WO2011115069A1

WO2011115069A1 - Exhaustive searching for crystals

Info

Publication number: WO2011115069A1
Application number: PCT/JP2011/055958
Authority: WO
Inventors: 克弘小林; 宏之山脇
Original assignee: 第一三共株式会社
Priority date: 2010-03-19
Filing date: 2011-03-14
Publication date: 2011-09-22

Abstract

Disclosed is a method for preparing the various salts of a target compound, the co-crystal of the salts, the solvate of the salts and the co-crystal, and/or the crystal form of the salts, the co-crystal and the solvate, which involves: a step (1) for preparing an amorphous of a free form or the salt thereof, or a low-crystallinity solid of the free form, the salt thereof, the co-crystal of the free form and the salt, or the solvate of the free form, the salt and the co-crystal; a step (2) for exposing said amorphous or said low-crystallinity solid to a solvent vapor; a step (3) for analyzing the crystal form of the compound obtained in step (2); and a step (4) for repeating steps (1) to (3) for no less than one time by varying the solvent vapor exposure conditions.

Description

Comprehensive search for crystals

The present invention provides a method for easily and comprehensively preparing various salts of target compounds, their co-crystals, their solvates and their crystal forms, and the resulting salts, their co-crystals, their solvents The present invention relates to a method for selecting a desired form from hydrates and their crystal forms.

In order to rapidly develop good pharmaceuticals, it is required to use salts and / or crystals with good solubility and stability as the drug substance form. The drug substance forms that the drug can take include salts and solvates in addition to the free form, and furthermore, there are crystal polymorphs for each of these. Since the properties of a compound vary greatly depending on the state of the salt, solvation, and crystal polymorphism, selection of a preferred form of the compound is a very important matter particularly in the pharmaceutical field.

Examples of methods that can be used to obtain new salts of the target compounds and their co-crystals, their solvates, and / or their crystal forms include slurry methods, concentration methods, poor solvent addition methods, vapor diffusion methods, and cooling methods. And neutralization crystallization methods are known (for example, Non-Patent Documents 1 to 4).

The method of crystallizing a compound after dissolving it in a solution, such as a slurry method or recrystallization, is not suitable for large-scale screening because it requires information on the solubility of the target compound in advance or requires a large amount of specimen. It is. As a method for screening a salt or crystal of a compound using a small amount of specimen, high-throughput screening using a 96-well plate or the like using recrystallization, slurry purification, evaporation method, etc. has been developed (for example, non- According to Patent Document 2), recrystallization at a small scale, slurry purification, evaporation method and the like are difficult to adjust crystallization conditions, and anyone cannot easily perform crystallization screening with high reproducibility and high probability.

As for solvent vapor exposure, crystals are formed by exposing an amorphous lactose or erythromycin to solvent vapor (Non-patent Document 5), or by exposing co-crystals to various solvent vapors. (Non-Patent Document 6) is known.

In drug development, when candidate compounds are obtained, it is important to quickly investigate as many salts, co-crystals, solvates and crystal forms as possible, and to select the appropriate one as the drug substance form. It is. However, until now, the salts of compounds, their co-crystals, their solvates and their crystal forms have been prepared quickly and easily by anyone with high crystallization probability, and the desired There is no screening method available to select one, and within a limited number of salts, their co-crystals, their solvates or their crystal forms obtained under limited crystallization conditions. There was no choice but to select the form to develop from.

The present invention relates to the following.
[1] A method for preparing various salts of a target compound, their co-crystals, their solvates and / or their crystal forms, comprising:
(1) A step of producing an amorphous free body or a salt thereof, or a low crystalline solid of a free body, a salt thereof, a co-crystal or a solvate thereof;
(2) exposing the amorphous or the low crystalline solid to solvent vapor;
(3) analyzing the crystal form of the compound obtained in the step (2); and (4) changing the conditions of the solvent vapor exposure and repeating the steps (1) to (3) one or more times. ,Method;
[2] The method for producing the amorphous or low crystalline solid is [1], wherein the free form, a salt thereof, a co-crystal thereof or a solvate thereof is pulverized, cooled by cooling, freeze-dried or spray-dried. Described method;
[3] The method according to [2], wherein the method for producing the amorphous or low crystalline solid is lyophilization of the free form, a salt thereof, a co-crystal thereof or a solvate thereof;
[4] Water, 1,4-dioxane, dimethyl sulfoxide, hydrous 1,4-dioxane, dimethyl sulfoxide / 1,4-dioxane mixed solvent or the free form, its salt, co-crystal or solvate thereof The method according to [3], which is dissolved in water / dimethyl sulfoxide / 1,4-dioxane and then lyophilized to produce an amorphous or low crystalline solid;
[5] The method according to [4], wherein the steps (1) to (3) are repeated at least 10 times in the step (4);
[6] The method according to [5], including (1-1) a step of chlorinating or co-crystallizing the target compound before the step (1);
[7] A salt of the target compound, a co-crystal, a solvate thereof, and / or a crystal form thereof obtained by the method according to any one of [1] to [6];
[8] A method for preparing various salts of the target compound, their co-crystals, their solvates and / or their crystal forms, comprising:
(1a) producing an amorphous free body or a salt thereof, or a low crystalline solid of a free body, a salt thereof, a co-crystal thereof or a solvate thereof in the first container;
(2a) placing the first container in a second container and exposing the amorphous or low crystalline solid to solvent vapor;
(3a) analyzing the crystal form of the compound obtained in step (2a);
(4a) A method comprising the step of repeating the steps (1a) to (3a) one or more times while changing the conditions of solvent vapor exposure;
[9] The method for producing the amorphous or low crystalline solid is [8], wherein the free form, a salt thereof, a co-crystal thereof, or a solvate thereof is pulverized, melt-cooled, freeze-dried or spray-dried. Described method;
[10] The method according to [9], wherein the method for producing the amorphous or low crystalline solid is lyophilization of the free form, a salt thereof, a co-crystal thereof, or a solvate thereof;
[11] Water, 1,4-dioxane, dimethyl sulfoxide, hydrous 1,4-dioxane, dimethyl sulfoxide / 1,4-dioxane mixed solvent or water in a free form, a salt thereof, a co-crystal or a solvate thereof The method according to [10], wherein the method is dissolved in / dimethylsulfoxide / 1,4-dioxane and then lyophilized in a first container to produce an amorphous or low crystalline solid;
[12] The method according to [11], wherein the steps (1) to (3) are repeated at least 10 times in the step (4);
[13] The method according to [12], which comprises the step of (1a-1) chlorination or cocrystallization of the target compound before the step (1a);
[14] A salt of the target compound, a co-crystal, a solvate thereof, and / or a crystal form thereof obtained by the method according to any one of [8] to [13].

