CN116199668A - Evobrutinib compound salt form and preparation method thereof - Google Patents

Abstract

The invention relates to a crystal form of a compound I mesylate and a preparation method thereof. The crystal form of the compound I mesylate provided by the invention has stable physicochemical properties, can be stored stably for a long time, is simple and convenient in preparation method and good in repeatability, and has important practical application value for the development of the drug in the future.

Description

Evobrutinib compound salt form and preparation method thereof

Technical Field

The present invention relates to the field of pharmaceutical chemistry, and in particular to a salt crystal form of an Evobrutinib compound and methanesulfonic acid and a preparation method thereof.

Background Art

Evobrutinib is an investigational, oral, highly selective Bruton's tyrosine kinase (BTK) inhibitor with potential anti-tumor activity. Following administration, Evobrutinib inhibits BTK activity and suppresses activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents B-cell activation and activation of BTK-mediated downstream survival pathways, thereby inhibiting the growth of malignant B-cells that overexpress BTK. BTK is a member of the BTK/Tec family of cytoplasmic tyrosine kinases, which are SRC-related and overexpressed in B-cell malignancies; it plays an important role in the development, activation, signal transduction, proliferation, and survival of B lymphocytes.

The chemical name of the Evobrutinib compound is 1-[4-[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidin-1-yl]prop-2-en-1-one (hereinafter referred to as "Compound I"), and its structural formula is as follows:

Nearly half of drug molecules exist and are administered in the form of salts. Salt formation can improve some undesirable physical, chemical or biopharmaceutical properties of drugs, such as changing the solubility or dissolution of drugs, reducing hygroscopicity, improving stability, changing melting point, improving grinding performance, facilitating preparation and purification, and improving permeability. It is very necessary to select the appropriate salt form for drug development. At the same time, a salt form may exist in polymorphic forms. Different crystal forms have different melting points, solubility, dissolution properties, chemical stability, mechanical stability, etc. These physical and chemical properties sometimes directly affect the effectiveness and processing performance of the drug. Therefore, comprehensive and systematic salt form screening and crystal form screening in drug research and development, and selecting the most suitable salt form and its crystal form for development are one of the important research contents that cannot be ignored.

Some crystal forms of the compound of formula (I) have been reported. Yuanyan Company reported the malonate NF1, succinate NF1, oxalate NF1, fumarate NF1, maleate NF1, and citrate NF1 of compound I in US10464923B2. The patent text describes that compared with the free crystal form A1, the solubility of the above salt forms in FaSSIF and FeSSIF is improved to a certain extent. However, in order to further improve the solubility of compound I in different media, and then improve the bioavailability and efficacy, it is very necessary to screen and select more salt forms and crystal forms of compound I with excellent properties, thereby providing new options for the industrial production of the drug, which has important practical significance.

The inventors of the present application surprisingly discovered during the experiment that Compound I and methanesulfonic acid can exist stably in the form of a salt, which has advantages in terms of physical and chemical properties, formulation processing performance and bioavailability, such as melting point, solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability. This provides a better choice for the development of drugs containing Compound I and has very important practical application value.

Summary of the invention

The main purpose of the present invention is to provide a salt-type crystal form of compound I and methanesulfonic acid and a preparation method thereof.

According to the purpose of the present invention, the present invention provides a salt form of Compound I and methanesulfonic acid.

Furthermore, the present invention provides a salt form of Compound I and methanesulfonic acid in the form of crystalline DCI (hereinafter referred to as salt form DCI).

中的1处、或2处、或3处有特征峰。On the one hand, using Cu-Ka radiation, the X-ray powder diffraction of the salt DCI at a diffraction angle 2theta value is

There are characteristic peaks at 1, 2, or 3 of the above.

