JP2019156756A - Crystal of 1-amino-3,5-dimethyladamantane hydrochloride - Google Patents

Abstract

To provide a novel crystal of 1-amino-3,5-dimethyladamantane hydrochloride.SOLUTION: The crystal of 1-amino-3,5-dimethyladamantane hydrochloride having a crystal aspect ratio of 7.5 to 15 is provided.SELECTED DRAWING: None

Description

  The present invention relates to crystals of 1-amino-3,5-dimethyladamantane hydrochloride.

  1-Amino-3,5-dimethyladamantane hydrochloride (also called memantine hydrochloride) has NMDA (N-methyl-D-aspartate) receptor antagonistic activity and is useful for the treatment of Alzheimer's dementia. It is known (for example, refer to Patent Documents 1 and 2).

  Patent Document 1 discloses Form I and Form II as 1-amino-3,5-dimethyladamantane hydrochloride crystals. Form I crystals can be obtained by crystallization from isopropyl alcohol or methanol, and Form II crystals can be obtained by crystallization from water, 5% aqueous ethanol or acetone. The average aspect ratio of Form I crystals is 7.25, and the average aspect ratio of Form II crystals is 1.59. In addition, the average aspect ratio of the crystals of Form II hardly changes even after long-term storage.

International Publication No. 2005/069742 US Pat. No. 3,391,142 International Publication No. 2010/083996 International Publication No. 2006/077652 Russian Patent No. 2246482

Russian Journal of Organic Chemistry, 2015, Vol. 51, no. 12, 1703-1709.

  An object of the present invention is to provide new crystals of 1-amino-3,5-dimethyladamantane hydrochloride.

The present invention provides the following [1] to [14].
[1] Crystal of 1-amino-3,5-dimethyladamantane hydrochloride having a crystal aspect ratio of 7.5 to 15.
[2] In powder X-ray crystal diffraction, diffraction angles (2θ ± 0.2 °) have diffraction peaks at 12.4 °, 14.0 °, and 16.5 °, and diffraction angles (2θ ± 0.2 °) Crystals of 1-amino-3,5-dimethyladamantane hydrochloride having a diffraction intensity of 12.4 ° higher than the diffraction intensity of 2θ ± 0.2 ° 14.0 °.
[3] In powder X-ray crystal diffraction, the diffraction intensity (2θ ± 0.2 °) of 14.0 ° is lower than the diffraction intensity (2θ ± 0.2 °) of 16.5 °, [ 2].
[4] The crystal according to any one of [1] to [3], which has an endothermic peak at 330 to 400 ° C. in differential scanning calorimetry.
[5] The crystal according to any one of [1] to [4], wherein the content of the 1-amino-3,5-dimethyladamantane hydrochloride is 99.90% or more.
[6] The crystal according to any one of [1] to [5], wherein in the moisture adsorption / desorption measurement, the mass of the crystal changes so as to be directly proportional to the ambient humidity.
[7] A pharmaceutical composition comprising the crystal according to any one of [1] to [6].
[8] The pharmaceutical composition according to [7], further comprising a pharmaceutically acceptable medium.
[9] A method for producing the crystal according to any one of [1] to [6], comprising a step of crystallizing 1-amino-3,5-dimethyladamantane hydrochloride from hydrous acetone.
[10] The method according to [9], wherein the mass ratio of water to acetone in the hydrous acetone is 0.05: 1 to 0.5: 1.
[11] A powdery preparation containing the crystal according to any one of [1] to [6], wherein the bulk density is 0.15 g / mL or more and less than 0.40 g / mL.
[12] The powder formulation according to [11], wherein at least 75% of the powder formulation has a particle size of 200 μm or less.
[13] A pharmaceutical composition comprising the powdery preparation according to [11] or [12].
[14] The pharmaceutical composition according to [13], further comprising a pharmaceutically acceptable medium.

  The crystal of the present invention can be easily crushed and can be refined in a shorter time. The crystal of the present invention is also excellent in water solubility.

