustrative purposes only and do not constitute any limitation on the present invention. Modifications and improvements on the basis of the present invention are intended to be within the scope of the invention as claimed, without departing from the spirit thereof.

According to the rough solubility result of the trefaritine and the characteristics of the compound, a suspension stirring method, a slow volatilization method and an anti-solvent addition method are adopted to carry out a polymorphism screening experiment on the trefaritine. The starting material of trafagotine used in the examples was a mixed crystal. Of course, any other crude trefaropentin may be used.

The test method comprises the following steps:

XRPD (X-ray powder diffraction) method: the instrument model is as follows: brook D8 advanced x-ray diffractometer; the test method comprises the following steps: about 10-20 mg of sample was used for XRPD detection; the detailed XRPD parameters are as follows: light pipe: the concentration of Cu, k alpha,

(ii) a Voltage of light pipe: 40kV, light tube current: 40mA of the total volume; scanning range: 3-45deg; step diameter: 0.02deg; step length: 0.12 second.

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

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

Table 1 below is the definition and range of hygroscopicity for the drug in the Chinese pharmacopoeia 2020 version after equilibration at 25 ℃. + -. 1 ℃, 80%. + -. 2% RH.

TABLE 1

Deliquescence	Absorb sufficient water to form liquid
		Has moisture absorption property	The moisture-drawing weight gain is not less than 15 percent
Has hygroscopicity increasing effect	The moisture-attracting weight gain is less than 15 percent but not less than 2 percent
		Slightly hygroscopic	The moisture-drawing weight gain is less than 2 percent but not less than 0.2 percent
No or almost no hygroscopicity	The moisture-attracting weight gain is less than 0.2 percent

Example 1 preparation of crystalline form I of treflunomide

Method 1-1 (suspension stirring method): to the flask was added 1ml of 2-methyltetrahydrofuran, followed by 184.2mg of trefaritine to bring the system into suspension. The suspension formed by the trefavudine and the 2-methyltetrahydrofuran is placed in a room temperature environment and stirred for fourteen days. The suspension was then centrifuged to give a solid product. And (3) placing the product at 40 ℃ for vacuum drying to obtain a white solid, and detecting to obtain the crystal form I of the trefluvastatin.

Method 1-2 (heating and cooling method): approximately 30mg of trefaropentin was added to the flask, followed by 2ml of methanol, and dissolved by heating. And filtering the solution after being dissolved and cleaned by a 0.22-micron PTFE filter membrane, standing and crystallizing the obtained filtrate at room temperature or in an environment of 2-8 ℃, collecting a precipitated product, and placing the product at 40 ℃ for vacuum drying to obtain a white solid which is detected as a crystal form I of the trefariptin.

Method 1-3 (heating and cooling method): approximately 30mg of trefarotene was added to the flask, followed by 1.5ml of acetone, and dissolved by heating. Filtering the solution after being dissolved and cleaned by a 0.22 mu m PTFE filter membrane, standing the obtained filtrate at room temperature or 2-8 ℃ for crystallization, collecting the precipitated product, and placing the product at 40 ℃ for vacuum drying to obtain a long rod-shaped crystal which is detected as a crystal form I of trefariptin.

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

TABLE 2 XRPD data for form I

Serial number	2θ	d value	Relative strength	Serial number	2θ	d value	Relative strength
								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

The DSC result of the crystal form I shows that the crystal form I has an endothermic peak within the range of 260-262 ℃, a single strong endothermic peak appearing at about 260.7 ℃ is a melting peak of the crystal form I, and other thermal phenomena are not found on a graph.

Example 2 preparation of crystalline form II of treflunomide

Method 2-1 (volatilization method): approximately 30mg of trefarotene was added to the flask, followed by 6ml of acetone and dissolved at room temperature. The clear solution was filtered through a 0.22 μm PTFE membrane filter, the resulting filtrate was transferred to a flask, and the flask was sealed with a parafilm seal and punctured with three small holes. The flask was then left to evaporate slowly at room temperature. And when a product is separated out, collecting the product, and placing the product at 40 ℃ for vacuum drying to obtain a white solid which is detected as crystal form II of the trefluvastatin.

