CN110577494B

CN110577494B - Polymorphic substance of benzimidazole derivative and preparation method and application thereof

Info

Publication number: CN110577494B
Application number: CN201810581350.XA
Authority: CN
Inventors: 张俊贤; 扈占坤; 刘沫毅; 杨琰; 池芳泽
Original assignee: China Resources Saike Pharmaceutical Co Ltd
Current assignee: China Resources Saike Pharmaceutical Co Ltd
Priority date: 2018-06-07
Filing date: 2018-06-07
Publication date: 2021-07-16
Anticipated expiration: 2038-06-07
Also published as: CN110577494A

Abstract

The invention belongs to the field of medicine crystal forms, and particularly relates to a polymorphic substance of a benzimidazole derivative, a preparation method and application thereof, in particular to a polymorphic substance of 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] sodium propionate, a preparation method and application thereof. The crystal form of the invention has the advantages of improving hygroscopicity, chemical stability, preparation adaptability and the like. The polymorphic substance prepared by the invention has high purity and good stability, and the crystal form of the polymorphic substance is still unchanged under the conditions of high temperature, high humidity and illumination. For example, the crystal form remains stable after storage for 12 months at room temperature. The preparation method of the polycrystalline type is simple in process, easy to implement, mild in reaction condition and easy to control the crystal form. In addition, the obtained product does not need to be purified for many times, is safe and environment-friendly to operate, and is beneficial to the industrial production of the polycrystalline type.

Description

Polymorphic substance of benzimidazole derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of medicine crystal forms, and particularly relates to a polymorphic substance of a benzimidazole derivative, a preparation method and application thereof, in particular to a polymorphic substance of 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] sodium propionate, a preparation method and application thereof.

Background

It is known in the prior art that 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid and its derivatives represented by the following formula can be used as URAT1 inhibitors for the treatment of gout or hyperuricemia.

The inventor finds that the compound and the derivative thereof have the problems of poor water solubility and the like, and the preparation has poor dissolution rate, so that the compound and the derivative thereof are not beneficial to the full absorption and utilization of the medicine. In addition, the amorphous form and the known crystal form of the compound have the problems of poor stability, strong hygroscopicity and the like.

Therefore, the pharmaceutically acceptable salt, amorphous substance or crystal form of the 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid with improved properties in the aspects is developed, so that the aim of remarkably improving the stability, hygroscopicity and bioavailability of the finished medicine is fulfilled, and the method has important significance for the application prospect of the medicine.

Disclosure of Invention

In order to solve the problems in the prior art, the invention firstly provides a crystal form A of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate, which uses Cu-Ka radiation and has characteristic peaks at 8.9 +/-0.2 °, 11.3 +/-0.2 °, 16.2 +/-0.2 °, 17.5 +/-0.2 °, 18.8 +/-0.2 ° and 23.2 +/-0.2 ° in X-ray powder diffraction represented by 2 theta angles.

According to the invention, the sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate has the following structure:

preferably, the form a has the characteristic peak at 5.4 ± 0.2 °, 8.9 ± 0.2 °, 9.5 ± 0.2 °, 11.3 ± 0.2 °, 15.3 ± 0.2 °, 16.0 ± 0.2 °, 16.2 ± 0.2 °, 17.5 ± 0.2 °, 18.8 ± 0.2 °, 19.6 ± 0.2 °, 21.5 ± 0.2 °, 21.8 ± 0.2 °, 22.2 ± 0.2 °, 23.2 ± 0.2 °, 24.2 ± 0.2 °, 24.7 ± 0.2 °, 25.2 ± 0.2 °, 26.5 ± 0.2 °, 27.2 ± 0.2 °, 28.5 ± 0.2 °, 29.4 ± 0.2 °, 30.8 ± 0.2 °, 32.2 ± 0.2 ° and 32.8 ± 0.2 ° in X-ray powder diffraction expressed by 2 θ using Cu-K α radiation;

preferably, said crystalline form a of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate has an X-ray powder diffraction pattern substantially as shown in figure 2;

according to the invention, the Differential Scanning Calorimetry (DSC) of said form A presents a characteristic endothermic peak at 280 ± 2 ℃;

preferably, said form a has a DSC profile substantially as shown in figure 3;

preferably, the crystalline form a has a thermogravimetric analysis (TGA) profile substantially as shown in figure 4;

preferably, the infrared spectrum analysis (IR) of the crystal form A is 2222 +/-1 cm^-1、1615±1cm^-1、1593±1cm^-1、1568±1cm^-1、1511±1cm^-1、1469±1cm^-1、1440±1cm^-1、1431±1cm^-1、1395±1cm^-1、1368±1cm^-1、1358±1cm^-1、1306±1cm^-1、1270±1cm^-1、1125±1cm^-1、929±1cm^-1、850±1cm^-1、768±1cm^-1、758±1cm^-1、754±1cm^-1And 747. + -.1 cm^-1A characteristic peak exists;

preferably, said form a has an IR absorption spectrum substantially as shown in figure 5.