2 is a powder X-ray diffraction pattern of the crystal of Example 1. FIG. The horizontal axis indicates the diffraction angle 2θ (°), and the vertical axis indicates the intensity (cps). 2 is a graph showing the results of differential scanning calorimetry analysis of the crystal of Example 1. FIG. The horizontal axis represents temperature (° C.), and the vertical axis represents heat flow (mW). 2 is a powder X-ray diffraction pattern of the crystal of Reference Example 1. The horizontal axis indicates the diffraction angle 2θ (°), and the vertical axis indicates the intensity (cps). 6 is a graph showing the results of differential scanning calorimetry of the crystal of Reference Example 1. The horizontal axis represents temperature (° C.), and the vertical axis represents heat flow (mW). 4 is a graph showing the results of moisture adsorption / desorption measurement of the crystal of Example 1. The horizontal axis represents specific humidity P / P ₀ (%), and the vertical axis represents mass change (%) of crystals.

  Hereinafter, crystals of 1-amino-3,5-dimethyladamantane hydrochloride according to an embodiment of the present invention will be described in detail.

  The crystal according to this embodiment is a crystal of 1-amino-3,5-dimethyladamantane hydrochloride, and its crystal aspect ratio is 7.5 to 15.

1-amino-3,5-dimethyladamantane is a compound represented by the following chemical formula. The compound and its salt have NMDA (N-methyl-D-aspartic acid) receptor antagonistic action and are useful for the treatment of Alzheimer-type dementia.

  In this specification, “crystal aspect ratio” means the aspect ratio of individual crystals. The crystal aspect ratio is a value obtained by measuring the length in the major axis direction and the length in the minor axis direction of a certain crystal and dividing the length in the major axis direction by the length in the minor axis direction. The length of each axis of the crystal can be measured by methods well known to those skilled in the art. As a measuring method of the crystal, for example, it can be measured by a general image method such as an electron microscope.

  Preferred crystals have a crystal aspect ratio of 7.5-15. The crystal aspect ratio may be an average value of the aspect ratios of a plurality of crystals, for example.

  In the present invention, a crystal refers to a solid whose internal structure consists of a regular repetition of three-dimensional constituent atoms (or a group thereof), and is distinguished from an amorphous solid that does not have such a regular internal structure. The Whether or not a certain solid is a crystal can be confirmed by crystallographically well-known methods (for example, powder X-ray crystal analysis, differential scanning calorimetry, etc.). For example, if a clear peak is observed in an X-ray diffraction pattern obtained by irradiating a certain solid with characteristic X-rays (for example, copper Kα1 line), the solid is determined to be a crystal, If no clear peak is observed, the solid is determined to be an amorphous solid. If the peak can be read but the peak is not clear (for example, broad), the solid is determined to be a crystal with low crystallinity, and such a crystal with low crystallinity is also included in the present invention. Are included in the crystal.

  One side surface of the crystal according to the present embodiment has diffraction peaks at diffraction angles (2θ ± 0.2 °) of 12.4 °, 14.0 °, and 16.5 ° in powder X-ray crystal diffraction, 1-amino-3,5-dimethyladamantane hydrochloric acid having a diffraction angle (2θ ± 0.2 °) of 12.4 ° higher than that of 14.0 ° of diffraction angle (2θ ± 0.2 °) It is a salt crystal.

  In powder X-ray crystal diffraction, the X-ray intensity is usually measured when a sample solid is irradiated with Kα rays obtained by irradiating copper with an accelerated electron flow, and the relationship with the diffraction angle is determined as a pattern (also called an X-ray diffraction pattern) To say). Here, the Kα line includes a Kα1 line and a Kα2 line, and the Kα line means that the Kα1 line and the Kα2 line are not separated unless otherwise specified. The X-ray diffraction pattern may be obtained by analyzing the diffraction derived from both the Kα1 line and the Kα2 line, and only the diffraction derived from the Kα1 line from the diffraction derived from both the Kα1 line and the Kα2 line. It may be obtained by analysis after extraction. In the present invention, the powder X-ray diffraction pattern obtained by irradiation with Kα rays is an X-ray diffraction pattern obtained by analyzing diffraction derived from Kα rays, and X obtained by analyzing diffraction derived from Kα1 rays. An X-ray diffraction pattern that includes a line diffraction pattern and is preferably obtained by analyzing diffraction derived from the Kα1 line.