Method 2-2 (heating and cooling method): approximately 30mg of trefaropentin was added to the flask, followed by 1.5ml of isopropanol, and dissolved by heating. Filtering the clear solution through a 0.22-micron PTFE filter membrane, standing and crystallizing the obtained filtrate at room temperature or at the temperature of 2-8 ℃, collecting a precipitated product, and placing the product at 40 ℃ for vacuum drying to obtain a white solid, wherein the white solid is detected to be the crystal form II of the trebrogliptin.

Method 2-3 (antisolvent addition method): approximately 400mg of the trefavudine compound was weighed into a flask, and 8ml of tetrahydrofuran solvent was added thereto and dissolved by sonication. The clear solution was filtered through a 0.22 μm PTFE filter to obtain a clear solution. Adding 2 parts of 1ml solution into 2 flasks respectively, adding 2ml acetonitrile or 2ml n-heptane serving as a poor solvent, standing at room temperature for crystallization, collecting precipitated samples, and drying at 40 ℃ in vacuum to obtain white solids, wherein the white solids are detected as crystal form II of trematolutin.

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

TABLE 3 XRPD data for form II

The DSC result of the crystal form II shows that the crystal form II has an endothermic peak in the range of 257-260 ℃, a single strong endothermic peak appearing at about 258.6 ℃ is a melting peak of the crystal form II, and other thermal phenomena are not found on the graph.

The TG result of the crystal form II shows that the crystal form II does not have a thermal weight loss process, which indicates that the crystal form II is an anhydrate crystal form.

Example 3 preparation of crystalline form III of trefavudine

Method 3-1 (suspension stirring method): 1ml of purified water was added to the flask, and then 41.7mg of trafavudine was added to bring the system into suspension. The suspension formed by the trefavudine and the purified water is placed in a room temperature environment and stirred for fourteen days. The suspension was then centrifuged to give a solid product. And (3) placing the product at 40 ℃ for vacuum drying to obtain a white solid, which is detected to be crystal form III of the trefluvastatin.

Method 3-2 (suspension stirring method): 1ml of n-heptane was added to the flask, followed by 50.4mg of trefaritine to bring the system into suspension. The suspension formed by the trefaritine and the n-heptane is placed in a room temperature environment and stirred for fourteen days. The suspension was then centrifuged to give a solid product. And (3) placing the product at 40 ℃ for vacuum drying to obtain a white solid which is detected to be crystal form III of the trefavudine.

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

TABLE 4 XRPD data for form III

The DSC result of the crystal form III shows that the crystal form III has an endothermic peak in the range of 253-256 ℃, a single strong endothermic peak appearing at about 255.9 ℃ is a melting peak of the crystal form III, and other thermal phenomena are not found on a graph.

Example 4 preparation of crystalline form IV of trefarretine

Method 4-1 (suspension stirring method): 1ml of n-propanol or 1ml of ethyl acetate was added to the flask, followed by 54mg of trefaritine to bring the system into suspension. The suspension of trefavudine and n-propanol or ethyl acetate was stirred at room temperature for three days. The suspension was then centrifuged to give a solid product. And (3) placing the product at 40 ℃ for vacuum drying to obtain a white solid, which is detected to be crystal form IV of the trebrogliptin.

Method 4-2 (volatilization method): to the flask was added about 30mg of trefarotene, followed by 6ml of ethyl acetate, and dissolved at room temperature. The clear solution was filtered through a 0.22 μm PTFE membrane filter, the resulting filtrate was transferred to a flask, and the flask was sealed with a parafilm seal and punctured with three small holes. The flask was then left to evaporate slowly at room temperature. And when a product is separated out, collecting the product, and placing the product at 40 ℃ for vacuum drying to obtain a light yellow solid which is detected as crystal form IV of the trefariptin.