The invention also provides a crystal form B of sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate, which has characteristic peaks at 4.4 + -0.2 °, 7.8 + -0.2 °, 8.8 + -0.2 °, 13.2 + -0.2 °, 13.5 + -0.2 °, 14.8 + -0.2 °, 15.6 + -0.2 °, 16.9 + -0.2 °, 17.6 + -0.2 ° and 23.4 + -0.2 ° by X-ray powder diffraction expressed by 2 theta angle using Cu-Kalpha radiation.

Preferably, the crystal form B has characteristic peaks at 4.4 +/-0.2 °, 7.8 +/-0.2 °, 8.8 +/-0.2 °, 10.4 +/-0.2 °, 13.2 +/-0.2 °, 13.5 +/-0.2 °, 14.8 +/-0.2 °, 15.6 +/-0.2 °, 16.9 +/-0.2 °, 17.6 +/-0.2 °, 18.7 +/-0.2 °, 19.7 +/-0.2 °, 20.6 +/-0.2 °, 23.1 +/-0.2 °, 23.4 +/-0.2 °, 25.2 +/-0.2 °, 25.8 +/-0.2 °, 26.0 +/-0.2 °, 29.2 +/-0.2 ° and 30.8 +/-0.2 ° by X-ray powder diffraction expressed in terms of 2 theta angle using Cu-Kalpha radiation;

preferably, said crystalline form B of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate has an X-ray powder diffraction pattern substantially as shown in figure 7.

According to the invention, the Differential Scanning Calorimetry (DSC) of the form B has characteristic endothermic peaks at 75 +/-2 ℃ and 274 +/-2 ℃;

preferably, the form B has a DSC profile substantially as shown in figure 8.

Preferably, the crystalline form B has a TGA profile substantially as shown in figure 9.

Preferably, the infrared spectroscopic analysis (IR) of the crystal form B is 2221 +/-1 cm^-1、1657±1cm^-1、1618±1cm^-1、1600±1cm^-1、1585±1cm^-1、1511±1cm^-1、1461±1cm^-1、1396±1cm^-1、1264±1cm^-1、1215±1cm^-1、1121±1cm^-1、1114±1cm^-1、1041±1cm^-1、932±1cm^-1、846±1cm^-1、768±1cm^-1And 756. + -.1 cm^-1There is a characteristic peak.

Preferably, said form B has an infrared spectrum substantially as shown in figure 10.

The present invention also provides a polymorphic mixture of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate having characteristic peaks at 4.4 ± 0.2 °, 11.2 ± 0.2 °, 15.8 ± 0.2 °, 16.5 ± 0.2 °, 17.5 ± 0.2 °, 18.7 ± 0.2 °, 21.4 ± 0.2 °, 22.0 ± 0.2 ° and 23.1 ± 0.2 ° by X-ray powder diffraction expressed in terms of 2 θ angles using Cu-ka radiation.

Preferably, the polymorphic mixture has characteristic peaks at 4.4 ± 0.2 °, 8.8 ± 0.2 °, 10.5 ± 0.2 °, 11.2 ± 0.2 °, 15.8 ± 0.2 °, 16.5 ± 0.2 °, 17.5 ± 0.2 °, 18.7 ± 0.2 °, 21.4 ± 0.2 °, 22.0 ± 0.2 °, 23.1 ± 0.2 °, 24.3 ± 0.2 °, 24.8 ± 0.2 °, 28.4 ± 0.2 ° and 30.9 ± 0.2 ° by X-ray powder diffraction, expressed in terms of 2 θ, using Cu-ka radiation.

Preferably, the polymorphic mixture of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate has an X-ray powder diffraction pattern substantially as shown in figure 12.

According to the invention, Differential Scanning Calorimetry (DSC) of said polymorphic mixture presents characteristic endothermic peaks at 68. + -. 2 ℃, 256. + -. 2 ℃ and 269. + -. 2 ℃.

Preferably, the polymorphic mixture has a DSC profile substantially as shown in figure 13.

Preferably, the polymorphic mixture has a TGA profile substantially as shown in figure 14.