  In general, the diffraction angle (2θ) in powder X-ray diffraction can cause an error within a range of ± 0.2 °. Therefore, the value of the diffraction angle should be understood as including a numerical value within a range of about ± 0.2 °. That is, not only crystals whose peak diffraction angles in powder X-ray diffraction completely match, but also crystals whose peak diffraction angles match with an error of about ± 0.2 ° are included in the scope of the present invention. The resolution of the diffraction peak can vary depending on various conditions such as the crystal state and powder X-ray diffraction measurement conditions. However, the crystal can be identified by the ratio of the diffraction intensity, the diffraction angle, the pattern of a plurality of diffraction peaks, and the like.

  In the present specification, for example, the description “having a diffraction peak at a diffraction angle (2θ ± 0.2 °) of 12.4 °” means “diffracting at a diffraction angle (2θ) of 12.2 ° to 12.6 °. It should be understood in the same way for other diffraction angles.

Preferred crystals have diffraction peaks at diffraction angles (2θ ± 0.2 °) of 6.2 °, 12.4 °, 14.0 °, 16.5 °, and 18.7 ° in powder X-ray crystal diffraction. Have.
More preferred crystals are diffraction angles (2θ ± 0.2 °) 6.2 °, 10.7 °, 12.4 °, 14.0 °, 16.5 °, 18.7 in powder X-ray crystal diffraction. And have diffraction peaks at 21.7 °.

  In the powder X-ray crystal diffraction of the crystal according to this embodiment, the diffraction intensity at a diffraction angle (2θ ± 0.2 °) of 12.4 ° is a diffraction intensity at a diffraction angle (2θ ± 0.2 °) of 14.0 °. You may have the feature of being higher than.

  In the powder X-ray crystal diffraction of the crystal according to the present embodiment, the diffraction intensity at the diffraction angle (2θ ± 0.2 °) of 14.0 ° is the diffraction intensity at the diffraction angle (2θ ± 0.2 °) of 16.5 °. It may be further provided with the feature that it is lower.

  One aspect of the crystal according to the present embodiment is a crystal of 1-amino-3,5-dimethyladamantane hydrochloride having an endothermic peak in the range of 330 to 400 ° C. in differential scanning calorimetry.

  Preferred crystals have an endothermic peak in the range of 330-390 ° C, 340-380 ° C, or 350-370 ° C.

  Differential scanning calorimetry is a method of measuring the temperature of a reference material and a sample while applying a certain amount of heat to the reference material and the sample, and taking the thermal properties of the sample as a temperature difference. It is an analysis technique to measure. According to differential scanning calorimetry, it is possible to grasp not only the reaction of state change due to simple heat such as melting, but also the phase transition and crystallization of the crystal structure.

  In this specification, “in differential scanning calorimetry, it has an endothermic peak in the range of 330 to 400 ° C.” means that in a graph in which temperature (° C.) is plotted on the horizontal axis and heat flow (mW) is plotted on the vertical axis, It means that the peak of the endothermic peak exists within the temperature range of 400 ° C.

  If the crystal has an endothermic peak in the range of 330 to 400 ° C., there is no change in crystal form due to phase transition or the like in a temperature environment during the preparation operation, and it becomes easy to produce a stable preparation.

  In the crystal according to this embodiment, the content of 1-amino-3,5-dimethyladamantane hydrochloride is preferably 99.90% or more. The content of 1-amino-3,5-dimethyladamantane hydrochloride can be calculated based on, for example, a chromatogram obtained by gas chromatography. Specifically, in gas chromatography, the ratio of the peak area of the peak corresponding to 1-amino-3,5-dimethyladamantane hydrochloride to the peak area of all detected peaks is 99.90% or more. That's fine.

  A more preferable crystal has a content of 1-amino-3,5-dimethyladamantane hydrochloride of 99.93% or more, or 99.95% or more.

The crystal according to the present embodiment can change so that the mass of the crystal is directly proportional to the ambient humidity in moisture adsorption / desorption measurement. For example, when moisture adsorption / desorption measurement described later is performed, the mass of the crystal increases so as to be directly proportional to an increase in the specific humidity P / P ₀ (%) (humidity of air to which the crystal is exposed). Further, when the same measurement is performed, the mass of the crystal decreases so as to be directly proportional to the decrease in the specific humidity P / P ₀ (%). By increasing or decreasing the mass of the crystal so as to be directly proportional to the specific humidity, a crystal having a desired water content can be obtained more easily.