中的1处、或2处、或3处有特征峰；优选地，所述盐型DCI的X射线粉末衍射在衍射角2theta值为

中的3处有特征峰。Further, using Cu-Ka radiation, the X-ray powder diffraction of the salt-type DCI at a diffraction angle 2theta value is

There is a characteristic peak at one, two, or three of the above; preferably, the X-ray powder diffraction of the salt-type DCI has a diffraction angle 2theta value of

There are characteristic peaks at three locations.

中的1处、或2处、或3处有特征峰；优选地，所述盐型DCI的X射线粉末衍射在衍射角2theta值为

中的3处有特征峰。Further, using Cu-Ka radiation, the X-ray powder diffraction of the salt-type DCI at a diffraction angle 2theta value is

There is a characteristic peak at 1, 2, or 3 of the salt-type DCI; preferably, the X-ray powder diffraction of the salt-type DCI has a diffraction angle 2theta value of

There are characteristic peaks at three locations.

Without limitation, the X-ray powder diffraction pattern of salt form DCI is substantially as shown in FIG1 .

Without limitation, the salt-type DCI begins to show an endothermic peak at around 191° C., and the differential scanning calorimetry analysis diagram is substantially as shown in FIG. 2 .

Without limitation, the ¹ H NMR of salt form DCI is substantially as shown in FIG3 .

According to the purpose of the present invention, the present invention also provides a method for preparing the salt-type DCI, the preparation method comprising:

The solid of compound I and methanesulfonic acid are added to a vial in a molar ratio of 1:(0.66-1.5), and then a ketone or ester solvent is added, stirred for 12-72 hours, separated and dried to obtain a salt-type crystalline form of compound I and methanesulfonic acid DCI.

Furthermore, the selected ketone is preferably acetone; the selected ester is preferably ethyl acetate; the stirring temperature is preferably -20°C to 60°C, more preferably 30°C; the drying condition is preferably 20°C to 50°C; and the separation is centrifugation or filtration.

The salt-type DCI provided by the present invention has the following beneficial effects:

1) The salt-type DCI provided by the present invention has good stability.

The salt-type DCI of the present invention is sealed and placed for 3 months under 25°C/60%RH (relative humidity) and 40°C/75%RH conditions, and the crystal form remains unchanged, indicating that the salt-type DCI has good physical stability, especially under the accelerated condition of 40°C/75%RH, the crystal form remains stable after being placed for 3 months, and no crystal transformation occurs, which further illustrates that the salt-type DCI still has good physical stability even under high temperature and high humidity conditions, which ensures that the drug is not prone to crystal transformation during subsequent processes, production and transportation; in addition, the chemical purity of the salt-type DCI does not change before and after being placed under 25°C/60%RH (relative humidity), and the purity is maintained at nearly 99%, indicating that the salt-type DCI has good chemical stability. In addition, even under the accelerated condition of 40°C/75%RH, the chemical purity still does not decrease significantly, which further illustrates that the salt-type DCI has good chemical stability. Good physical and chemical stability ensures that the drug can maintain stable quality and ensure drug quality and efficacy during subsequent formulation development and process production, as well as drug production and transportation, which is of great significance.

In addition, salt-type DCI has better mechanical stability. Before and after grinding, salt-type DCI did not undergo crystal transformation, and no significant decrease in sample crystallinity was observed. However, after grinding of free base crystal form A2, the crystallinity decreased significantly, indicating that salt-type DCI has better mechanical stability. Good mechanical stability can ensure that the sample will not easily undergo crystal transformation due to external forces such as mechanical grinding and crushing during the later formulation process, reducing the risk of crystal transformation during the formulation process and improving the developability of the formulation process.

Crystal stability is of great significance to drug development. If crystal transformation occurs, it will directly affect the solubility of the drug and then affect the bioavailability of the drug, thereby changing the efficacy of the drug. Good chemical stability can ensure that the drug produces almost no new impurities or the impurity content hardly increases during storage, thereby ensuring the safety of the drug. Good mechanical stability can also improve the drug's tolerance to mechanical damage during the formulation process and reduce the risk of crystal transformation. Therefore, the good physicochemical stability and good mechanical stability of salt-type DCI provide guarantees for the subsequent production and development of drugs, and have high industrial development value.