Preferably, the infrared spectroscopic analysis of said polymorphic mixture is 2223. + -.1 cm^-1、1593±1cm^-1、1511±1cm^-1、1466±1cm^-1、1429±1cm^-1、1396±1cm^-1、1359±1cm^-1、1264±1cm^-1、1123±1cm^-1、926±1cm^-1、848±1cm^-1、766±1cm^-1And 744. + -.1 cm^-1There is a characteristic peak.

Preferably, the polymorphic mixture has an infrared spectrum substantially as shown in figure 15.

The present invention also provides an amorphous form of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate having an X-ray powder diffraction pattern substantially as shown in figure 17.

Preferably, the amorphous form has a DSC profile substantially as shown in figure 18.

Preferably, the amorphous form has a TGA profile substantially as shown in figure 19.

Preferably, the infrared spectrum analysis of the amorphous substance is 2224 +/-1 cm^-1、1591±1cm^-1、1511±1cm^-1、1466±1cm^-1、1428±1cm^-1、1394±1cm^-1、1357±1cm^-1、1300±1cm^-1、1262±1cm^-1、1205±1cm^-1、1162±1cm^-1、1122±1cm^-1、1031±1cm^-1、924±1cm^-1、847±1cm^-1、763±1cm^-1And 742. + -.1 cm^-1There is a characteristic peak.

Preferably, the amorphous form has an infrared spectrum substantially as shown in figure 20.

The invention also provides a preparation method of the crystal form A, which comprises the following steps:

(a) stirring and crystallizing a sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate solution (such as dissolved in an ethanol-water mixed solvent) under the condition shown as a region I in a figure 1 to obtain a crystal form A; the conditions shown in the I area are temperature conditions and/or percentage conditions of ethanol water solution.

Or (B) stirring at least one of form B, a polymorphic mixture, or an amorphous form in a solvent to obtain form a;

according to the invention, the operation of step (a) may be: mixing 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] sodium propionate with a solvent, heating for dissolving, cooling, stirring, and precipitating crystals to obtain a crystal form A;

the heating may be carried out by heating the solvent to reflux or non-reflux;

according to the invention, the conditions for stirring crystallization in step (a) are adjusted according to the temperature in zone I in FIG. 1 and the volume percentage of the ethanol aqueous solution;

according to an embodiment of the invention, in step (a), the crystallization may be carried out at a temperature below the boiling point of the aqueous ethanol solvent, e.g. from 0 ℃ to 84.6 ℃, such as from 20 ℃ to 78 ℃, such as from 20 ℃ to 30 ℃, e.g. 25 ℃.

According to an embodiment of the invention, in step (a), the crystallization may be performed in an aqueous ethanol solution, which may be present in a volume percentage of 60% to 100%, such as 68.98% to 100%, for example 75% to 85%, such as 80%.

According to the invention, the time of stirring in step (a) and in step (b), which is the same or different, is chosen independently of one another from 1 to 48 hours, such as 2 or 12 hours.

According to the invention, the stirring speed in step (a) or (b) is the same or different and is, independently of one another, 200 and 800 revolutions per minute, preferably 250 and 300 revolutions per minute;

according to the invention, in step (a) or (b), the mass-to-volume ratio (g/mL) of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate to solvent is 1 (1-10), for example 1 (3-6), such as 1:4 or 1: 5.

According to the present invention, in the step (b), the solvent is selected from one, two or more of alcohol solvents, ketone solvents, aromatic hydrocarbon solvents, nitrile solvents, ester solvents, halogenated hydrocarbon solvents, and ether solvents, for example, one, two or more of methanol, ethanol, isopropanol, acetone, butanone, toluene, acetonitrile, ethyl acetate, dichloromethane, 1, 4-dioxane, or tetrahydrofuran.

The invention also provides a preparation method of the crystal form B, which comprises the following steps: standing and crystallizing a solution (such as a solution dissolved in an ethanol-water mixed solvent) of sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate under the condition shown as a region I in the figure 1 to obtain a crystal form B.

According to the invention, the preparation method may be: mixing 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] sodium propionate with a solvent, heating to dissolve, cooling, standing for crystallization to obtain a crystal form B;

the heating may be carried out by heating to reflux or non-reflux;

according to the invention, the conditions of standing crystallization are adjusted according to the temperature in the area I in the figure 1 and the volume percentage of the ethanol water solution;

according to an embodiment of the invention, the crystallization may be carried out below the boiling point of the aqueous ethanol solvent, such as from 0 ℃ to 84.6 ℃, for example from 10 ℃ to 78 ℃, such as from 20 ℃ to 30 ℃, for example at 25 ℃.