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

TABLE 5 XRPD data for form IV

The DSC result of the crystal form IV shows that the crystal form IV has an endothermic peak in the range of 245-252 ℃, a single strong endothermic peak appearing at about 248.5 ℃ is a melting peak of the crystal form IV, and other thermal phenomena are not found on a graph.

Example 5 Crystal form amplification preparation

5.1 amplified preparation of form I

The inventor prepares the crystal form I by referring to the method of example 1, and finds that the crystal form I is difficult to be produced in an enlarged way, and the prepared white solid is the crystal form II.

The specific method comprises the following steps:

500mg of trefavudine was weighed into a flask, and 30ml of methanol solvent was added and heated to dissolve it. Filtering the solution after dissolving through a PTFE filter membrane with the diameter of 0.22 mu m to obtain a clear solution, and standing and crystallizing at room temperature. After about 12 hours, a solid is separated out, the solid is filtered, a filter cake is leached by methanol, and a wet product is obtained and placed at 40 ℃ for vacuum drying to obtain a white solid. XRPD results showed the resulting crystalline form to be form ii.

500mg of trefavudine was weighed into a flask, and 25ml of acetone solvent was added and heated to dissolve it. Filtering the solution after dissolving through a PTFE filter membrane with the diameter of 0.22 mu m to obtain a clear solution, and standing and crystallizing at room temperature. After about 12 hours, a solid is separated out, the solid is filtered, a filter cake is leached by acetone, and a wet product is placed at 40 ℃ for vacuum drying to obtain a white solid. XRPD results showed the resulting compound to be form ii (fig. 10, 1).

5.2 amplified preparation of crystalline form II

The inventor prepares the crystal form II by referring to the method of the example 2, and the result shows that the crystal form II can be produced in an enlarged way, and the white solid obtained by the preparation is the crystal form II.

The specific method comprises the following steps:

5g of trefavudine is weighed into a flask, 100ml of isopropanol solvent is added, and the mixture is heated, stirred and dissolved. Transferring to room temperature after dissolving, stirring and crystallizing for 12 hours, separating out a large amount of solid, filtering, leaching a filter cake with isopropanol, placing the obtained wet product at 40 ℃ and drying in vacuum to obtain a white solid. XRPD results showed the resulting compound to be form ii.

5.3 Crystal form II I amplification preparation

The inventor prepares the crystal form III by referring to the method of example 3, and the result shows that the crystal form III can not be produced in an enlarged way, and the prepared white solid is the crystal form II.

The specific method comprises the following steps:

400mg of the trefaropentin compound was weighed and added to a flask, 10ml of purified water was added, and the mixture was stirred and slurried at room temperature. After 14 days, the mixture is filtered, the filter cake is rinsed with purified water, and the wet product is dried in vacuum at 40 ℃ to obtain a white solid. XRPD results showed the resulting compound to be form ii.

500mg of the trefaritine compound was weighed into a flask, 10ml of an n-heptane solvent was added, and stirred and slurried at room temperature. After 14 days, filtering, leaching a filter cake with n-heptane, and placing the obtained wet product at 40 ℃ for vacuum drying to obtain a white solid. XRPD results showed the resulting compound to be form ii (fig. 10, 2).

5.4 Crystal form IV amplification preparation

The inventor prepares the crystal form IV by referring to the method of example 4, and the result shows that the crystal form IV can not be produced in a large scale, and the prepared white solid is the crystal form II.

The specific method comprises the following steps:

400mg of the trefavudine compound was weighed into a flask, 10ml of n-propanol solvent was added, and stirred and beaten at room temperature. Filtering after 3 days, leaching a filter cake with n-propanol to obtain a wet product, and drying in vacuum at 40 ℃ to obtain a white solid. XRPD results showed the resulting compound to be form ii (fig. 10, 3).

500mg of trefaropentin compound was weighed and added to a flask, 10ml of ethyl acetate solvent was added, and the mixture was stirred and slurried at room temperature. After 3 days, filtering, leaching a filter cake by using ethyl acetate, and placing the obtained wet product at 40 ℃ for vacuum drying to obtain a white solid. XRPD results showed the resulting compound 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 completely obtained during amplification production. The patterns of the crystal form II prepared by different methods are consistent, wherein the XRPD pattern is basically as shown in figure 3.