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, a drug substance form can be quickly and easily examined by anyone easily and comprehensively with a high crystallization probability.

The powder X-ray diffraction pattern of the sample collect | recovered in Example 1 is shown (solvent exposure time: 1 day). The powder X-ray diffraction pattern of the sample collect | recovered in Example 1 is shown (solvent exposure time: 1 week). The representative powder X-ray diffraction pattern of the sample collected in Example 2 is shown. The representative powder X-ray diffraction pattern of the sample collected in Example 3 is shown. The representative powder X-ray diffraction pattern of the sample collected in Example 3 is shown. The representative powder X-ray diffraction pattern of the sample collected in Example 4 is shown. The representative powder X-ray diffraction pattern of the sample collected in Example 4 is shown. The representative powder X-ray diffraction pattern of the sample collected in Example 5 is shown. The representative powder X-ray diffraction pattern of the sample collected in Example 5 is shown. The representative powder X-ray diffraction pattern of the sample collected in Example 5 is shown. The representative powder X-ray diffraction pattern of the sample collected in Example 5 is shown.

The present invention relates to a method for preparing various salts of the target compound, their co-crystals, their solvates and / or their crystalline forms, comprising the following steps:
(1) A step of producing an amorphous free body or a salt thereof, or a low crystalline solid of a free body, a salt thereof, a co-crystal or a solvate thereof;
(2) exposing the amorphous or the low crystalline solid to solvent vapor;
(3) a step of analyzing the crystal form of the compound obtained in the step (2); and (4) a step of repeating the steps (1) to (3) one or more times while changing the conditions of the solvent vapor exposure.

The present invention also relates to a method of making various salts of the target compound, their co-crystals, their solvates and / or their crystalline forms, comprising the following steps:
(1a) producing a low crystalline solid of a free form or a salt thereof, or a free form, a salt thereof, a co-crystal thereof or a solvate thereof in the first container;
(2a) placing the first container in a second container and exposing the amorphous or low crystalline solid to solvent vapor;
(3a) analyzing the crystal form of the compound obtained in step (2a);
(4a) A step of repeating the steps (1a) to (3a) one or more times while changing the conditions of solvent vapor exposure.

In the present specification, the “target compound” means an organic compound to be investigated for a salt, a solvate, a co-crystal or a crystal form. In the present specification, unless otherwise specified, the “target compound” refers to a compound in a free form that is neither a salt form nor a solvate form, or a guest ( guest) A host compound that is looking for a compound.

In this specification, the “crystal polymorph” or “polymorph” means that the same compound in the chlorination state or the solvation state has two or more different crystal structures, or each such crystal. Say. Further, in this specification, “crystal polymorph” or “polymorph” used for a co-crystal means a co-crystal having the same host compound-guest compound combination and the same chlorination state and solvation state. It has two or more different crystal structures, or each such crystal. Since polymorphs have different crystal structures, they may show different peak characteristics in X-ray crystal analysis and infrared spectroscopy, draw different TG / DTA curves, and have different melting points and moisture absorption / desorption behavior. Are known.

In this specification, the “crystal form” means that the free form or the portion of the host compound is a crystal of two common compounds, even if the chlorinated state or the solvated state, or the combination of the host compound and the guest compound is different. That means. In the present specification, “crystal polymorph” and “polymorph” are included in the range of “crystal form”. For example, in the present specification, a certain free form compound X shows two kinds of crystal polymorphs as a free form, two kinds of crystal polymorphs as a sodium salt anhydrate, and two kinds as a sodium salt pentahydrate. When two crystal polymorphs are shown as a co-crystal with a certain guest compound, these eight types of crystal polymorphs are referred to as crystal forms, respectively or collectively.

As used herein, “co-crystal” refers to a crystal formed from a plurality of compounds, generally two compounds. Looking at the “co-crystal” at the molecular level, the molecules of the two types of compounds have a crystal structure with a regular arrangement. This “co-crystal” is known to have a different crystal structure from the crystals formed by each of the two types of compounds that form the co-crystal, and thus may exhibit different physiochemical properties. ing.

In this specification, “amorphous” is also referred to as amorphous, and refers to an amorphous solid having no regular three-dimensional crystal structure. Whether or not the target compound is amorphous is, for example, when the compound is subjected to powder X-ray diffraction analysis, a specific peak does not exist and a broad powder X-ray diffraction profile (halo) is generated. It is confirmed to be amorphous.

In the present specification, “low crystalline solid” means a metastable crystal having a low powder X-ray diffraction peak, which does not show a broader powder X-ray diffraction profile as amorphous, but has a low powder X-ray diffraction peak. To do.

In this specification, “amorphous” and “low crystalline solid” may be collectively referred to as amorphous or the like.

In the present specification, “salt, co-crystal, solvate and / or crystal form thereof” of “target compound” means free salt, free solvate, free form of target compound. Solvates of free-form salts, free-form crystal forms, free-form salt crystal forms, free-form solvate crystal forms, free-form salt solvate crystal forms, free-form co-crystal partners (Guest compound), Free-form salt co-crystal partner (Guest compound), Free-form co-crystal solvate, Free-form salt co-crystal solvate, Free-form co-crystal crystal form, Free Producing a form selected from the group consisting of a crystalline form of a co-crystal of a free-form salt, a crystalline form of a solvate of a free-form co-crystal, and a crystalline form of a solvate of a free-form salt co-crystal means.

Hereinafter, each step of the present invention will be described in detail.