According to an embodiment of the invention, the crystallization may be performed in an aqueous ethanol solution, which may be present in a volume percentage of 60% to 100%, such as 68.98% to 100%, for example 75% to 85%, such as 80%.

According to the invention, the standing time is 1 to 48 hours, for example 2 hours.

According to the invention, the mass-to-volume ratio (g/mL) of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate to solvent is 1 (1-10), for example 1 (3-6), such as 1:4 or 1: 5.

The present invention also provides a process for the preparation of a polymorphic mixture as described above, comprising: (c) a solution of sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate in a solvent (such as in an ethanol-water mixed solvent) is cooled and crystallized under the condition shown as a region II in a figure 1 to obtain a polymorphic mixture;

or (d) placing the amorphous substance under at least one of high temperature, high humidity and illumination to obtain a polymorphic mixture;

alternatively, (e) form B is left to stand under high humidity conditions to give a polymorphic mixture.

According to the invention, the elevated temperature may be a temperature above 35 ℃, for example above 40 ℃, such as 40 ℃, 60 ℃.

The high humidity may be a humidity above 65% RH, such as above 70% RH, for example above 75% RH.

The illumination refers to illumination conditions of 45001x ± 5001x or more.

According to the invention, in step (c), the mass-to-volume ratio (g/mL) of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate to solvent is 1 (1-10), e.g. 1:1 to 1:2, such as 1: 1.25.

According to the invention, the operation of step (c) may be: mixing sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate with a solvent, heating for dissolving, cooling, and crystallizing under stirring or non-stirring conditions to obtain a polycrystalline mixture;

in step (c), the heating may be carried out by heating to reflux or non-reflux;

according to the invention, in step (c), the crystallization conditions are adjusted according to the temperature in zone II of FIG. 1 and the volume percentage of the ethanol aqueous solution;

according to an embodiment of the invention, in step (c), the crystallization may be carried out at a temperature below the boiling point of the aqueous ethanol solvent, such as from 0 ℃ to 95.6 ℃, such as from 20 ℃ to 86.8 ℃, for example from 20 ℃ to 30 ℃, such as 25 ℃;

according to an embodiment of the invention, in step (c), the crystallization may be performed in an aqueous ethanol solution, which may be in a volume percentage of 20% to 60%, for example 35% to 45%, such as 40%.

According to the present invention, in the step (c), the stirring speed may be 200 revolutions per minute, preferably 250 revolutions per minute, 300 revolutions per minute;

according to the invention, in step (c), the stirring time is, for example, from 1 to 48 hours, such as 2 hours.

The invention also provides a preparation method of the amorphous substance, which comprises the following steps:

1) preparing a solution of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

2) rotary evaporation to remove the solvent from the solution in step 1) to give the amorphous material.

According to the present invention, the solvent used in step 1) may be an organic solvent, for example, one, two or more selected from alcohol solvents, ketone solvents, aromatic hydrocarbon solvents, nitrile solvents, ester solvents, halogenated hydrocarbon solvents, ether solvents, for example, one or a mixed solvent of two or three selected from methanol, ethanol, tetrahydrofuran.

The invention also provides a pharmaceutical composition comprising one, two or more of crystal form a, crystal form B, polymorphic mixtures, amorphous substance of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate, and optionally a pharmaceutically acceptable excipient.

The invention also provides application of one, two or more of crystal form A, crystal form B, polymorphic mixture and amorphous substance of sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate as described above in preparation of medicines for treating and/or preventing gout or hyperuricemia.

The present invention also provides a method for the treatment and/or prevention of gout or hyperuricemia comprising administering the form a, form B, polymorph mixture, amorphous substance or pharmaceutical composition as described above to an individual in need thereof.

Definition and description of terms

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

The polymorphic substance of sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate of the present invention has characteristic X-ray powder diffraction peaks expressed in terms of 2 theta angles, wherein "+/-0.2 DEG" is an allowable measurement error range.

Crystallization in the context of the present invention refers to the process of transforming crystals from the amorphous state to the crystalline state of a compound, for example the process of precipitating crystals from a solution of the compound, including but not limited to the crystallization stage in recrystallization, or the stage of directly crystallizing a solution of the compound. It will be understood by those skilled in the art that the compound may be dissolved in the solvent with or without heating to reflux to obtain a solution.

According to the invention, "stirring" can be applied to systems such as homogeneous solutions, supersaturated solutions or a mixture of solid and liquid phases. As an example, when applied to a supersaturated solution or a system in which two phases of a solid and a liquid are mixed, stirring brings the solid phase and the liquid phase in the system into dynamic contact, which is also referred to as "agitation washing".

