CN111559961A

CN111559961A - Peptidil acid crystal form and preparation method thereof

Info

Publication number: CN111559961A
Application number: CN202010453262.9A
Authority: CN
Inventors: 郑旭春; 张一平; 吴怡华; 蒋怀志
Original assignee: Hangzhou Cheminspire Technologies Co ltd
Current assignee: Hangzhou Cheminspire Technologies Co ltd
Priority date: 2020-05-26
Filing date: 2020-05-26
Publication date: 2020-08-21

Abstract

The invention discloses a novel crystalline form I of besipidic acid and a preparation method thereof, wherein the crystalline form I of besipidic acid has characteristic peaks at 10.38 +/-0.2 degrees and 18.00 +/-0.2 degrees of Theta values of an X-ray powder diffraction pattern 2 obtained by Cu-Kalpha ray measurement. The crystal form is simple in preparation process and simple and convenient to operate, the quality index and the crystal form of the obtained crystal form are basically kept unchanged in a stability acceleration experiment, the crystal form has good stability, is easy to store in the production and circulation process, and provides a good choice for the preparation of a pharmaceutical preparation of the crystal form.

Description

Peptidil acid crystal form and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a novel crystal form of a novel oral lipid-lowering drug bipedac acid and a preparation method thereof.

Background

Bempedanic acid (reference ETC-1002) is a once daily, non-statin oral drug that lowers LDL-C developed by Esperion Therapeutic, USA. Within 2 months of 2020, the united states Food and Drug Administration (FDA) approved the use of biperidic acid in heterozygous patients with familial hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD), providing an important new and complementary oral drug option for ASCVD patients or ASCVD high risk groups, particularly those patients with statin intolerance, who need additional LDL-C reduction.

The chemical name of beipai di is: 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedioic acid. The structural formula is as follows:

it is known that different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability, etc., thereby affecting the stability, bioavailability and therapeutic effect of the drug, and the phenomenon is particularly obvious in the aspect of oral solid preparations. The crystal form of the besipidic acid is not reported in the prior patent, the inventor discovers that the besipidic acid has a new crystal form in the experimental research process, and the invention provides a new crystal form I of the besipidic acid, which provides more choices for the application of the besipidic acid.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a novel crystal form I of pipadiric acid and a preparation method thereof. The preparation process of the crystal form is simple, the operation is simple and convenient, the quality index and the crystal form of the obtained crystal form are basically kept unchanged in a stability acceleration experiment, and the crystal form is easy to store in the production and circulation process.

The invention aims to provide a novel crystal form of pipadiric acid, which adopts the following technical scheme:

crystal form I of Patadixic acid having characteristic peaks at 10.38 + -0.2 DEG and 18.00 + -0.2 DEG in an X-ray powder diffraction pattern 2Theta value measured using Cu-Kalpha radiation.

Further, the X-ray powder diffraction pattern 2Theta value also has characteristic peaks at 17.59 +/-0.2 degrees, 18.76 +/-0.2 degrees, 20.40 +/-0.2 degrees and 21.87 +/-0.2 degrees.

Furthermore, the X-ray powder diffraction pattern 2Theta value also has characteristic peaks at 15.58 +/-0.2 degrees, 19.60 +/-0.2 degrees, 20.76 +/-0.2 degrees, 22.60 +/-0.2 degrees and 27.60 +/-0.2 degrees.

The X-ray powder diffraction pattern of crystalline form I of budesonide of the present invention is substantially in accordance with that shown in fig. 1.

A Differential Scanning Calorimetry (DSC) curve of the crystalline form I of the beipaidic acid shows that an endothermic peak appears when the crystalline form I is heated to 86.0-89 ℃.

The DSC diagram of crystalline form I of budesonide is substantially in accordance with that shown in figure 2.

The thermogravimetric analysis curve (TGA) of the crystalline form I of the pimelic acid shows that the evaporation or the decomposition starts when the temperature is increased to 215-225 ℃, and the evaporation or the decomposition is completed when the temperature is increased to 370-380 ℃.