(Process 1)
Amorphous and the like are appropriately selected in consideration of the thermal stability of a free form, a salt thereof, a co-crystal thereof, or a solvate thereof (hereinafter sometimes referred to as a free form). Can be done. The lower limit of the amount of free body used for the production of amorphous or the like is not particularly limited, but may be at least 0.1 mg or more per one solvent exposure condition, and preferably 1 mg or more and 3 mg per one solvent exposure condition. As long as it is 5 mg or more, 6 mg or more, 7 mg or more, 8 mg or more, 9 mg or more, or 10 mg or more. The upper limit of the amount of free body or the like is not particularly limited, and is determined depending on the amount of available free body or the like and the number of exposure conditions. Amorphous or the like may be produced for each solvent exposure condition, or a plurality of solvent exposure conditions may be produced together. As a method for preparing a plurality of solvent exposure conditions for a free body or the like, for example, 1 to 10 g of a free body or the like is dissolved in 2 to 2000 mL of solvent, and the number of solvent exposure conditions to be examined The sample dissolved in the container may be divided and then processed so that amorphous or the like is formed.

The method for producing amorphous or the like is not limited to these. For example, a method of pulverizing a free body or the like, a method of melting and cooling (sometimes referred to as a melting cooling method in this specification), and a method of freeze-drying. (Sometimes referred to as a freeze-drying method in the present specification) or a method of spraying and drying (sometimes referred to as a spray-drying method in the present specification). A drying method is mentioned, More preferably, a freeze-drying method is mentioned. A method for producing an amorphous compound is described in, for example, Ralph Hilfiker, Polymorphism, 2006, Willy-VCH Weinheim, p263-269. Moreover, what is necessary is just to use, when a free body etc. can be purchased as an amorphous etc.

For example, when a TG-DTA measurement of a free body or the like is performed and a weight reduction due to decomposition is observed immediately after melting, an amorphous or the like can be prepared by a freeze-drying method. When producing amorphous materials such as free bodies by freeze-drying, after free bodies are dissolved in a solvent, the solution is frozen in liquid nitrogen or a low-temperature chamber, and then the solvent is gradually increased under reduced pressure. It can be freeze-dried by removing.

In the lyophilization method, the solvent for dissolving the free form or the like is not particularly limited, and examples thereof include water, dioxane, dimethyl sulfoxide, methanol, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, trifluoroethanol, and the like. And preferably include water, dioxane, hydrous dioxane, dimethyl sulfoxide, dioxane / dimethyl sulfoxide mixed solvent, water / dioxane / dimethyl sulfoxide mixed solvent, methanol, acetonitrile, tetrahydrofuran, hydrous tetrahydrofuran Dimethylformamide, dimethylacetamide, chloroform, trifluoroethanol, more preferably water, 1,4-dioxa , Hydrous 1,4-dioxane, 1,4-dioxane / dimethyl sulfoxide mixed solvent include water / 1,4-dioxane / dimethyl sulfoxide mixed solvent. When the solvent is a water-containing solvent, the water content is appropriately selected according to the free form or the like or the solvent to be used, and is not particularly limited. For example, a water content in the range of 5% to 95% can be mentioned, preferably 5 %, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% water content. Here, the water content means the ratio of the volume of water to the total volume of the solvent. When the said solvent is a mixed solvent, the mixing ratio of each solvent can be suitably determined according to a free body etc. or the solvent to mix. The amount of the solvent is not particularly limited. For example, the solvent is 2 mL to 200 mL, preferably 10 mL to 100 mL with respect to 1 g of the free form.

The temperature at which the free form or the like is dissolved in the solvent is appropriately selected according to the free form or the like or the solvent used, and is not particularly limited, but is, for example, 5 ° C. to 60 ° C., preferably 15 ° C. to 40 ° C.

The temperature for lyophilization is appropriately selected according to the free form or the like or the solvent used, and is not particularly limited. For example, it is preferably −80 ° C. to 60 ° C., more preferably −60 to 40 ° C. The time until lyophilization is appropriately selected according to the free form, the solvent used, and the lyophilization temperature, and is not particularly limited. For example, it is preferably 12 hours to 1 week, more preferably 1 day to 3 days.

Alternatively, when a TG-DTA measurement of a free body or the like is performed and a weight reduction due to decomposition is not observed immediately after melting, an amorphous or the like can be created by a melting cooling method. Specifically, the melting and cooling method can obtain amorphous or the like by melting a free body or the like and then rapidly cooling it with liquid nitrogen or the like.

The metal container used in the melting and cooling method is not particularly limited, but is selected depending on the amount and properties of the free body. For example, an aluminum container for thermal analysis, a platinum container, an aluminum foil and the like can be mentioned, and an aluminum container for thermal analysis is preferable. The temperature for melting the free body or the like is selected in consideration of the stability of the free body or the like, and is, for example, from about the melting point to about 30 ° C. higher than the melting point, and preferably from the melting point to about 5 ° C. higher than the melting point. As a cooling method, liquid nitrogen, dry ice, or a freezer can be used, but liquid nitrogen is preferable. In order to handle amorphous at room temperature, it is necessary to return the cooled amorphous body or the like to room temperature. However, in order to suppress crystallization, the amorphous body is stored in a container with controlled humidity. For example, it is left in a container containing a desiccant such as silica gel or phosphorus pentoxide or in a thermo-hygrostat controlled at low humidity. Silica gel is preferable as the desiccant, and a constant temperature and humidity machine is also preferable. The standing time is not particularly limited, but is about 10 minutes to about 1 day, preferably about 30 minutes to about 2 hours.

The step of producing the amorphous body such as the free body is preferably performed in a first container (where the first container is sized to be accommodated in the second container) as described later.

<Prior to step (1), the free form may be chlorinated or co-crystallized. For example, when preparing a crystalline form of a free-form salt, if the material to be used is a salt, the salt may be subjected to the above-described amorphization or low-crystallization step. Alternatively, after adding a base to salify the free form, the above-described amorphization or low crystallization may be performed. In addition, for example, when a crystal form of a co-crystal is produced, if the material used is a co-crystal, the co-crystal may be subjected to the above-described low crystallization step. If the material used is a host compound, After adding a co-crystal partner, the above-described low crystallization may be performed.