  The crystal according to the present embodiment is excellent in water solubility and is easily used for various dosage forms. When the crystals according to the present embodiment are used for oral administration preparations such as tablets, powders, capsules and the like, they can be easily miniaturized and can be formulated more rapidly. When the crystal is orally administered, it is easy to dissolve in the digestive tract and the reliability of the drug effect is high. Moreover, when using the crystal | crystallization concerning this embodiment for liquid preparations, such as an injection and a syrup, the dissolution rate to water is high, it is hard to melt | dissolve, and it is excellent in productivity.

  Another embodiment of the present invention is a powdery formulation of crystals of 1-amino-3,5-dimethyladamantane hydrochloride, wherein the bulk density is 0.15 g / mL or more and less than 0.40 g / mL It is a pharmaceutical preparation.

  The powdery formulation according to this embodiment has a bulk density of 0.15 g / mL or more and less than 0.40 g / mL, 0.18 g / mL or more and 0.37 g / mL or less, 0.21 g / mL or more and 0.34 g. / ML or less, or 0.23 g / mL or more and less than 0.32 g / mL. When the bulk density is within the above range, the fluidity of the powdered preparation is more excellent, and the preparation work becomes easier.

  In this specification, the bulk density is a value calculated by dividing the mass (g) of the crystal by the volume (mL). Examples of the method for calculating the bulk density include a method in which crystals are put in a glass container and the mass and volume thereof are measured.

  When the bulk density of the crystal of 1-amino-3,5-dimethyladamantane hydrochloride is 0.40 g / mL or more, the crystal is pulverized to a desired bulk density to prepare a powdery formulation May be. The pulverization method may be a method well known to those skilled in the art as long as the crystal structure does not change. The crystals may be pulverized using a pulverizer such as a roll vibration mill, a high-speed rotary pulverizer, a ball mill, a medium stirring mill, a jet mill, a vibration rod mill, or a hammer mill.

  In one aspect of the powder preparation according to this embodiment, at least 75% of the powder preparation has a particle size of 200 μm or less. That is, the proportion of the powder having a longer particle size of 200 μm or less in each powder of the powdery preparation is at least 75% based on the volume. In the powder preparation, it is preferable that 80% or more, 85% or more, or 90% or more of the powder has a particle size of 200 μm or less. Moreover, in a powdery formulation, it is preferable that at least 75% of the powdery formulation has a particle size of 150 μm or less, 100 μm or less, or 80 μm or less.

  In another aspect of the powder preparation according to the present embodiment, at least 50% of the powder preparation may have a particle size of 35 μm or less. That is, it means that the proportion of the powder having a longer particle size of 35 μm or less in each powder of the powdery preparation is at least 50% based on the volume. In a powdery formulation, it is preferable that 55% or more, 60% or more, 70% or more, 80% or more, or 90% or more of the powder has a particle size of 35 μm or less. Further, in the powder preparation, it is preferable that at least 50% of the powder preparation has a particle size of 35 μm or less or 30 μm or less.

  Furthermore, as for the other side surface of the powdery formulation which concerns on this embodiment, at least 90% of the powders in the said powdery formulation may have a particle size of 130 micrometers or less. That is, the proportion of the powder having a longer particle size of 130 μm or less in each powder of the powdery preparation is at least 90% based on the volume. In the powder preparation, it is preferable that 93% or more, 95% or more, or 98% or more of the powder has a particle size of 130 μm or less. In the powder preparation, at least 90% of the powder preparation preferably has a particle size of 120 μm or less, 110 μm or less, 100 μm or less, or 90 μm or less.

(Method for producing 1-amino-3,5-dimethyladamantane)
1-amino-3,5-dimethyladamantane can be produced by a known method. Further, 1-amino-3,5-dimethyladamantane may be produced by the following method. Commercially available 1-amino-3,5-dimethyladamantane may be used after pretreatment as necessary.

  For example, Patent Documents 3 to 5 and Non-Patent Document 1 disclose methods for producing from 1,3-dimethyladamantane. Specifically, in the methods described in Patent Documents 3 and 4, the following methods are disclosed. 1,3-Dimethyladamantane is halogenated to give 1-halo-3,5-dimethyladamantane. Next, the obtained 1-halo-3,5-dimethyladamantane is reacted with formamide, acetamide, urea or acetonitrile to obtain N-substituted-1-amino-3,5-dimethyladamantane, and then hydrolyzed. Disassemble.