The polymorphic form of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate according to the invention may be used in combination with other active ingredients, provided that it does not produce other adverse effects, such as allergic reactions.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Polymorphs of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate according to the present invention can be prepared into suitable pharmaceutical compositions using known pharmaceutical carriers by those skilled in the art. The pharmaceutical compositions may be specifically formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.

The pharmaceutical composition can be formulated into various dosage forms for convenient administration, for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are ready to use upon addition of a pharmaceutical vehicle prior to injection).

As used herein, the term "therapeutically and/or prophylactically effective amount" is the amount of a drug or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other person.

When used for the above-mentioned therapeutic and/or prophylactic uses, the total daily amount of the polymorphic forms of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate and the pharmaceutical compositions of the present invention must be determined by a physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved.

The invention has the advantages of

The crystal form A, the crystal form B and the polycrystalline mixture have the advantages of improving hygroscopicity, chemical stability, preparation adaptability and the like. The crystal form A, the crystal form B and the polycrystalline mixture prepared by the invention have high purity and good stability, and the crystal forms of the crystal form A, the crystal form B and the polycrystalline mixture are still unchanged under the conditions of high temperature, high humidity and illumination. For example, the crystal form remains stable after storage for 12 months at room temperature. In addition, the hygroscopicity of the crystal form A, the crystal form B and the polycrystalline mixture obtained by the invention is obviously superior to that of an amorphous substance.

Also, the inventors have surprisingly found that different post-treatment conditions during crystallization (e.g. different speeds of stirring or standing the solution) may lead to differences in the resulting crystalline form, e.g. crystallization at stirring speeds below 200 rpm will contain a large amount of mixed crystals in the product, leading to poor stability.

In addition, the preparation method of the crystal form A, the crystal form B and the polycrystalline mixture has the advantages of simple process, easy implementation, mild reaction conditions and easy control of crystal forms. In addition, the obtained product does not need to be purified for many times, is safe and environment-friendly to operate, and is beneficial to the industrial production of the polycrystalline type.

Drawings

FIG. 1 is a diagram of crystallization conditions of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate in ethanol and an aqueous solvent;

FIG. 2 is an XRPD pattern for sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate form A;

FIG. 3 is a DSC of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate form A;

FIG. 4 is a TGA diagram of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate crystalline form A;

FIG. 5 is an IR absorption curve of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate form A;

FIG. 6 is an HPLC chart of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate crystalline form A;

FIG. 7 is an XRPD pattern for sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate form B;

FIG. 8 is a DSC of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate form B;

FIG. 9 is a TGA diagram of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate crystalline form B;

FIG. 10 is an IR absorption curve of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate form B;

FIG. 11 is an HPLC chart of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate crystalline form B;

FIG. 12 is an XRPD pattern for a polymorphic mixture of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

FIG. 13 is a DSC of a polymorphic mixture of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

FIG. 14 is a TGA diagram of a polymorphic mixture of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

FIG. 15 is an IR absorption curve of a polymorphic mixture of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

FIG. 16 is an HPLC chart of a polymorphic mixture of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

FIG. 17 is an XRPD pattern for the amorphous form of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

FIG. 18 is a DSC of amorphous sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

FIG. 19 is a TGA diagram of amorphous sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

FIG. 20 is an IR absorption curve of amorphous sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate;

FIG. 21 is an HPLC chart of amorphous sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate.

Detailed Description

The polymorph of the present invention, methods of preparation and uses thereof are described in further detail below with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

The abbreviations used in the present invention are explained as follows:

XRPD: powder X-ray diffraction

DSC: differential scanning calorimetry

TGA: thermogravimetric analysis

IR: infrared spectroscopic analysis

Detection method

And characterizing the crystal form A, the crystal form B, the polycrystalline mixture and the amorphous substance by adopting X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry analysis and infrared spectrum.

(1) Powder X-ray diffraction

Instruments and equipment: an X-ray powder diffractometer;

the specific method parameters are as follows:

ray: cu Ka 1, 1.54056

Voltage: 36 kilovolt (kV)

Current: 20 milliampere (mA)

Slit: DS 1, RS 0.15, SS 1

Scanning mode: continuous

Scanning range: 3 to 50 degrees

Sampling step width: 0.01 degree

And (4) measuring the sample based on the instruments and parameters to obtain a corresponding X-ray powder diffraction pattern.