In the screening of free-form salt, free-form co-crystal or free-form salt co-crystal, when adding an acid or base and / or a co-crystal partner, the timing of addition is before and after dissolving the target compound in the solvent. Any of these may be used, but it is preferable to add the target compound after dissolving it in a solvent. The amount of acid or base to be added is not particularly limited, but is determined with reference to the number of dissociable groups and the pKa value of the target compound. For example, the amount is 0.75 to 2.0 equivalents, preferably 0.9 to 1.1 equivalents, with respect to the target compound having one dissociating group.

(Process 2)
Step 2 relates to a step of exposing amorphous or the like to solvent vapor.

The solvent vapor exposure of the target compound such as amorphous is not limited to this method, but examples include the following method. First, a first container and a second container that is smaller than the first container and can be stored in the first container are prepared, an exposure solvent is put in the first container, and the amorphous or the like is put in the second container. Or place and leave each until exposure temperature conditions are reached. When each container is at an exposure temperature condition, the second container is placed in the first container without sealing. Here, when the said exposure solvent is a liquid, the said solvent liquid is not made to contact amorphous etc. In a state where the second container is in the first container, the first container is sealed with a lid, a parafilm, or the like of the first container, so that the amorphous material in the second container or on the second container Etc. are exposed to the vapor of solvent that was in the first container. After the amorphous or the like is exposed to the solvent at the target temperature and time, the first container is opened and the crystals in the second container or on the second container exposed to the solvent can be collected.

The type of the first container is not particularly limited as long as it can accommodate the second container, and can be appropriately selected according to the nature and amount of the target compound. The material of the first container is not particularly limited, and examples thereof include glass and metal containers, and can be appropriately selected according to the nature and amount of the target compound. Examples of the first container include a beaker, a vial bottle, a glass bottle, and a metal drum. The method for sealing the first container is not particularly limited, and a container with a lid may be used, or sealing may be performed by plugging with a parafilm or the like.

The type of the second container is not particularly limited as long as amorphous or the like can be disposed and can be stored in the first container, and can be appropriately selected according to the property and amount of the target compound. . The material of the first container is not particularly limited, and examples thereof include glass and metal containers, and can be appropriately selected according to the nature and amount of the target compound. Examples of the second container include a flask, a beaker, a test tube, a vial bottle, a glass bottle, a petri dish, or a plate.

The first container and the second container may be integrated or separable.

As the first container and the second container, for example, a commercially available square 96-well deep plate, an aluminum container for thermal analysis having the same size as the diameter of the well, and an aluminum container slightly smaller than the diameter of the well are combined. Can also be exposed to steam. For example, as described in the Examples, when an organic solvent is placed in a square 96-well deep plate and a thermal analysis aluminum container having the same size as the diameter of the well is placed in the well, the aluminum container is placed in the middle of the well. stay. By placing a thermal analysis aluminum container slightly smaller than the diameter of the well containing amorphous or the like on the aluminum container and plugging it with a parafilm or a plate lid, the amorphous or the like can be exposed to the solvent vapor.

Examples of the solvent exposed to vapor include anisole, acetone, 2-butanone, toluene, benzene, phenol, naphthalene, acetonitrile, dimethoxyethane, dimethoxymethane, chloroform, acetic acid, ethyl acetate, dioxane, dimethyl sulfoxide, tetrahydrofuran, 1-propanol. 2-propanol, ethanol, methanol or water, or a mixed solvent thereof, preferably acetone, toluene, benzene, phenol, naphthalene, acetonitrile, 2-dimethoxyethane, chloroform, acetic acid, ethyl acetate, 1,4- Examples thereof include dioxane, dimethyl sulfoxide, tetrahydrofuran, 1-propanol, 2-propanol, ethanol, methanol or water, or a mixed solvent thereof. More preferably, the solvent exposed to vapor includes benzene, phenol, naphthalene, acetic acid, 1,4-dioxane, dimethyl sulfoxide, or a mixed solvent thereof. The solvent to be exposed to vapor is not limited to a solvent that is liquid at the exposure temperature, and may be a solid as long as it has a vapor pressure. In Step 3, these polymorphs can be obtained by exposing a target compound, a salt thereof, an amorphous form of a co-crystal or the like to a vapor of these solvents. When screening for a solvate of a target compound or a polymorph thereof, a mixed solvent is prepared with these solvent and the target solvated solvent, and amorphous or the like may be exposed to vapor using the mixed solvent. Therefore, the vapor exposure solvent in step 3 may be a mixed solvent of a solvent for screening polymorphs and a solvating solvent, and may be arbitrarily selected according to the purpose.

The temperature at the time of solvent vapor exposure can be appropriately selected depending on the solvent to be exposed, and is not particularly limited, but is, for example, −20 ° C. to 80 ° C., preferably 5 ° C. to 60 ° C.

It can be appropriately selected depending on the exposure time to the solvent vapor, the exposure solvent and the exposure temperature, and is not particularly limited. For example, it is 15 minutes to 1 week, preferably 1 to 3 days.

The preferred temperature and time of the solvent vapor exposure are 5 ° C. to 60 ° C. for 1 day to 4 days, preferably 5 ° C. to 40 ° C. for 2 days to 3 days.

The amount of the solvent put into the first container is not particularly limited, but is usually an amount from the amount covering the entire bottom of the first container to about 1 cm below the edge of the second container, preferably the first container The amount from about 1 cm from the bottom of the container to about 1 cm below the edge of the container. If the exposed solvent remains in the first container after the solvent is exposed to amorphous or the like, the solvent can be used for exposure of another amorphous or the like.

(Process 3)
The target compound subjected to solvent exposure is then subjected to a crystal form analysis step.

The analysis includes various devices useful for crystal analysis, such as a powder X-ray diffractometer well known to those skilled in the art of crystal chemistry, such as an infrared spectrometer, a thermal analyzer (TG / TDA), and water vapor adsorption. An analysis using a measuring device can be mentioned. These analyzes are described, for example, in Ralph Hilfiker, Polymorphism, 2006, Willy-VCH Weinheim, p43-207, edited by Stephen Byrn, et al., Solid-state Chemistry of Drug, 1999, SS45. Yes.

(Process 4)
Step 4 relates to a step of repeating the steps (1) to (3) one or more times using conditions different from the previously used conditions of chlorination, cocrystallization or solvent vapor exposure for the target compound. By repeating steps (1) to (3) using a plurality of exposed solvents, another type of crystal form of the target compound can be found, or different crystallization conditions can be used for the same crystal form. Can be found.