  Patent Document 5 and Non-Patent Document 1 are obtained by reacting 1,3-dimethyladamantane, nitric acid and acetic acid to obtain 1-nitrooxy-3,5-dimethyladamantane, and then reacting it with urea. Disclosed is a method for hydrolyzing N- (3,5-dimethyladamantan-1-yl) urea.

  1-amino-3,5-dimethyladamantane can be produced by adding a base to a commercially available salt of 1-amino-3,5-dimethyladamantane to produce free 1-amino-3,5-dimethyladamantane. Good.

  The base is not particularly limited as long as it can convert 1-amino-3,5-dimethyladamantane hydrochloride into free 1-amino-3,5-dimethyladamantane. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; calcium carbonate and the like. Alkaline earth metal carbonates; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide And alkali metal alkoxides.

  The amount of the base used is not particularly limited as long as it is an amount effective for converting 1-amino-3,5-dimethyladamantane hydrochloride into free 1-amino-3,5-dimethyladamantane. The amount of the base used is preferably 1 to 5 mol with respect to 1 mol of 1-amino-3,5-dimethyladamantane hydrochloride.

  The reaction for converting 1-amino-3,5-dimethyladamantane hydrochloride to free 1-amino-3,5-dimethyladamantane may be carried out without a solvent or in a solvent. It is preferable to carry out in a solvent from the viewpoint of excellent stirring properties and uniformity.

  Examples of the solvent include water; alcohols such as methanol, ethanol, isopropyl alcohol, and t-butyl alcohol; carboxylic acids such as formic acid and acetic acid; aliphatic hydrocarbons such as pentane, hexane, heptane, and cyclohexane; methylene chloride, chloroform, Halogenated aliphatic hydrocarbons such as 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate Esters such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, cyclohexanone; diethyl ether, diisopropyl ether, t-butyl methyl ether, cyclopentyl Methyl ether, dimethoxyethane, tetrahydrofuran, dioxane, ethers such as anisole. A plurality of types of solvents may be mixed and used.

  The amount of the solvent used is not particularly limited as long as 1-amino-3,5-dimethyladamantane hydrochloride can be sufficiently dissolved. The usage-amount of a solvent is 400-2200 mL with respect to 1 mol of 1-amino-3,5-dimethyladamantane hydrochloride normally.

  The reaction temperature for converting 1-amino-3,5-dimethyladamantane hydrochloride to free 1-amino-3,5-dimethyladamantane is preferably 0 to 120 ° C., and the reaction pressure is not particularly limited.

(Method for producing crystals of 1-amino-3,5-dimethyladamantane hydrochloride)
The crystal according to the present embodiment can be manufactured by the following three methods.
Method 1: Free 1-amino-3,5-dimethyladamantane is dissolved in water-containing acetone, hydrochloric acid is added, and the mixture is cooled to -10 to 30 ° C.
Method 2: 1-amino-3,5-dimethyladamantane hydrochloride is dissolved in hydrous acetone and cooled to 10-30 ° C.
Method 3: The crystals of 1-amino-3,5-dimethyladamantane hydrochloride obtained in Reference Example 1 are suspended in water-containing acetone and stirred at 15 to 35 ° C.

  In the method 1, the ratio of water to acetone in the water-containing acetone is preferably 0.05: 1 to 0.5: 1 by mass ratio, and preferably 0.08: 1 to 0.25: 1. More preferred. The amount of hydrous acetone used may be 0.3 to 100 g, 0.3 to 50 g, or 0.5 to 10 g based on 1 g of free 1-amino-3,5-dimethyladamantane used.

  Moreover, in the said method 2, it is preferable that the ratio of the water and acetone in water-containing acetone is 0.05: 1-0.5: 1 by mass ratio, and is 0.08: 1-0.25: 1. More preferably. The amount of hydrous acetone used may be 0.3 to 100 g, 0.3 to 50 g, or 0.5 to 10 g based on 1 g of 1-amino-3,5-dimethyladamantane hydrochloride used.

  In the method 3, the ratio of water to acetone in the water-containing acetone is the same as that in the method 2.