Example 6 stability Studies of crystalline form II of Trevacizine

6.1 thermodynamics of form IIStability study

Taking 12 parts of approximately 50mg crystal form II of trefaropentin into 12 flasks, adding 1ml of corresponding solvents in the following table 6 respectively to form a suspension, sealing, and stirring at room temperature for three days. And after three days, sampling, centrifuging, removing a liquid phase, vacuum-drying a solid phase at 40 ℃, and drying to obtain a sample. And (4) measuring DSC of the dried sample, and judging the change of the crystal form according to the DSC result. The results are shown in Table 6.

TABLE 6 thermodynamic stability study of form I

And (4) analyzing results: the research on the thermodynamic stability of the crystal form II shows that the crystal form II has partial phase change in an ethanol solvent to form a mixed crystal form of the crystal form II and the crystal form III; partial phase change is carried out in ethyl acetate to form a mixed crystal form of a crystal form II, a crystal form III and a crystal form IV; remain stable as form ii in most other solvents. In conclusion, the thermodynamic stability of form ii is good.

6.2 study of physical and chemical stabilities of form II

A crystal form II sample of the trefagotine is placed open and spread evenly, physical stability of the sample under the conditions of high temperature (60 ℃), high humidity (RH 92.5%) and illumination is considered, a certain sample is taken for DSC and XRPD detection for evaluating the physical stability in 0 day, 10 days and 30 days, and a certain sample is taken for HPLC detection for evaluating the chemical stability. The results are shown in Table 7.

TABLE 7 physical and chemical stability results for crystalline form II of trafagotine

The experimental results are as follows: the DSC pattern and XRPD pattern of the crystal form II of the trofavudine are consistent with those of the crystal form II of the trefavudine at 0 day when the crystal form II of the trofavudine is placed under the conditions of high temperature (60 ℃), high humidity (RH 92.5%) and illumination for 30 days. The crystal form II of the trefavudine is not changed, and the physical stability is good. In addition, the crystal form II of the trafagotine 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, which shows that the chemical stability of the crystal form I of the trafagotine is good.

In conclusion, the crystal form I, the crystal form II, the crystal form III and the crystal form IV of the trefariptin are obtained by screening the polymorphic forms of the trefariptin compound. Polymorphic forms of a compound may exhibit different melting points, hygroscopicity, stability, bioavailability, etc., which are important factors affecting drug potency. The crystal form II of the trefariptin is anhydrous, the melting point is about 257-260 ℃, the crystal form II has no hygroscopicity, and the interconversion research and stability investigation tests among the crystal forms prove that the crystal form II provided by the invention is the most stable crystal form, is suitable for the subsequent drug development research, can be prepared in an enlarged mode, and is suitable for industrial production and application.

Based on the above disclosure, those skilled in the art can change the technical scheme and method of the present invention, and the changes are within the protection scope of the present invention without departing from the spirit of the present invention.

Claims

1. A crystal of a trefaritine compound represented by formula (I),

the crystal is selected from crystal form I, crystal form II, crystal form III and crystal form IV; the method is characterized in that:

the X-ray powder diffraction pattern of form I comprises the following 2 Θ values: 3.65 +/-0.1 degrees, 7.26 +/-0.1 degrees, 8.82 +/-0.1 degrees, 10.86 +/-0.1 degrees, 14.47 +/-0.1 degrees, 16.54 +/-0.1 degrees, 18.10 +/-0.1 degrees, 23.15 +/-0.1 degrees and 24.19 +/-0.1 degrees;

the X-ray powder diffraction pattern of form II comprises the following 2 Θ values: 3.26 +/-0.1 degrees, 6.43 +/-0.1 degrees, 12.78 +/-0.1 degrees, 15.97 +/-0.1 degrees, 16.42 +/-0.1 degrees, 18.57 +/-0.1 degrees, 19.30 +/-0.1 degrees and 20.78 +/-0.1 degrees;