Since the method of the present invention uses few samples for one solvent exposure condition and is easy to operate, steps (1) to (3) can be repeated multiple times. In the step (4), the number of times the steps (1) to (3) are repeated is preferably 10 times or more, 20 times or more, 30 times or more, 40 times or more, 50 times or more, or 100 times or more, preferably 30 times or more, 40 times More than once, 50 times or more or 100 times or more are more preferable. It is preferable that the steps (1) to (3) are repeated more frequently because the salt, crystal form, etc. of the target compound can be examined more comprehensively, and the choices for selecting the desired drug substance form are expanded.

Using the results obtained in this way, using the results of a plurality of solvent exposures obtained for the target compound, the profile of the salt of the target compound, their co-crystals, their solvates or their crystal forms (Sometimes referred to herein as a compound profile), and using the compound profile, the preferred salt of the target compound, their co-crystals, their solvates and / or their crystal forms You can choose. Therefore, another aspect of the present invention provides a step of creating a profile of the target compound using the result of step (3) and the results obtained by repeating steps (1) to (3) one or more times, and Selecting a preferred salt of the target compound, their co-crystal, their solvate and / or their crystal form using a profile, preferred salt of the target compound, their co-crystal, their solvation The invention relates to a method for selecting products and / or their crystal forms.

The method of the present invention can easily perform a large number of crystallization conditions for a desired compound with a small amount of sample without using complicated operations. This facilitates the creation of profiles relating to the salt, co-crystal, solvate and crystal form of the target compound. An exhaustive search of the present invention enables the creation of a more detailed compound profile of the target compound. By using the detailed compound profile obtained by the method of the present invention, it is possible to select a preferable crystal form without further analyzing each crystal form by elemental analysis or the like.

In the method of the present invention, the salt, co-crystal, solvate and crystal form of the target compound can all be screened at the same time, or desired items can be screened according to the purpose. For example, one compound can be screened for salt forms and crystal forms of those salt forms (see, eg, Example 3 or Example 4), and another compound can be co-crystal form. And their co-crystal forms can also be screened (see, eg, Example 5).

Examples are described below, but the present invention is not limited thereto.

(Crystal search for indomethacin)
Indomethacin (about 5 mg, about 13.9 μmol) was weighed into a sample pan made of aluminum for thermal analysis measurement (smaller than a sample pan used later as a pedestal). The sample pan was placed on a hot plate previously heated to 200 ° C. to completely melt the indomethacin solid. The sample pan was then cooled with liquid nitrogen for about 20 seconds. The sample pan was transferred to a container containing silica gel and left for about 1 hour. By repeating this operation, a total of 36 melt-cooled specimens were prepared.

1 mL of each solvent shown in Table 1 was placed in a 96-well square deep plate. Subsequently, an aluminum sample pan for thermal analysis having a diameter approximately the same as the width of the well was placed in each well. This sample pan is held near the middle of the well without entering the bottom of the well. The sample pan containing the molten and cooled specimen was placed in a sample pan held near the middle of each well, and then sealed with a lid of a silicon rubber well plate. After leaving at room temperature for 1 day or 1 week, the sample pan containing the specimen was taken out and dried at room temperature. Powder X-ray diffraction was measured in order to identify the crystal form of the obtained specimen.

The powder X-ray diffraction (CuKα, λ = 1.54 angstrom) pattern of the collected sample is shown in FIGS. 1A and 1B.

Table 1 shows the results of indomethacin crystal search created from the powder X-ray diffraction results.

The alphabetical notation from a to d in Table 1 indicates the pattern of the powder X-ray diffraction profile, and the same alphabetical notation indicates that the powder X-ray diffraction profiles are similar to each other. * Indicates that the solid was amorphous. The parentheses indicate that although the crystal form was identified, the powder X-ray diffraction peak was weak and the crystallinity was low.

(Cholic acid crystal search)
Cholic acid crystal polymorphism screening was performed under 96 solvents and 3 temperature conditions.

Cholic acid (1.20 g, 0.561 mmol) was dissolved in 30 mL of a 1,4-dioxane / dimethylsulfoxide (volume ratio: 5/1) mixed solution, and 100 μL was dispensed into 288 HPLC vials. These vials were placed in a lyophilizer, and the dispensed solution was lyophilized while changing the shelf temperature from −45 ° C. to 40 ° C.

1 mL of each solvent described in Table B was put into a glass bottle, and then an HPLC vial containing a freeze-dried sample was put into the glass bottle. The glass bottle containing the HPLC vial was placed in a thermostat set at 5 ° C., 25 ° C., and 40 ° C. and left for 2 days. Thereafter, the HPLC vial was taken out from the glass bottle, and the specimen was dried at the same temperature. Powder X-ray diffraction was measured to identify the crystal form of each specimen obtained.

Of the collected sample X-ray powder diffraction (CuKα, λ = 1.54 Å), a typical diffraction pattern is shown in FIG.

Table 2 shows the results of crystal search for cholic acid prepared from the results of powder X-ray diffraction.

The alphabetical notation from A to L in Table 2 indicates the pattern of the powder X-ray diffraction profile, and the same alphabetical notation indicates that the powder X-ray diffraction profiles are similar to each other. In Table 2, Low indicates that the solid was low crystalline, * indicates that the solid was amorphous, and Can indicates that the specimen was candy-like.

(Search for acid salt and crystal form of nicardipine)
For nicardipine, the following 47 types of acid salts were screened, and for free forms and each acid salt, the crystal form was screened using 17 types of solvents shown in Table 3 below.

47 types of acid salts: 1 hydrochloride, 1 hydrobromide, 1 nitrate, 1/2 sulfate, 1 sulfate, 1/2 phosphate, 1 phosphate, 1 methanesulfonate, 1 ethane Sulfonate, 1 benzene sulfonate, 1p-toluene sulfonate, 1 naphthalene-2-sulfonate, 1/2 fumarate, 1 fumarate, 1/2 maleate, 1 maleate, 1 / 2 tartrate, 1 tartrate, 1/2 citrate, 1 citrate, 1/2 L-malate, 1 L-malate, 1/2 α-ketoglutarate, 1α-ketoglutarate, 1 / 2 oxalate, 1 oxalate, 1/2 malonate, 1 malonate, 1/2 succinate, 1 succinate, 1/2 glutarate, 1 glutarate, 1/2 Adipate, 1 adipate, 1/2 camphorate, 1 camphorate, 1 acetate, 1 lactate 1 benzoate, 1 salicylate, 1 gentisate, 1 nicotinate, 1 isonicotiate, 1 hippurate, 1 cinnamic acid, 1 glycolate, 1 pyroglutamate, 4-hydroxybenzoic acid salt.