  In the above method 1, the amount of hydrochloric acid used is preferably 1 to 20 mol per 1 mol of free 1-amino-3,5-dimethyladamantane. Instead of hydrochloric acid, hydrogen chloride gas may be circulated, or hydrous acetone containing dissolved hydrogen chloride may be used. The amount of hydrous acetone in which hydrogen chloride gas or hydrogen chloride is dissolved may be any amount that can convert free 1-amino-3,5-dimethyladamantane into the hydrochloride form.

  In the above methods 1 and 2, 1-amino-3,5-dimethyladamantane or its hydrochloride may be pretreated with activated carbon after being dissolved in water-containing acetone and before cooling. The usage-amount of activated carbon is 1-50 mass% with respect to the mass of 1-amino-3,5-dimethyladamantane or its hydrochloride, for example.

  Another embodiment of the present invention is a pharmaceutical composition comprising crystals of 1-amino-3,5-dimethyladamantane hydrochloride as described above. The pharmaceutical composition may contain crystals of 1-amino-3,5-dimethyladamantane hydrochloride in the form of a powdered preparation having a bulk density of 0.20 g / mL or more and less than 0.45 g / mL.

  Since 1-amino-3,5-dimethyladamantane hydrochloride has an NMDA antagonistic action, the pharmaceutical composition according to this embodiment can also be used for the treatment of Alzheimer-type dementia.

  The dosage form when the crystal of this embodiment is used as a pharmaceutical composition can be selected from various dosage forms described in the “Japanese Pharmacopoeia” general formulation according to the purpose. Examples of the dosage form include oral preparations such as powders, tablets, capsules, and suppositories. When forming into a tablet form, it is customary to select an orally ingestible ingredient used in the field.

  In addition to the crystals of 1-amino-3,5-dimethyladamantane hydrochloride, the pharmaceutical composition may contain a pharmaceutically acceptable medium as necessary. Examples of the pharmaceutically acceptable medium include excipients, binders, disintegrants, lubricants, anti-aggregation agents and the like. Examples of the excipient include lactose, crystalline cellulose, sucrose, and potassium phosphate.

  The amount of 1-amino-3,5-dimethyladamantane hydrochloride crystals contained in the pharmaceutical composition is not particularly limited. The amount of crystals may be 2 to 98% by weight, based on the total weight of the pharmaceutical composition.

  This embodiment also includes an aspect of a method for treating Alzheimer-type dementia, comprising a step of administering a pharmaceutical composition containing crystals of 1-amino-3,5-dimethyladamantane hydrochloride to a subject in need thereof. Have. The subject is, for example, a patient with Alzheimer's dementia.

  The dosage of the pharmaceutical composition can be appropriately changed based on its usage, patient age, sex and other conditions, disease severity, and the like. For example, in the case of an oral administration preparation, 1-amino-3,5-dimethyladamantane hydrochloride crystals may be administered at 1 μg to 20 mg / kg body weight, preferably 10 μg to 2 mg / kg body weight per day. In addition, it can be appropriately administered in 1 to 4 times per day.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

The crystal aspect ratio is calculated by measuring the major axis and minor axis of a crystal using an optical microscope.
The measurement conditions of the optical microscope are as follows.
<Measurement conditions>
Optical microscope: SHIMADZU BA-210
Eyepiece magnification: 10x Objective lens magnification: 10x or 40x

The measurement conditions for gas chromatography are as follows.
<Measurement conditions>
Detector: Hydrogen flame ionization detector (FID)
Column: HP-ULTRA2 0.32 mmI. D. × 50m Film thickness 0.52μm (manufactured by Agilent Technologies)
Inlet temperature: 220 ° C
Detector temperature: 300 ° C
Carrier gas: helium Flow rate: 4.0 ± 0.4 mL / min Column temperature: Initial temperature from 50 ° C. to 145 ° C., heating rate of 5 ° C./min, rising temperature after reaching 145 ° C., 10 ° C./min, final temperature of 250 Maintained for 20 minutes after reaching ° C. Injection volume: 1 μL
Injection mode: Split (1:50)
Solvent: Hexane

The measurement conditions of powder X-ray crystal diffraction are as follows.
<Measurement conditions>
Apparatus: X-ray diffractometer MiniFlex600 (manufactured by Rigaku Corporation)
Sample holder: Through-type sample plate Target: CuKα
Detector: Scintillation counter Scan mode: Continuous Scan speed: 5.0o / min 2θ measurement range: 2o to 40o
Accuracy: ± 0.2o
Goniometer: MiniFlex 300/600 +

The method for measuring the bulk density is as follows.
Crystals were collected in a 50 mL graduated cylinder so that the volume of the sample to be measured was 20 mL. The mass of the collected measurement specimen was weighed and the bulk density was calculated.