(2) DSC differential scanning calorimetry

Instruments and equipment: SDT Q600 synchronous thermal analyzer;

the specific method parameters are as follows:

scanning rate: 10 ℃/min

Protective gas: nitrogen gas

The samples were measured based on the above instruments and parameters to give the corresponding DSC plots.

(3) TGA thermogravimetric analysis

Instruments and equipment: SDT Q600 synchronous thermal analyzer;

the specific method parameters are as follows:

scanning rate: 10 ℃/min

Protective gas: nitrogen gas

Measurements were taken on the samples based on the above instruments and parameters, resulting in the corresponding TGA profile.

(4) Infrared spectrometry

Instruments and equipment: a dual beam infrared spectrophotometer;

the experimental steps are as follows: adopting potassium bromide tabletting method at 4000-^-1Measuring the range, weighing about 1.0mg of the sample, adding about 200mg of anhydrous potassium bromide powder, grinding uniformly, pressing into a proper sheet, and measuring to obtain a corresponding infrared spectrogram.

(5) High performance liquid chromatography assay

A chromatographic column: waters Xbridge C8, 4.6X 150mm, 5 μm

Mobile phase A: pH3.0 phosphate solution (weighing 2.72g anhydrous potassium dihydrogen phosphate, adding 1L water to dissolve, phosphoric acid pH value 3.0)

Mobile phase B: methanol

Elution gradient: 0min, A70%; 20min, A50%; 40min, A40%; 50min, A25%; 50.1min, A70%; 60min, A70%

Detection wavelength: 225nm

Column temperature: 40 deg.C

Sample introduction amount: 10 μ L

Flow rate: 1.5mL/min

Based on the above parameter measurements, the corresponding HPLC chromatogram was obtained.

Preparation example 1: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid

Adding ethyl 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate (70g) into 700mL of ethanol, adding 70mL of aqueous solution of sodium hydroxide (13.4g) under stirring at room temperature, reacting for 4-5H, detecting by TLC that no raw material remains, stopping the reaction, adjusting the pH to 2-3 with hydrochloric acid, concentrating the system to dryness, adding the remainder into water, adjusting the pH to 10 with 20% sodium hydroxide solution, fully dissolving the solid, adjusting the pH to 2-3 with hydrochloric acid, precipitating a large amount of solid, filtering, and drying the filter cake to obtain 58.8g of white solid with the yield of 84%. The product is 2-methyl-2- [ [1- (4-cyano naphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid with the purity of 99.94 percent.

Preparation example 2: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt

Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid (40g) into ethanol (400mL), adding 40mL of aqueous solution of sodium hydroxide (4.2g) at room temperature under stirring, reacting for 2H, separating out a large amount of solid in the system, filtering, and drying a filter cake to obtain 34g of white solid with the yield of 80%. The product is 2-methyl-2- [ [1- (4-cyano naphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] sodium propionate with the purity of 99.95 percent. This product was further tested as a starting material in the following examples.

Example 1

2g of 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] sodium propionate and 8mL of 80% (v/v) ethanol water mixed solution are mixed, heated, refluxed and dissolved, cooled to 25 ℃ under the stirring condition at the speed of 300 revolutions per minute, stirred for 2 hours at the speed of 300 revolutions per minute at the temperature for full crystallization, and the solid obtained by centrifugation is the crystal form A, wherein the purity of the solid is 99.98%. The XRPD pattern is shown in FIG. 2.

Example 2

2g of 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] sodium propionate and 8mL of 80% (v/v) ethanol water mixed solution are mixed, heated, refluxed and dissolved, and then kept stand for 2 hours after being kept stand and cooled to 25 ℃, and the solid obtained by centrifugation is the crystal form B, and the purity of the crystal form B is 99.96%. The XRPD pattern is shown in FIG. 7.

Example 3

Mixing 4g of sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate and 5mL of 40% (v/v) ethanol water mixed solution, heating, refluxing and dissolving, cooling to 25 ℃ under the stirring condition of 300 revolutions per minute, stirring for 2 hours under the stirring condition of 300 revolutions per minute, and centrifuging to obtain a solid, namely a polycrystalline mixture, wherein the purity of the polycrystalline mixture is 99.97%. The XRPD pattern is shown in FIG. 12.

Example 4

2g of sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate and 35mL of methanol are mixed, stirred and dissolved under a heating reflux state, the solution is clarified and filtered when the solution is hot, the obtained filtrate is rapidly subjected to solvent removal by using a rotary evaporator, and the obtained solid is an amorphous substance with the purity of 99.95%. The XRPD pattern is shown in FIG. 17.