After adding ethyl acetate (16 mL), tetrahydrofuran (40 mL) and water (12.5 mL) to nicardipine hydrochloride (4.00 g, 7.75 mmol), an aqueous sodium hydroxide solution (11.57 mL, 11.63 mmol) was added. It was. After stirring the mixed solution for 5 minutes, the organic layer and the aqueous layer were separated using a separating funnel. The separated organic layer was washed with water (12.5 mL) and saturated brine (12.5 mL), and then an appropriate amount of anhydrous sodium sulfate was added. Thereafter, sodium sulfate was filtered, the filtrate was concentrated under reduced pressure, methanol (40 mL) was further added, and the mixture was concentrated under reduced pressure. The residue was cooled to −20 ° C. to precipitate a solid, 16 mL of a methanol / water (volume ratio: 25/75) mixture was added, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and dried under reduced pressure, 1,4-dioxane (100 mL) was added, and the solution concentration was measured by HPLC (30.77 mg / mL).

Next, 1988 μl each of this solution was dispensed into 49 glass sample tubes. Subsequently, the acid solution was added to each of the 48 sample tubes. The type and amount of acid solution are described below. Monohydrochloride (1.004 M aqueous solution, 127.2 μl), monohydrobromide (1.004 M aqueous solution, 127.6 μl), 1 nitrate (1.001 M aqueous solution, 127.6 μl), 1/2 sulfate ( 1.004 M aqueous solution, 63.6 μl), monosulfate (1.004 M aqueous solution, 127.2 μl), 1/2 phosphate (1.001 M aqueous solution, 63.8 μl), 1 phosphate (1.001 M aqueous solution) 127.6 μl), 1 methanesulfonate (1.001 M aqueous solution, 127.6 μl), 1 ethanesulfonate (1.00M aqueous solution, 127.6 μl), 1 benzenesulfonate (1,000 M aqueous solution, 127 1.6 μl), 1p-toluenesulfonate (1.021 M aqueous solution, 125.0 μl), 1 naphthalene-2-sulfonate (1,000 M aqueous solution, 127.6 μl), 1/2 fumarate (1.0 00M 1,4-dioxane / dimethylsulfoxide (1/1) solution, 63.8 μl), 1 fumarate (1,000 M１1,4-dioxane / dimethylsulfoxide (1/1) solution, 127.6 μl), 1 / 2 maleate (1,000 M aqueous solution, 63.8 μl), 1 maleate (1,000 M aqueous solution, 127.6 μl), 1/2 tartrate (1,000 M aqueous solution, 63.8 μl), 1 tartrate (1,000 M aqueous solution, 127.6 μl), 1/2 citrate (1,000 M aqueous solution, 63.8 μl), 1 citrate (1,000 M aqueous solution, 127.6 μl), 1/2 L-malate (1,000 M aqueous solution, 63.8 μl), 1 L-malate (1,000 M aqueous solution, 127.6 μl), 1 / 2α-ketoglutarate (1,000 M aqueous solution, 63.8 μl), 1α-ketoglutarate ( .000 M aqueous solution, 127.6 μl), 1/2 oxalate (1.001 M aqueous solution, 63.8 μl), 1 oxalate (1,000 M aqueous solution, 127.6 μl), 1/2 malonate (1. 000 M aqueous solution, 63.8 μl), 1 malonate (1,000 M aqueous solution, 127.6 μl), 1/2 succinate (0.5001 M aqueous solution, 127.6 μl), 1 succinate (0.5001 M aqueous solution, 255 μl), 1/2 glutarate (1,000 M 1,4-dioxane / dimethylsulfoxide (1/1) solution, 63.8 μl), 1 glutarate (1,000 M０００1,4-dioxane / dimethylsulfoxide ( 1/1) solution, 127.8 μl), 1/2 adipate (1,000 M１1,4-dioxane / dimethyl sulfoxide (1/1) solution, 63.8 μl), 1 adipate (1,000 M 1) , 4-Geo Sun / dimethyl sulfoxide (1/1) solution, 127.6 μl), 1/2 camphorate (1,000 M 1,4-dioxane / dimethylsulfoxide (1/1) solution, 63.8 μl), 1 camphorate (1,000 M 1,4-dioxane / dimethylsulfoxide (1/1) solution, 127.8 μl), 1 acetate (0.9909 M aqueous solution, 128.8 μl), 1 lactate (1,000 M aqueous solution, 127.6 μl) ), 1 benzoate (1,000 M 1,4-dioxane solution, 127.6 μl), 1 salicylate (1,000 M 1,4-dioxane solution, 127.6 μl), 1 gentisate (1,000 M 1) , 4-dioxane solution, 127.6 μl), 1 nicotinate (0.101 M aqueous solution, 1264 μl), 1 isonicotiate (0.040 M aqueous solution, 3191 μl), 1 hippurate (1.01 M aqueous solution 1,4- Geo Sun / dimethyl sulfoxide (1/1) solution, 127.6 μl), cinnamic acid (1.005 M 1,4-dioxane / dimethyl sulfoxide (1/1) solution, 127.0 μl), 1 glycolate (1. 000 M aqueous solution, 127.0 μl), 1 pyroglutamate (1.001 M aqueous solution, 127.6 μl), 4-hydroxybenzoate (1.005 M aqueous 1,4-dioxane / dimethylsulfoxide (1/1) solution, 127. 0 μl). The acid solution was not added to one sample tube, and it was used for the solvent vapor exposure process using 17 types of solvents as they were. When a precipitate was precipitated, water or dimethyl sulfoxide was added to make a solution. The mixed solution in the tube was stirred with a vortex mixer for about 10 minutes, and then dispensed so that each of 49 bottles had an equal volume in 18 HPLC vials. A total of 882 HPLC vials prepared in this manner were placed in a lyophilizer and lyophilized while changing the shelf temperature from −45 ° C. to 25 ° C.