The thermogravimetric analysis (TGA) profile of crystalline form I of Patasid is substantially in accordance with that shown in FIG. 3

The invention also relates to a preparation method of the besipid crystal form I, which adopts the following technical scheme:

a preparation method of a crystalline form I of prepidedic acid comprises the steps of adding prepidedic acid into a solvent A, heating to a certain temperature, stirring for a period of time, adding or not adding an inert solvent B, stirring in an obtained mixed solvent system or a single solvent for a period of time, slowly cooling to a certain temperature, crystallizing, preserving heat, pulping to obtain a suspension, filtering and drying to obtain a white solid, namely the crystalline form I.

Further, the solvent A is selected from ethyl acetate, isopropyl acetate, dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, toluene, methyl tert-butyl ether or isopropyl ether; the inert solvent B is selected from petroleum ether, n-heptane or water.

More preferably, the solvent A is ethyl acetate, and the inert solvent B is n-heptane, so as to form an ethyl acetate-n-heptane mixed solvent system; the solvent A is ethyl acetate, the inert solvent B is petroleum ether, and an ethyl acetate-petroleum ether mixed solvent system is formed; the solvent A is isopropyl acetate, the inert solvent B is n-heptane, and an isopropyl acetate-n-heptane mixed solvent system is formed; the solvent A is methyl tertiary butyl ether, the inert solvent B is n-heptane, and a methyl tertiary butyl ether-n-heptane mixed solvent system is formed; the solvent A is isopropyl ether, the inert solvent B is n-heptane, and an isopropyl ether-n-heptane mixed solvent system is formed; the solvent A is ethanol, the inert solvent B is water, and an ethanol-water mixed solvent system is formed; the solvent A is isopropanol, the inert solvent B is water, and an isopropanol-water mixed solvent system is formed; the solvent A is methanol, the inert solvent B is water, and a methanol-water mixed solvent system is formed; the solvent A is acetone, the inert solvent B is water, and an acetone-water mixed solvent system is formed; the solvent A is methyl tertiary butyl ether, and an inert solvent B is not added to form a methyl tertiary butyl ether single solvent system; the solvent A is isopropyl ether, and an inert solvent B is not added, so that an isopropyl ether single solvent system is formed.

Further, the volume mass ratio of the solvent A to the betimeric acid used in the method is 0.2-10: 1, preferably in the range of 1-3: 1; the volume mass ratio of the solvent B to the betulic acid is 1-40: 1, preferably in the range of 3-18: 1.

further, in the method, the volume ratio of the solvent A to the solvent B in the mixed solvent system is 1: 0.2-20, and the preferable range is 1: 3 to 6.

Further, the heating temperature adopted in the method is 35-110 ℃, and preferably 55-60 ℃; the cooling temperature is-20 to 30 ℃, and preferably 0 to 5 ℃.

The invention discovers a new crystal form of the pipadiric acid, the preparation process of the crystal form is simple, the operation is simple and convenient, and the quality index and the crystal form of the obtained crystal form are basically kept unchanged in a stability acceleration experiment, which shows that the crystal form I of the product has good stability, is easy to store in the production and circulation process, provides good selection for the preparation of a pharmaceutical preparation thereof, and has very important significance for the development of the medicine.

Drawings

1. FIG. 1 is an XRPD pattern for crystalline form I of bipedac acid prepared in example 1;

2. FIG. 2 is a DSC of crystalline form I of budesonide obtained in example 1;

3. FIG. 3 is a TGA profile of crystalline form I of bipedac acid made in example 1;

4. FIG. 4 is an XRPD pattern for crystalline form I of bipedac acid prepared in example 6;

5. FIG. 5 is a DSC of crystalline form I of budesonide obtained in example 6;

6. FIG. 6 is a TGA profile of crystalline form I of bipedac acid made in example 6;

7. FIG. 7 is an XRPD pattern for crystalline form I of bipedac acid prepared as example 9;

8. FIG. 8 is a DSC of crystalline form I of budesonide obtained in example 9;

9. FIG. 9 is a TGA profile of crystalline form I of budipidic acid prepared in example 9;

10. figure 10 is an XRPD pattern of crystalline form I of bipidelic acid at 1 month of accelerated experiment;

11. figure 11 is an XRPD pattern of crystalline form I of bipidelic acid at 2 months of accelerated experiment;

12. figure 12 is an XRPD pattern of crystalline form I of bipidelic acid at 3 months of accelerated experiment.