The measurement conditions for differential scanning calorimetry are as follows.
<Measurement conditions>
Device name: Differential scanning calorimeter DSC7020 (manufactured by Hitachi High-Tech Science Corporation)
Sample mass: 1.0-3.0 mg
Temperature range: 30-420 ° C
Temperature increase rate: 10 ° C./min N ₂ flow rate: 50 mL / min

The measurement conditions for moisture adsorption / desorption measurement are as follows.
<Measurement conditions>
Device name: Dynamic moisture adsorption measuring device DVS Advantage (manufactured by Surface Measurement Systems)
Sample mass: 20mg
Temperature: 25 ° C
Humidity range: 0.0-95.0% RH

(Example 1: Method 1)
In a 10 L internal vessel equipped with a stirrer, a thermometer and a reflux condenser, 1300 g (6.0 mol) of 1-amino-3,5-dimethyladamantane hydrochloride having a purity of 99.595%, 2417 g of purified water, n- After adding 3541 g of heptane and 2407 g (15.0 mol) of 25% sodium hydroxide and stirring at 20 to 30 ° C. for 30 minutes, the organic layer was separated. The organic layer was washed sequentially with 5200 g of purified water and 5200 g of 10% brine. Subsequently, the insoluble matter of the obtained organic layer was removed by filtration (clear filtration), and the obtained filtrate was concentrated under reduced pressure to obtain free 1-amino-3,5-dimethyladamantane.
To 1080 g of the obtained free 1-amino-3,5-dimethyladamantane (calculated from the used 1-amino-3,5-dimethyladamantane hydrochloride), water-containing acetone (purified water / Acetone = 1/10 (mass ratio)) was added, 753.2 g (7.2 mol) of 35% hydrochloric acid was added dropwise at 25 to 35 ° C., and stirred at the same temperature for 1 hour, and then −5 to 5 ° C. The mixture was cooled to rt and further stirred for 2 hours.
The precipitated solid was collected by filtration, washed with 1300 g of cold hydrous acetone (purified water / acetone = 1/10 (mass ratio)), and 1-amino-3,5 having a purity of 99.949% as white needle crystals. -1073 g of dimethyladamantane hydrochloride was obtained (yield: 83%). The impurity content was reduced from 0.405% to 0.051%.

  The bulk density of the obtained crystal was 0.29 g / mL. In addition, six crystals randomly extracted from the obtained crystals were observed with an electron microscope, and the crystal aspect ratio was measured. As a result, the crystal aspect ratios were 7.5, 9.4, 9.5, 10.0, 13.8, and 14.8, respectively.

  The obtained crystals were subjected to powder X-ray crystal diffraction and differential scanning calorimetry. The results are shown in FIGS. 1 and 2, respectively. According to FIG. 2, the crystal of Example 1 showed an endothermic peak at 364.4 ° C., and the endothermic amount was 227 mJ / mg.

  The results of the moisture adsorption / desorption measurement of the crystals obtained in Example 1 are shown in FIG. According to FIG. 5, when the humidity was changed, the mass of the crystal increased in proportion to the increase in humidity. In addition, the mass of the crystal decreased in proportion to the decrease in humidity.

(Reference Example 1)
In a 10 L vessel equipped with a stirrer, thermometer and reflux condenser, 1300 g (6.0 mol) of 1-amino-3,5-dimethyladamantane hydrochloride with a purity of 99.595%, 2414 g of purified water, n- After adding 3543 g of heptane and 2409 g (15.1 mol) of 25% sodium hydroxide and stirring at 20 to 30 ° C. for 30 minutes, the organic layer was separated. The organic layer was washed sequentially with 5200 g of purified water and 5200 g of 10% brine. Subsequently, the insoluble matter of the obtained organic layer was removed by filtration (clear filtration), and the obtained filtrate was concentrated under reduced pressure to obtain free 1-amino-3,5-dimethyladamantane.
To 1080 g of the obtained free 1-amino-3,5-dimethyladamantane (calculated from the used 1-amino-3,5-dimethyladamantane hydrochloride), water-containing acetone (purified water / Acetone = 1.9 / 1 (mass ratio)) was added, 753.1 g (7.2 mol) of 35% hydrochloric acid was added dropwise at 25 to 35 ° C., and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 5 ° C. and further stirred for 2 hours.
The precipitated solid was collected by filtration and washed with 1310 g of cold acetone to obtain 1150 g of 1-amino-3,5-dimethyladamantane hydrochloride having a purity of 99.969% as white plate crystals (yield: 88 %). The crystallization from hydrous acetone reduced the impurity content from 0.405% to 0.031%.