1 mL of each solvent described in Table 3 was put into a glass bottle, and then an HPLC vial containing a freeze-dried specimen was put into the glass bottle and sealed. Glass bottles with HPLC vials were exposed to solvent vapor at 25 ° C. for 4 days. Thereafter, the HPLC vial was taken out and the specimen was dried at 25 ° C. When each specimen was obtained as a solid, powder X-ray diffraction was measured to identify the crystalline form.

The salt was obtained as a solid as monohydrochloride, hydrobromide, mononitrate, fumarate, and oxalate.

3A and 3B show typical powder X-ray diffraction (CuKα, λ = 1.54 angstrom) patterns of the collected samples.

Table 3 shows the results of searching for the salt and crystal form of nicardipine prepared from the results of powder X-ray diffraction.

表 In Table 3, the salt type and its crystal form are distinguished using the salt type abbreviations (HCl, HBr, HNO, Fum or Oxa) and alphabetical notation from A to D. When the salt type is the same, the same alphabetical letters at the end indicate that the powder X-ray diffraction profiles are homologous to each other. For example, monohydrobromide exposed to solvent vapor in dichloromethane or ethyl acetate are both labeled as HBr_A, indicating that both powder X-ray diffraction profiles were homologous. If the salt types are different, their powder X-ray diffraction profiles are not relevant even if the alphabetical suffix is the same. For example, HCl_B and HBr_B have the same alphabet at the end, but the types of salt differ between monohydrochloride and monohydrobromide, so the powder X-ray diffraction profiles do not correspond to each other.

Although the peak positions of the powder X-ray diffraction are slightly different from each other, those that are homologous as an overall profile are distinguished by numbers described after the alphabet. For example, for 1/2 oxalate and 1 oxalate, a total of 15 powder X-ray diffraction profiles were obtained in total, although each peak position of powder X-ray diffraction was slightly different from each other ( Oxa_A1 to Oxa_A15).

In Table 3, Low indicates that the solid was low crystalline, * indicates that the solid was amorphous, Candy indicates that the specimen was in a candy state, and parentheses indicate crystal Although the shape was identified, the powder X-ray diffraction peak was weak and the crystallinity was low.

(Search for alkali metal and alkaline earth metal salts of sulfasalazine and their crystal forms)
For sulfasalazine, lithium salt, sodium salt, potassium salt, 1/2 magnesium salt, 1/2 calcium salt, 1/2 zinc salt, and 1/3 aluminum salt were screened. The crystal form was screened using nine types of solvents shown in FIG.

Sulfasalazine (400 mg, 1 mmol) is dissolved in 10 mL of 1,4-dioxane / dimethyl sulfoxide (volume ratio: 50/50), and this solution is added to 1200 μl (equivalent to 48 mg, equivalent to 0.123 μmol) in 8 glass sample tubes. Each was dispensed. Nothing was added to one of these tubes, and it was directly subjected to the next freeze-drying step. In three sample tubes, 4M lithium hydroxide aqueous solution (30.8 μl, 0.123 μmol), 1.005 M sodium hydroxide aqueous solution (123 μl, 0.123 μmol), or 1.004 M potassium hydroxide aqueous solution (123 μl, 0.123 μmol) was added. To the remaining four sample tubes, 4M lithium hydroxide aqueous solution (30.8 μl, 0.123 μmol) was added, respectively, followed by 1.000 M magnesium chloride aqueous solution (62 μl, 0.062 μmol) and 1.001 M chloride, respectively. An aqueous calcium solution (62 μl, 0.062 μmol), 0.9998 M zinc bromide aqueous solution (62 μl, 0.062 μmol), or 1.002 M aluminum chloride aqueous solution (41 μl, 0.041 μmol) was added. When a precipitate was deposited, water or dimethyl sulfoxide was added to obtain a uniform solution. After stirring these 8 sample tubes with a vortex mixer for about 10 minutes, each sample tube was dispensed so as to have an equal volume in 10 HPLC vials. A total of 80 HPLC vials thus prepared were placed in a freeze dryer and freeze dried while changing the shelf temperature from −45 ° C. to 25 ° C.

1 mL of each solvent described in Table 4 was put into a glass bottle, and then an HPLC vial containing a freeze-dried sample was put into the glass bottle and sealed. The glass bottle containing the HPLC vial was exposed to solvent vapor at 40 ° C. for 1 day. Thereafter, the HPLC vial was taken out and the specimen was dried at 25 ° C. Powder X-ray diffraction was measured to identify the crystal form.

4A and 4B show typical powder X-ray diffraction (CuKα, λ = 1.54 angstrom) patterns of the collected samples.

Table 4 shows the results of searching for alkali metals and alkaline earth metal salts of sulfasalazine and their crystal forms prepared from the results of powder X-ray diffraction.

In Table 4, the salt type and its crystal form are distinguished by using the salt type abbreviations (Fr, Li, Na, K, HMg, HCa, HZn, or TAl) and the alphabetical notation from A to F. When the salt type is the same, the same alphabetical letters at the end indicate that the powder X-ray diffraction profiles are homologous to each other. For example, monolithium salts exposed to solvent vapor in acetonitrile or acetone are both labeled LiA, indicating that both powder X-ray diffraction profiles were homologous. If the salt types are different, their powder X-ray diffraction profiles are not relevant even if the alphabetical suffix is the same. For example, although LiA and HCaA have the same alphabet at the end, the powder X-ray diffraction profiles do not correspond to each other because the type of salt differs between 1 lithium salt and 1/2 calcium salt.

Although the peak positions of the powder X-ray diffraction are slightly different from each other, those that are homologous as an overall profile are distinguished by numbers described after the alphabet. For example, for the monosodium salt, two types of powder X-ray diffraction profiles that are totally homologous were obtained (NaA1 and NaA2) although the peak positions of the powder X-ray diffraction were slightly different from each other.

In Table 4, Low indicates that the solid was low crystalline, * indicates that the solid was amorphous, Candy indicates that the specimen was candy-like, and parentheses indicate crystal Although the shape was identified, the powder X-ray diffraction peak was weak and the crystallinity was low.