2) The salt-type DCI of the present invention has lower hygroscopicity.

According to the Pharmacopoeia method (Chinese Pharmacopoeia 2020 Edition General Principles 9103 Drug Hygroscopicity Experimental Guidelines, Experimental Conditions: 25±1°C, 80% Relative Humidity), the hygroscopicity of the salt-type DCI of the present invention was investigated, and the results showed that the salt-type DCI hygroscopic weight gain was 0.7%. In addition, regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition General Principles 9103 Drug Hygroscopicity Experimental Guidelines, Experimental Conditions: 25±1°C, 80% Relative Humidity), the weight gain category of the salt-type DCI is: the hygroscopic weight gain is less than 2.0% but not less than 0.2%, which is slightly hygroscopic. This result shows that the salt-type DCI has a lower hygroscopicity. Lower hygroscopicity can ensure that the sample can maintain a lower hygroscopic weight gain without deliquescence during later production, processing, storage and transportation, thereby ensuring the stability of the drug quality.

In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, and the mechanical stirring is preferably 100-300 rpm.

The "separation" is accomplished by conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is: placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until all solids sink to the bottom of the centrifuge tube.

The "drying" can be carried out at room temperature or higher. The drying temperature is from room temperature to about 50°C, or to 40°C. The drying time can be 2 to 48 hours, or overnight. The drying is carried out in a fume hood, a forced air oven or a vacuum oven.

In the present invention, "crystal" or "polymorph" refers to a solid confirmed by the characterization of an X-ray powder diffraction pattern. It will be understood by those skilled in the art that the physicochemical properties discussed here can be characterized, and the experimental errors therein depend on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray powder diffraction pattern will usually change with different instrument conditions. It should be particularly noted that the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the order of the diffraction peak intensity cannot be used as the only or decisive factor. In fact, the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal. The diffraction peak intensity shown in the present invention is illustrative rather than for absolute comparison. In addition, the experimental error of the diffraction peak position is usually 5% or less, and the errors of these positions should also be taken into account, and an error of ±0.2 is usually allowed. In addition, due to the influence of experimental factors such as sample thickness, the overall offset of the diffraction peak angle will be caused, and a certain offset is usually allowed. Therefore, it can be understood by those skilled in the art that the X-ray powder diffraction pattern of the protected crystal form of the present invention is not necessarily completely consistent with the X-ray powder diffraction patterns in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is the same as or similar to the characteristic peaks in these patterns falls within the scope of the present invention.

A person skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

In some embodiments, the salt form DCI of the present invention is pure and substantially free of any other crystalline forms. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more preferably less than 5% (by weight) of other crystalline forms, and more preferably less than 1% (by weight) of other crystalline forms.

The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5% or ±0.1%.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an XRPD diagram of the salt-type DCI obtained according to Example 1.

FIG. 2 is a DSC graph of the salt-type DCI obtained according to Example 1.

FIG. 3 is a ¹ H NMR graph of the salt-type DCI obtained in Example 1.

Figure 4 is an XRPD overlay of the stability of salt form DCI before and after (from top to bottom: initial crystal form, placed at 25°C/60% RH for 3 months, placed at 40°C/75% RH for 3 months).

Figure 5 is an XRPD overlay of salt form DCI before and after grinding (the upper curve is the graph before grinding, and the lower curve is the graph after grinding).

FIG6 is an XRPD overlay of two samples of Example 1.

Figure 7 is an XRPD overlay of the free base form A2 before and after grinding (the upper curve is the image before grinding, and the lower curve is the image after grinding).

DETAILED DESCRIPTION

The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many changes in both materials and methods may be made without departing from the scope of the present invention.

The explanations of the abbreviations used in the present invention are as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

Instruments and methods used to collect data:

The X-ray powder diffraction pattern of the present invention is collected on a Bruker D2 PHASER X-ray powder diffractometer.