  The bulk density of the obtained crystal was 0.36 g / mL. Crystals randomly extracted from the obtained crystals were observed with an electron microscope, and the crystal aspect ratio was measured. As a result, the crystal aspect ratios were 1.1, 1.4, and 1.5, respectively.

  The obtained crystals were subjected to powder X-ray crystal diffraction and differential scanning calorimetry. The results are shown in FIGS. 3 and 4, respectively. According to FIG. 4, the crystal of Reference Example 1 showed an endothermic peak at 364.7 ° C., and the endothermic amount was 259 mJ / mg.

(Crushing test)
A crushing test was performed using the needle-like crystals obtained in Example 1 and the plate-like crystals obtained in Reference Example 1. Specifically, 200 g of the obtained crystal was crushed for 3 minutes at a spindle rotation speed of 6000 rpm using a hammer mill grinder (manufactured by Fuji Powder Co., Ltd., sample mill KIIWG-1 type).

The particle size distribution of the obtained powder was measured under the following conditions.
<Measurement conditions>
Apparatus: Laser diffraction / scattering particle size distribution measuring apparatus LA-950V2
(Horiba, Ltd.)
Measurement unit: Dry unit Measurement mode: V-type shooter Measurement range: 0.1 μm to 3000 μm
Compressed air: 0.2 MPa
Relative refractive index: 1.50-0.00i
Particle diameter standard: Volume standard Sample collection amount: about 0.1 g
Number of measurements: n = 2

The results of the crushing test are shown in Table 1. When the crystals of Example 1 and Reference Example 1 were crushed under the same conditions, the powder obtained from the crystals of Example 1 had a major diameter of 90% of the powder based on the volume of 94.2 μm or less. That is, it was found that the crystal of Example 1 was easier to refine than the crystal of Reference Example 1.

Claims (11)

  Crystals of 1-amino-3,5-dimethyladamantane hydrochloride having a crystal aspect ratio of 7.5 to 15.   In powder X-ray crystal diffraction, diffraction angles (2θ ± 0.2 °) have diffraction peaks at 12.4 °, 14.0 °, and 16.5 °, and a diffraction angle (2θ ± 0.2 °) of 12. The crystal according to claim 1, wherein the diffraction intensity of 4 ° is higher than the diffraction intensity of diffraction angle (2θ ± 0.2 °) of 14.0 °.   In powder X-ray crystal diffraction, the diffraction intensity at a diffraction angle (2θ ± 0.2 °) of 14.0 ° is lower than the diffraction intensity of a diffraction angle (2θ ± 0.2 °) of 16.5 °. The described crystals.   The crystal according to any one of claims 1 to 3, which has an endothermic peak at 330 to 400 ° C in differential scanning calorimetry.   The crystal according to any one of claims 1 to 4, wherein a content of the 1-amino-3,5-dimethyladamantane hydrochloride is 99.90% or more.   The crystal according to any one of claims 1 to 5, wherein, in moisture adsorption / desorption measurement, the mass of the crystal changes so as to be directly proportional to ambient humidity.   The pharmaceutical composition containing the crystal | crystallization as described in any one of Claims 1-6. A method for producing the crystal according to any one of claims 1 to 6,
Crystallizing 1-amino-3,5-dimethyladamantane hydrochloride from hydrous acetone.   The method according to claim 8, wherein a mass ratio of water to acetone in the water-containing acetone is 0.05: 1 to 0.5: 1.   It is a powdery formulation containing the crystal | crystallization as described in any one of Claims 1-6, Comprising: Bulky density is 0.15 g / mL or more and less than 0.40 g / mL. The powder-form preparation according to claim 10, wherein at least 75% of the powder-form preparation has a particle size of 200 µm or less.

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