(Piroxicam co-crystal screening)
For piroxicam, 32 types of co-crystal partners shown in Table 5 below (including those without co-crystal partners) were screened, and each co-crystal partner (including those without co-crystal partners) was shown in Table 5. The crystal form was screened using six types of solvents.

Piroxicam (1000 mg, 3.018 mmol) was dissolved in a dioxane solution (60 mL), and this was dispensed in 1680 μl portions into 32 glass sample tubes. Further, 1 equivalent each of water of a co-crystal partner or a mixed solution of 1,4-dioxane / dimethyl sulfoxide (volume ratio 50:50) was added. When a precipitate was deposited, water or dimethyl sulfoxide was added to obtain a uniform solution. These 32 sample tubes were stirred with a vortex mixer for about 10 minutes, and each sample tube was then dispensed in 7 HPLC vials to an equal volume. A total of 224 HPLC vials prepared in this manner were placed in a freeze dryer, and freeze-dried while changing the shelf temperature from −45 ° C. to 25 ° C.

1 mL of each solvent described in Table 5 was put in a glass bottle, and then an HPLC vial containing a freeze-dried sample was put in the glass bottle and sealed. Glass bottles with HPLC vials were exposed to solvent vapor for 3 days at room temperature. Thereafter, the HPLC vial was taken out and the specimen was dried at room temperature. Powder X-ray diffraction was measured to identify the crystal form.

A representative powder X-ray diffraction (CuKα, λ = 1.54 Å) pattern of the collected sample is shown in FIGS. 5A to 5D.

Table 5 shows the co-crystals of piroxicam prepared from the results of powder X-ray diffraction and the results of searching for these crystal forms.

In Table 5, the co-crystal partners and their crystal forms are distinguished by using the abbreviations of the co-crystal partners (Fr to Pgt) and alphabetical notations from A to F. If the co-crystal partners are the same, those with the same alphabetical letter at the end indicate that they have powder X-ray diffraction profiles that are homologous to each other. For example, the co-crystals of piroxicam and oxalic acid exposed to solvent vapor in tetrahydrofuran or methanol are both labeled OxaA, indicating that both powder X-ray diffraction profiles were homologous. If the co-crystal partners are different, their powder X-ray diffraction profiles are not relevant even if the alphabetical suffix is the same. For example, FumA and MleA have the same alphabet at the end, but the powder X-ray diffraction profiles do not correspond to each other because the co-crystal partners are different between fumaric acid and maleic acid.

In Table 5, the parenthesis indicates that the crystal form was identified but the powder X-ray diffraction peak was weak and the crystallinity was low, and Low is the powder X-ray diffraction peak weak and crystalline. Of the sample could not be identified, * indicates that the solid was amorphous, and Candy indicates that the specimen was candy-like.

Claims

Process for preparing various salts of the target compound, their co-crystals, their solvates and / or their crystalline forms, comprising:
(1) A step of producing an amorphous free body or a salt thereof, or a low crystalline solid of a free body, a salt thereof, a co-crystal or a solvate thereof;
(2) exposing the amorphous or the low crystalline solid to solvent vapor;
(3) analyzing the crystal form of the compound obtained in the step (2); and (4) changing the conditions of the solvent vapor exposure and repeating the steps (1) to (3) one or more times. ,Method.
The method according to claim 1, wherein the method for producing the amorphous or low crystalline solid is grinding, melting cooling, freeze drying or spray drying of the free form, a salt thereof, a co-crystal thereof or a solvate thereof. .
The method according to claim 2, wherein the method for producing the amorphous or low crystalline solid is lyophilization of the free form, a salt thereof, a co-crystal thereof, or a solvate thereof.
The free form, a salt thereof, a co-crystal thereof or a solvate thereof is mixed with water, 1,4-dioxane, dimethyl sulfoxide, hydrous 1,4-dioxane, dimethyl sulfoxide / 1,4-dioxane mixed solvent or water / dimethyl. 4. The method of claim 3, wherein the method is dissolved in sulfoxide / 1,4-dioxane and then lyophilized to produce an amorphous or low crystalline solid.
The method according to claim 4, wherein the steps (1) to (3) are repeated at least 10 times in the step (4).
6. The method according to claim 5, further comprising (1-1) a step of chlorinating or co-crystallizing the target compound before the step (1).
A salt of a target compound, a co-crystal thereof, a solvate thereof and / or a crystal form thereof obtained by the method according to any one of claims 1 to 6.
Process for preparing various salts of the target compound, their co-crystals, their solvates and / or their crystalline forms, comprising:
(1a) producing a low crystalline solid of a free form or a salt thereof, or a free form, a salt thereof, a co-crystal thereof or a solvate thereof in the first container;
(2a) placing the first container in a second container and exposing the amorphous or low crystalline solid to solvent vapor;
(3a) analyzing the crystal form of the compound obtained in step (2a);
(4a) A method comprising a step of repeating the steps (1a) to (3a) one or more times by changing the conditions of solvent vapor exposure.
The method according to claim 8, wherein the method for producing the amorphous or low crystalline solid is grinding, melting cooling, freeze drying or spray drying of the free form, a salt thereof, a co-crystal thereof or a solvate thereof. .
The method according to claim 9, wherein the method for producing the amorphous or low crystalline solid is lyophilization of the free form, a salt thereof, a co-crystal thereof or a solvate thereof.
Free forms, salts thereof, co-crystals or solvates thereof are mixed with water, 1,4-dioxane, dimethyl sulfoxide, hydrous 1,4-dioxane, dimethyl sulfoxide / 1,4-dioxane mixed solvent, or water / dimethyl sulfoxide. 11. The method of claim 10, wherein the method is dissolved in / 1,4-dioxane and then lyophilized in a first container to produce an amorphous or low crystalline solid.
The method according to claim 11, wherein the steps (1) to (3) are repeated at least 10 times in the step (4).
The method according to claim 12, comprising the step of (1a-1) chlorination or cocrystallization of the target compound before the step (1a).
A salt of the target compound, a co-crystal, a solvate thereof and / or a crystal form thereof obtained by the method according to any one of claims 8 to 13.