The method parameters of X-ray powder diffraction described in the present invention are as follows:

X-ray source: Cu Ka

Kal(A):1.54060;Ka2(A)1.54439

Ka2/Ka1 intensity ratio: 0.50

Voltage: 30 kilovolts (kV)

Current: 10 milliamperes (mA)

Scanning range: from 3.0 to 40.0 degrees

The differential scanning calorimetry (DSC) diagram of the present invention was collected on a Mettler DSC3.

The method parameters for analysis (DSC) are as follows:

Scan rate: 10℃/min

Protective gas: Nitrogen

HPLC purity test method:

Solution preparation: Take about 1 mg of sample and dissolve it in 1 ml of acetonitrile.

Note: Purity below 0.05% is not integrated.

Unless otherwise specified, the following examples are all operated at room temperature. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

According to the present invention, the compound I and/or its salt as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, the compound I and/or its salt as a raw material is in solid form.

The compound I used in the following examples can be prepared according to the method described in patent CN106831732B.

Example 1: Preparation method of salt-type DCI

About 50 mg of Compound I and about 9 mg of methanesulfonic acid were weighed and added to a 3 ml vial, and then a solvent (see Table 1 for details) was added to obtain a suspension. The suspension was stirred at room temperature for 72 hours, and the solid was separated by centrifugation and dried. XRPD detection showed that the obtained solids were all the crystalline form DCI shown in the present invention.

Table 1

The present invention is described below (including Examples 2-4) by taking Sample 1 in Example 1 as an example; similar results can also be obtained with Sample 2, which will be omitted to avoid redundancy.

The XRPD pattern of the salt-type DCI obtained from sample 1 in Example 1 is shown in FIG1 , and the XRPD data are shown in Table 2. The XRPD pattern of the salt-type DCI obtained from sample 2 is shown in FIG6 .

The DSC of sample 1 is shown in Figure 2. An endothermic peak begins to appear when heated to around 191°C.

Table 2

The NMR image of sample 1 is shown in Figure 3, and the specific data are:

¹ H NMR (400MHz, DMSO-d6) δ12.77(s,-1H),8.29(s,1H),7.43–7.39(m,2H),7.24–7.20(m,2H),7.18–7.08(m ,5H),7.01(t,J＝6.0Hz,1H),6.83(s,2H),6.73(dd,J＝16.7,10.5Hz,1H),6.02(dd,J＝16.7,2.4Hz,1H) ,5.60(dd,J＝10.5,2 .4Hz,1H),4.32(d,J＝12.6Hz,1H),3.97(d,J＝13.3Hz,1H),3.18(t,J＝6.5Hz,2H),2.93(t,J＝12.8Hz ,1H),2.53(t,J＝12.9Hz,1H),2.28(s,3H),1.78(ddt,J＝10.8,7.2,3.5Hz,1H),1.57(d,J＝12.6Hz,2H) ,0.93(p,J=11.4Hz,2H).

Example 2: Stability of salt-type DCI

The salt-type DCI prepared by the present invention was weighed, each portion was about 5 mg, and a total of 2 portions were taken. After the initial purity and crystal form were determined by HPLC and XRPD, the aluminum foil bag was sealed and placed under 25°C/60%RH and 40°C/75%RH for a period of time, and then the purity and crystal form were determined by HPLC and XRPD. The experimental results are shown in Table 3 below, and the XRPD overlay is shown in Figure 4.

Table 3

Placement conditions Placement time Crystal form purity Starting —— Salt type DCI 99.34% 25℃/60％RH 3 months Salt type DCI 99.26% 40℃/75％RH 3 months Salt type DCI 99.08%

The results show that the salt-type DCI of the present invention can maintain physical and chemical stability for at least 3 months under the conditions of 25°C/60%RH and 40°C/75%RH.