Detailed Description

The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.

In the examples described below, the test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer. The prepidetic acid starting material is prepared according to the prior art, the preparation method can refer to WO2004067489, and other raw materials and solvents are obtained by the market.

The X-ray powder diffraction pattern is collected on a D8ADVANCE X-ray powder diffractometer, the detection collection temperature is room temperature (about 25 ℃), and the detection method parameters are as follows:

a Differential Scanning Calorimetry (DSC) chart is acquired on TA Q2000, and the parameters of the detection method are as follows:

the thermogravimetric analysis (TGA) graph disclosed by the invention is collected on TA Q5000, and the detection method parameters are as follows:

example 1

Adding 1.0g of pimelic acid and 2mL of ethyl acetate into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding 10mL of n-heptane, stirring for 2-3 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 4-6 hours, centrifuging, and drying to obtain the crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 1 with an XRPD pattern as shown in figure 1, a DSC pattern as shown in figure 2, and a TGA pattern as shown in figure 3.

TABLE 1

2THETA	d interval	Strength%
			10.38	8.51	82.8％
11.78	7.51	4.5％
			15.58	5.68	11.1％
16.75	5.29	8.9％
			17.37	5.10	16.9％
17.59	5.04	35.0％
			18.00	4.92	100.0％
18.24	4.86	14.3％
			18.76	4.73	34.7％
19.59	4.53	19.9％
			20.40	4.35	32.3％
20.76	4.28	22.2％
			21.16	4.20	4.1％
21.87	4.06	27.2％
			22.60	3.93	19.5％
23.16	3.84	9.0％
			23.61	3.77	8.6％
23.84	3.73	5.3％
			27.60	3.23	11.1％
29.12	3.06	5.3％
			30.79	2.90	5.0％
34.39	2.61	6.1％
			36.23	2.48	4.3％

Example 2

Adding 1.0g of pimelic acid and 3mL of ethyl acetate into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding 20mL of petroleum ether, stirring for 2-3 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 4-6 hours, centrifuging, and drying to obtain the crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 2, and the DSC diagram and TGA diagram thereof are substantially identical to those of example 1.

TABLE 2

Example 3

Adding 1.0g of pimelic acid and 5mL of isopropyl acetate into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding 20mL of n-heptane, stirring for 2-3 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 4-6 hours, centrifuging, and drying to obtain the crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 3, and the DSC diagram and TGA diagram thereof are substantially identical to those of example 1.

TABLE 3

Example 4

Adding 1.0g of besmead acid and 3mL of methyl tertiary butyl ether into a three-neck flask, uniformly stirring, heating to 55 ℃, slowly adding 15mL of n-heptane, stirring for 2-3 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 4-6 hours, centrifuging, and drying to obtain the crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 4, and the DSC diagram and TGA diagram thereof are substantially identical to those of example 1.

TABLE 4

Example 5

Adding 1.0g of besmead acid and 3mL of isopropyl ether into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding 15mL of n-heptane, stirring for 2-3 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 4-6 hours, centrifuging, and drying to obtain the crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 5, and the DSC diagram and TGA diagram thereof are substantially identical to those of example 1.

TABLE 5

Example 6

Adding 1.0g of pimelic acid and 3mL of absolute ethyl alcohol into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding 15mL of water, stirring for 2-3 hours under the condition of heat preservation, slowly cooling to 0-5 ℃ for crystallization, stirring for 4-6 hours under the condition of heat preservation, centrifuging, and drying to obtain the crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 6 with an XRPD pattern as shown in figure 4, a DSC pattern as shown in figure 5, and a TGA pattern as shown in figure 6.