Example 5

Mixing 2g of sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate and 35mL of tetrahydrofuran, stirring and dissolving under a heating reflux state, standing for clarification of the solution, carrying out suction filtration while the solution is hot, and quickly removing the solvent from the obtained filtrate by using a rotary evaporator to obtain a solid, namely the amorphous substance. The XRPD pattern is shown in FIG. 17.

Example 6

Mixing 2g of 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] sodium propionate and 35mL of 50% (volume percentage) methanol tetrahydrofuran mixed solution, stirring and dissolving under a heating reflux state, filtering when the solution is clear and hot, and quickly removing the solvent from the obtained filtrate by using a rotary evaporator to obtain a solid, namely the amorphous substance. The XRPD pattern is shown in FIG. 17.

Example 7

2g of sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate polycrystalline mixture and 10mL of ethanol are mixed, stirred and washed for 12 hours at room temperature under the stirring condition of 300 revolutions per minute, and the solid obtained by centrifugation is the crystal form A. The XRPD pattern is shown in FIG. 2.

Example 8

The solubilities of 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid obtained in preparation 1 and sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoate obtained in preparation 2 were measured, and the results are shown in table 1 below.

TABLE 1

Noun terms regarding solubility expression (general rules in the four parts of the chinese pharmacopoeia 2015 year edition):

very easy dissolution: means that solute lg (mL) can be dissolved in less than 1mL of solvent;

easy dissolution: means that solute lg (mL) can be dissolved in solvent

Dissolving;

dissolving: means that solute lg (mL) can be dissolved in solvent

Dissolving;

slightly dissolving: means that solute lg (mL) can be dissolved in solvent

Dissolving;

slightly soluble: means that solute lg (mL) can be dissolved in solvent

Dissolving;

and (3) minimal dissolution: means that solute lg (mL) can be dissolved in solvent

Dissolving;

weighing the test sample ground into fine powder, placing the test sample in a solvent with a certain volume at the temperature of 25 +/-2 ℃, and strongly shaking for 30 seconds every 5 minutes; dissolution was observed within 30 minutes, as no visible solute particles or droplets were present, i.e., complete dissolution was observed.

From table 1 above, it can be seen that: the solubility of the sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate in water is obviously better than that of the sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate, and the dissolution rate of the sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate serving as a preparation is better, so that the sodium 2-methyl-2- [ [1- (4-cyano.

Example 9

The influence factors of the crystal form A, the crystal form B, the polycrystalline mixture and the amorphous substance are researched, the influence of temperature (40 ℃, 60 ℃), humidity (75% RH, 92.5% RH), illumination (45001x +/-5001 x) and composite conditions (60 +/-75% RH) on the purity and stability of the crystal forms is examined, and the results are shown in the following table 2:

TABLE 2

From the above table, it can be seen that: form a, form B, polymorphic mixtures and amorphous forms have good stability.

Example 10

Hygroscopicity studies were performed on form a, form B, the polymorphic mixture and the amorphous form, examining the weight gain for 24h at 80% RH, with the results as in table 3 below:

TABLE 3

Crystal form	Weight gain at 80% RH for 24h
		Crystal form A	0.14％
Crystal form B	15.85％
		Polymorphic mixtures	21.57％
Amorphous formArticle (A)	22.32％

Description of hygroscopicity characteristics and definition of hygroscopicity increase (guidelines for hygroscopicity of drugs 9103 in the four-part general rules of pharmacopoeia 2015, experimental conditions: 25 ℃ ± 1 ℃, 80% relative humidity):

deliquescence: absorb sufficient water to form liquid

Has the characteristics of moisture absorption: the moisture-drawing weight gain is not less than 15 percent

Moisture absorption: the moisture-drawing 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

Taking a dry glass weighing bottle with a plug, placing the glass weighing bottle in a constant temperature drier with the temperature of 25 +/-1 ℃ on one day before an experiment (placing a saturated ammonium chloride solution at the lower part) for precisely weighing the weight W1, taking about 500mg of a sample to be tested, flatly paving the sample in the weighing bottle, precisely weighing the weight W2, opening the weighing bottle, placing the weighing bottle and a bottle cap under the conditions of constant temperature and constant humidity for 24 hours, covering the bottle cap of the weighing bottle, and precisely weighing the weight W3.

Weight gain percentage calculation formula: percent weight gain (W3-W2)/(W2-W1). times.100%

From table 3 above, it can be seen that: form a is characterized by no or little hygroscopicity, based on defined criteria for hygroscopicity increase. The crystal form B and the polymorphic mixture have better hygroscopicity performance. The amorphous substance has hygroscopicity, so that the crystal form A, the crystal form B and the polycrystalline mixture are more suitable for further development into pharmaceutical preparations compared with the amorphous substance.