the X-ray powder diffraction pattern of form III comprises the following 2 Θ values: 3.24 +/-0.1 degrees, 8.77 +/-0.1 degrees, 12.13 +/-0.1 degrees, 13.88 +/-0.1 degrees, 16.50 +/-0.1 degrees, 18.08 +/-0.1 degrees, 19.85 +/-0.1 degrees and 23.15 +/-0.1 degrees;

the X-ray powder diffraction pattern of form IV comprises the following 2 Θ values: 3.63 +/-0.1 degrees, 8.77 +/-0.1 degrees, 9.72 +/-0.1 degrees, 13.00 +/-0.1 degrees, 14.45 +/-0.1 degrees, 16.50 +/-0.1 degrees, 18.08 +/-0.1 degrees, 22.16 +/-0.1 degrees and 24.19 +/-0.1 degrees.

2. The crystal of claim 1, wherein the crystal has a characteristic selected from the group consisting of:

1) The form I has an X-ray powder diffraction pattern substantially as characterized in figure 1;

2) The form II has an X-ray powder diffraction pattern substantially as characterized in figure 3;

3) The form III has an X-ray powder diffraction pattern substantially as characterized in figure 6;

4) The form IV has an X-ray powder diffraction pattern substantially as characterized in figure 8.

3. The crystal of claim 1, wherein form I is selected from the following features:

1) The DSC profile of form I is substantially as characterized in figure 2; and/or

2) The DSC chart of the crystal form I has an endothermic peak at the range of about 260-262 ℃; and/or

3) The melting point of form I is about 261 ℃.

4. The crystal of claim 1, wherein the form II is selected from the following characteristics:

1) A DSC profile for said form II substantially as characterized in figure 4; and/or

2) The DSC chart of the crystal form II has an endothermic peak at the range of about 257-260 ℃; and/or

3) The melting point of form II is about 259 ℃; and/or

4) The TG profile of form II is substantially as characterized in figure 5; and/or

5) The crystal form II is an anhydrate.

5. The crystal of claim 1, wherein the form III is selected from the following features:

1) A DSC profile for said form III substantially as characterized in figure 7; and/or

2) The DSC chart of the crystal form III has an endothermic peak in the range of about 253 to 256 ℃; and/or

3) The melting point of form III is about 256 ℃.

6. The crystal of claim 1, wherein the form IV is selected from the following features:

1) A DSC profile for said form IV substantially as characterized in figure 9; and/or

2) Said form IV having a DSC profile with an endothermic peak in the range of about 245 to 252 ℃; and/or

3) The melting point of form IV is about 248.5 ℃.

7. A method of preparing the crystal of claim 1, wherein the crystal is form II, the method comprising the steps of: heating and dissolving the crude product of the trefaritine in an organic solvent, and cooling and crystallizing to obtain a crystal form II of the trefaritine; the organic solvent is selected from methanol, isopropanol, n-propanol, ethyl acetate, isopropyl acetate, and methyl isobutyl ketone.

8. A method of preparing the crystal of claim 1, wherein the crystal is form II, the method comprising the steps of: dissolving a crude product of trefavudine in a benign solvent, and adding a poor solvent for crystallization to obtain a crystal form II; the benign solvent is selected from ethyl acetate and isopropyl acetate; the poor solvent is selected from n-heptane and acetonitrile.

9. A pharmaceutical composition comprising the crystalline trefariptin of any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

10. Use of the crystalline trefarotene of any one of claims 1 to 3 or the pharmaceutical composition of claim 6 for the preparation of a medicament for the prevention and/or treatment of a skin disorder; preferably the skin disorder is selected from the group consisting of acne vulgaris, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne, and secondary acne such as solar acne, acne associated with medical treatment or occupational acne; skin disorders caused by exposure to ultraviolet radiation, light-induced or chronological skin aging, or actinic pigmentation and keratosis; conditions associated with chronological or actinic skin aging.