TABLE 6

Example 7

Adding 1.0g of pimelic acid and 3mL of isopropanol into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding 15mL of water, stirring for 2-3 hours under the condition of heat preservation, slowly cooling to 0-5 ℃ for crystallization, stirring for 4-6 hours under the condition of heat preservation, centrifuging, and drying to obtain the crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 7, and the DSC diagram and TGA diagram thereof are substantially in accordance with example 2.

TABLE 7

Example 8

Adding 1.0g of pimelic acid and 3mL of methanol into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding 15mL of water, stirring for 2-3 hours under the condition of heat preservation, slowly cooling to 0-5 ℃ for crystallization, stirring for 4-6 hours under the condition of heat preservation, centrifuging, and drying to obtain the crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 8, and the DSC diagram and TGA diagram thereof are substantially in accordance with example 2.

TABLE 8

Example 9

Adding 1.0g of pimelic acid and 3mL of acetone into a three-neck flask, uniformly stirring, heating to 35-40 ℃, slowly adding 15mL of water, stirring for 2-3 hours under the condition of heat preservation, slowly cooling to 0-5 ℃ for crystallization, stirring for 4-6 hours under the condition of heat preservation, centrifuging, and drying to obtain the crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 9, and the DSC diagram and TGA diagram thereof are substantially in accordance with example 2.

TABLE 9

Example 10

Adding 1.0g of besmead acid and 8mL of methyl tertiary butyl ether into a three-neck flask, uniformly stirring, heating to 48-50 ℃, keeping the temperature, stirring for 2-3 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 4-6 hours, centrifuging, and drying to obtain a crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 10 with an XRPD pattern as shown in figure 7, a DSC pattern as shown in figure 8, and a TGA pattern as shown in figure 9.

TABLE 9

2THETA	d interval	Strength%
			10.28	8.61	100.0％
11.69	7.56	3.8％
			15.48	5.72	14.5％
17.01	5.21	3.1％
			17.28	5.13	16.2％
17.52	5.06	34.0％
			17.90	4.96	88.7％
18.17	4.88	15.5％
			18.68	4.75	23.2％
19.51	4.55	12.2％
			20.31	4.37	34.7％
20.656	4.30	28.4％
			21.06	4.21	3.2％
21.78	4.08	33.7％
			22.52	3.95	19.2％
23.09	3.85	7.5％
			23.53	3.78	7.8％
23.79	3.74	4.5％
			24.59	3.62	3.8％
25.65	3.47	4.4％
			27.51	3.24	6.8％
29.03	3.07	5.7％
			34.32	2.61	4.7％
36.16	2.48	3.3％

Example 11

Adding 1.0g of besmead acid and 8mL of isopropyl ether into a three-neck flask, uniformly stirring, heating to 55-60 ℃, keeping the temperature, stirring for 2-3 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 4-6 hours, centrifuging, and drying to obtain a crystal form I.

The X-ray powder diffraction data of form I obtained in this example are shown in table 11, and the DSC chart and TGA chart thereof are substantially identical to those of example 3.

TABLE 11

2THETA	d interval	Strength%
			10.28	8.61	100.0％
11.67	7.58	8.7％
			15.46	5.74	14.9％
17.01	5.21	4.2％
			17.26	5.13	16.7％
17.52	5.04	29.3％
			17.90	4.96	92.6％
18.17	4.90	20.1％
			18.66	4.75	23.3％
19.51	4.53	14.1％
			20.33	4.37	32.2％
20.66	4.32	26.1％
			21.06	4.19	4.7％
21.80	4.08	31.4％
			22.50	3.93	17.5％
23.09	3.85	10.4％
			23.53	3.78	10.6％
23.79	3.72	5.5％
			24.61	3.62	4.9％
25.67	3.47	5.0％
			27.51	3.24	9.9％
29.05	3.05	9.8％
			34.32	2.63	6.7％
36.14	2.48	5.1％

Example 12 stability study of Crystal form I of Pataric acid

The peidide crystal form I prepared in example 10 was placed at 40 ℃ ± 2 ℃ and RH 75% ± 5 ℃ to examine the stability of the peidide crystal form I for 1 month, 2 months and 3 months, and the purity, moisture and crystal form data of the product were determined, and the test results are shown in table 12.