Example 11

The stability of the crystal form A is studied, after the crystal form A is packaged (the packaging material is a low-density Polyethylene (PE) medicinal bag, and the outer sleeve is an aluminum foil bag), the influence of acceleration conditions (40 ℃/75% RH) and long-term conditions (25 ℃/60% RH) on the crystal form is examined, and the results are shown in the following table 4:

TABLE 4

Conditions of standing	Time of standing	Traits	Crystal form	Moisture content
					Untreated	0 month	White powder	Crystal form A	0.28％
Acceleration conditions
		6 month	White powder	Crystal form A	0.41％
Long term conditions						12 month	White powder	Crystal form A	0.48％

From table 4 above, it can be seen that: form A remains unchanged under accelerated conditions (40 ℃/75% RH) and prolonged conditions (25 ℃/60% RH) for 6 months and 12 months respectively. The experimental results show that the crystal form A has good stability under the encapsulation condition.

In conclusion, the crystal form A, the crystal form B and the polycrystalline mixture have good prospects in drug forming property, and can be used as effective components of drugs for treating gout or hyperuricemia.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

A process for the preparation of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate in crystalline form a, comprising:

(a) dissolving sodium 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate in an ethanol-water mixed solvent, and stirring for crystallization under the condition shown as a region I in a figure 1 to obtain a crystal form A; the condition shown in the I area is temperature condition and/or percentage condition of ethanol water solution;

or (b) stirring the polymorphic mixture of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate in a solvent to obtain crystal form a;

the crystal form A has characteristic peaks at 8.9 +/-0.2 degrees, 11.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.8 +/-0.2 degrees and 23.2 +/-0.2 degrees by X-ray powder diffraction represented by a 2 theta angle by using Cu-Kalpha radiation;

the polymorphic mixture has characteristic peaks at 4.4 + -0.2 °, 11.2 + -0.2 °, 15.8 + -0.2 °, 16.5 + -0.2 °, 17.5 + -0.2 °, 18.7 + -0.2 °, 21.4 + -0.2 °, 22.0 + -0.2 ° and 23.1 + -0.2 ° by X-ray powder diffraction at 2 θ using Cu-Kalpha radiation;

the volume percentage of the ethanol water solution is 60-100%;

the stirring speed in the step (a) or (b) is the same or different and is 300-800 rpm independently;

in step (b), the solvent is selected from ethanol.
2. The preparation method according to claim 1, wherein the form a has an X-ray powder diffraction peak at 2 Θ angles of 5.4 ± 0.2 °, 8.9 ± 0.2 °, 9.5 ± 0.2 °, 11.3 ± 0.2 °, 15.3 ± 0.2 °, 16.0 ± 0.2 °, 16.2 ± 0.2 °, 17.5 ± 0.2 °, 18.8 ± 0.2 °, 19.6 ± 0.2 °, 21.5 ± 0.2 °, 21.8 ± 0.2 °, 22.2 ± 0.2 °, 23.2 ± 0.2 °, 24.2 ± 0.2 °, 24.7 ± 0.2 °, 25.2 ± 0.2 °, 26.5 ± 0.2 °, 27.2 ± 0.2 °, 28.5 ± 0.2 °, 29.4 ± 0.2 °, 30.8 ± 0.2 °, 32.2 ± 0.2 ° and 32.2 ± 0.2 ° using Cu-ka radiation.
3. The preparation method of claim 1, wherein the form a has an X-ray powder diffraction pattern substantially as shown in figure 2.
4. The preparation method according to claim 1, wherein the differential scanning calorimetry analysis of form A has a characteristic endothermic peak at 280 ± 2 ℃.
5. The preparation method according to claim 1, wherein the form a has a DSC profile substantially as shown in figure 3.
6. The preparation method of claim 1, wherein the form a has a thermogravimetric analysis profile substantially as shown in figure 4.
7. The method of claim 1, wherein step (a) is performed by: mixing 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] sodium propionate with a solvent, heating for dissolving, cooling, stirring, and precipitating crystals to obtain a crystal form A;

adjusting the condition of stirring crystallization in the step (a) according to the temperature in the area I in the figure 1 and the volume percentage of the ethanol water solution;

in the step (a), the crystallization is performed at a boiling point of the solvent ethanol aqueous solution or lower.
8. The preparation method according to claim 1, wherein in step (a) or (b), the mass-to-volume ratio of sodium 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propionate to solvent is 1g (1-10) mL.