Example 3: Mechanical stability of salt-type DCI

About 10 mg of salt-type DCI was placed in a mortar and manually ground for 5 minutes, and XRPD tests were performed before and after grinding. The XRPD comparison before and after grinding is shown in Figure 5. The results show that the crystal form of the salt-type DCI of the present invention remains unchanged after grinding, and no obvious decrease in crystallinity is observed, which indicates that the salt-type DCI has good mechanical stability.

About 10 mg of Merck Evobutinib free base crystal form A2 (US20190010142A1) was placed in a mortar and manually ground for 5 minutes, and XRPD tests were performed before and after grinding. The comparison of XRPD before and after grinding is shown in Figure 7. The results show that the crystal form of Merck Evobutinib free base crystal form A2 remains unchanged after grinding, but the crystallinity decreases significantly.

The above shows that salt-type DCI has better mechanical stability.

Example 4: Hygroscopicity of salt-type DCI

About 30 mg of the salt-type DCI of the present invention was weighed and placed under conditions of 25±5° C. and 80% relative humidity for 24 hours, and the weight of the sample before and after was recorded. The specific results are shown in Table 4 below.

Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition General Chapter 9103 Drug Hygroscopicity Experiment Guidance Principles, Experimental Conditions: 25±1℃, 80% relative humidity, 24 hours):

Deliquescent: Absorbs enough water to form a liquid

Very hygroscopic: weight gain due to moisture absorption is not less than 15.0%

Hygroscopic: Weight gain due to moisture absorption is less than 15.0% but not less than 2.0%

Slightly hygroscopic: weight gain due to moisture absorption is less than 2.0% but not less than 0.2%

No or almost no hygroscopicity: moisture gain is less than 0.2%.

Table 4

The results show that the salt-type DCI of the present invention is slightly hygroscopic, but the hygroscopicity is relatively small, which indicates that the salt-type DCI is not prone to deliquescence during the production and storage of drugs.

The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly. They cannot be used to limit the protection scope of the present invention. Equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims (8)

1. Compound I

Crystal form of the mesylate salt. 2. the crystal form of compound I mesylate according to claim 1, is characterized in that, is eutectic DCI; Using Cu-Ka radiation, its X-ray powder diffraction pattern is 21.6 ° ± 0.2 ° at 2theta value, One or two or three of 18.3°±0.2° and 7.5°±0.2° have characteristic peaks. 3. the crystal form of compound I mesylate according to claim 2, is characterized in that, uses Cu-Ka radiation, and its X-ray powder diffraction figure is 20.3 ° ± 0.2 °, 24.0 ° ± 0.2 ° in 2theta value , 1 or 2 or 3 of 15.6°±0.2° have characteristic peaks. 4. the crystal form of compound I mesylate according to claim 2 is characterized in that, using Cu-Ka radiation, its X-ray powder diffraction pattern is 17.3 ° ± 0.2 °, 26.3 ° ± 0.2 ° at 2theta value , 1 or 2 or 3 of 27.4°±0.2° have characteristic peaks. 5. a preparation method of the crystal form of compound I mesylate salt as claimed in claim 2, is characterized in that: the solid of compound I, methanesulfonic acid and solvent are mixed; Described solvent is ketones, or esters Solvent; stirring for 12-72 hours, separating and drying to obtain the crystal form DCI of the compound I mesylate. 6. the preparation method according to claim 5, is characterized in that, the solid of compound I and methanesulfonic acid are added in the vial according to molar ratio 1:(0.66～1.5), then add ketones, or ester solvent, stir After 12-72 hours, it was separated and dried to obtain the crystal form DCI of the mesylate salt of compound I. 7. The preparation method according to claim 5, characterized in that, the selected ketones are preferably acetone; the selected esters are preferably ethyl acetate; the stirring temperature is preferably -20° C. to 60° C.; the drying condition is preferably 20° C. ℃～50℃; the separation is centrifugation or filtration. 8. The preparation method according to claim 5, characterized in that, the stirring temperature is 30°C.

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