Test results show that the crystalline form I of the pimelic acid is stable for 1 month, 2 months and 3 months under the conditions of 40 +/-2 ℃ and RH 75% +/-5%, and does not generate crystal form change and chemical degradation.

Claims

1. Crystal form I of Patadixic acid characterized by having characteristic peaks at 10.38 + -0.2 DEG and 18.00 + -0.2 DEG in an X-ray powder diffraction pattern 2Theta value measured using Cu-Kalpha radiation.

2. Crystal form I of budesonide according to claim 1, characterized in that the X-ray powder diffraction pattern 2Theta values measured using Cu-Ka radiation also have characteristic peaks at 17.59 ± 0.2 °, 18.76 ± 0.2 °, 20.40 ± 0.2 ° and 21.87 ± 0.2 °.

3. Crystal form I of budesonide according to claim 2, characterized by an X-ray powder diffraction pattern 2Theta values further having characteristic peaks at 15.58 ± 0.2 °, 19.60 ± 0.2 °, 20.76 ± 0.2 °, 22.60 ± 0.2 ° and 27.60 ± 0.2 °.

4. Crystalline form I of budesonide according to any of claims 1 to 3, characterized by a differential scanning calorimetry trace which shows an endothermic peak onset upon heating to 86.0 to 89 ℃.

5. Crystalline depigment I as claimed in any one of claims 1 to 3, wherein the thermogravimetric analysis of depigment I shows the onset of evaporation or decomposition at 215-225 ℃ and the completion of evaporation or decomposition at 370-380 ℃.

6. The preparation method of the crystalline form I of the pimelic acid is characterized by comprising the steps of adding the pimelic acid into a solvent A, heating to a certain temperature, stirring for a period of time, adding or not adding an inert solvent B, stirring in an obtained mixed solvent system or a single solvent for a period of time, slowly cooling to a certain temperature for crystallization, carrying out heat preservation and pulping to obtain a suspension, filtering and drying to obtain a white solid, namely the crystalline form I.

7. The process for the preparation of crystalline form I of budipidic acid according to claim 6, characterized in that said solvent a is selected from ethyl acetate, isopropyl acetate, dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, toluene, methyl tert-butyl ether or isopropyl ether; the inert solvent B is selected from petroleum ether, n-heptane or water.

8. The preparation method of crystalline blepharic acid form I according to claim 6, characterized in that solvent a is ethyl acetate and inert solvent B is n-heptane, forming an ethyl acetate-n-heptane mixed solvent system; the solvent A is ethyl acetate, the inert solvent B is petroleum ether, and an ethyl acetate-petroleum ether mixed solvent system is formed; the solvent A is isopropyl acetate, the inert solvent B is n-heptane, and an isopropyl acetate-n-heptane mixed solvent system is formed; the solvent A is methyl tertiary butyl ether, the inert solvent B is n-heptane, and a methyl tertiary butyl ether-n-heptane mixed solvent system is formed; the solvent A is isopropyl ether, the inert solvent B is n-heptane, and an isopropyl ether-n-heptane mixed solvent system is formed; the solvent A is ethanol, the inert solvent B is water, and an ethanol-water mixed solvent system is formed; the solvent A is isopropanol, the inert solvent B is water, and an isopropanol-water mixed solvent system is formed; the solvent A is methanol, the inert solvent B is water, and a methanol-water mixed solvent system is formed; the solvent A is acetone, the inert solvent B is water, and an acetone-water mixed solvent system is formed; the solvent A is methyl tertiary butyl ether, and an inert solvent B is not added to form a methyl tertiary butyl ether single solvent system; the solvent A is isopropyl ether, and an inert solvent B is not added, so that an isopropyl ether single solvent system is formed.

9. The preparation method of crystalline form I of prepetidic acid according to claim 6, characterized in that the volume to mass ratio of solvent A to prepetidic acid is 0.2-10: 1; the volume-mass ratio of the solvent B to the betulic acid is 1-40: 1.

10. the preparation method of crystalline form I of besipidic acid according to claim 6, characterized in that the heating temperature employed in said method is 35-110 ℃; the cooling temperature is-20 to 30 ℃.