JP2015501789A - Neramexane mesylate monohydrate and anhydride - Google Patents

Abstract

A method of preparing neramexane mesylate monohydrate, comprising steps (i) to (iii): (i) exposing neramexane mesylate anhydride to a humid atmosphere; (ii) neramexane mesylate anhydride Suspending in water; (iii) saturating water with neramexane mesylate;

Description

FIELD OF THE INVENTION The present invention relates to neramexane mesylate hydrate and crystal modification of neramexane mesylate anhydrate. The invention further relates to a method for preparing said hydrate from said hydrate and to the use of said hydrates and anhydrides in medical applications.

Background of the Invention Neramexane mesylate is a beneficial agent for the continuous therapy of patients suffering from diseases and conditions such as tinnitus, or skin diseases such as acne.

  WO 2010/118889 discloses the preparation of neramexane mesylate starting from neramexane and methanesulfonic acid. The product can be obtained by crystallization, recrystallization in various solvents and subsequent drying, respectively. Depending on the crystallization conditions, recrystallization conditions respectively, the product can be obtained in the form of columnar or star-like or plate-like crystals. These modifications represent a product free of water, ie neramexane mesylate anhydride. Recrystallization of neramexane mesylate from acetone and dichloromethane results in a solvate.

  The crystalline form of neramexane mesylate, which can be obtained by crystallization from various solvents including water, is also known as Steffen Schweizer: “Erstellung eines Praeformulierungskonzeptes fur mittelstandische Pharmaunternehmen unter besonderer Berucksichtigung der physikalisch-chemischen Eigenschnetenlder derzist -Antagonisten MRZ 2/579 und MRZ 2/576 ”, Dissertation, Johann-Wolfgang-Goethe-Universitat Frankfurt am Main, 2001, pages 188-196.

  It is known that solvates of drugs used for medical applications can have different properties compared to unsolvated drugs. It is further known that different crystalline forms of a drug can provide different properties.

Objects of the invention The object of the present invention is whether neramexane mesylate can be obtained in the form of a solvate different from the solvate comprising acetone and dichloromethane, respectively, or neramexane mesylate is obtained in a further crystalline form Whether and how such solvates and crystal modifications can be used in medical applications.

SUMMARY OF THE INVENTION This object is achieved by neramexane mesylate monohydrate, and neramexane mesylate anhydrate obtained from the monohydrate in the form of needle-like crystals, and a process for preparing said compound.

Accordingly, a first aspect of the present invention is a method for preparing neramexane mesylate monohydrate, comprising steps (i) to (iii):
(I) a step of exposing neramexane mesylate in a humid atmosphere (ii) a step of suspending neramexane mesylate in water (iii) a method comprising one of the steps of saturating neramexane mesylate with neramexane mesylate .

  In one embodiment of this aspect, the neramexane mesylate monohydrate is obtained in the form of plate-like crystals.

  In a second aspect, the present invention relates to neramexane mesylate monohydrate.

  In a third aspect, the present invention relates to neramexane mesylate monohydrate crystals, wherein the crystals are plate-like.

In a fourth aspect, the present invention provides a method for preparing neramexane mesylate anhydride comprising the step of (i):
(I) relates to a method comprising the step of dehydrating neramexane mesylate monohydrate.

  In one embodiment of this aspect, the neramexane mesylate anhydride is obtained in the form of needle-like crystals.

  In one embodiment, the needle-like crystal has an aspect ratio of 15 or more or 20 or more.

In one embodiment of this aspect or the previous embodiment of this aspect, the method comprises step (0) prior to step (i):
(0) The method further includes reacting neramexane with methanesulfonic acid in the presence of water.

  In a fifth aspect, the present invention relates to neramexane mesylate anhydrous crystals, wherein the crystals are needle-like.

  In one embodiment, the aspect ratio of the needle-like crystal is 15 or more or 20 or more.

  In a sixth aspect, the present invention relates to neramexane mesylate monohydrate for use as a medicament.

  The sixth aspect also relates to a pharmaceutical composition comprising an effective amount of neramexane mesylate monohydrate.

  In a seventh aspect, the present invention relates to neramexane mesylate monohydrate for use in the treatment of tinnitus or acne.

  The seventh aspect also relates to the use of neramexane mesylate monohydrate for the manufacture of a pharmaceutical composition for use in the treatment of tinnitus or acne.

  A seventh aspect also relates to a method of treating a patient suffering from tinnitus or acne comprising administering to said patient an effective amount of neramexane mesylate monohydrate.

  In one embodiment of the sixth or seventh aspect, neramexane mesylate monohydrate is in the form of plate-like crystals.

  In an eighth aspect, the present invention relates to neramexane mesylate anhydrate for use as a medicament, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals.

  The eighth aspect relates to a pharmaceutical composition comprising an effective amount of neramexane mesylate anhydrate, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals.

  In one embodiment, the aspect ratio of the needle-like crystal is 15 or more or 20 or more.

  In a ninth aspect, the present invention relates to neramexane mesylate anhydrate for use in the treatment of tinnitus or acne, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals.

  A ninth aspect relates to the use of neramexane mesylate anhydrate for the manufacture of a pharmaceutical composition for the treatment of tinnitus or acne, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals.

  A ninth aspect is also a method of treating a patient suffering from tinnitus or acne, wherein an effective amount of neramexane mesylate anhydrate is administered to the patient, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals. To a method comprising:

  In one embodiment, the aspect ratio of the needle-like crystal is 15 or more or 20 or more.

FIG. 1 shows an optical microscope image of neramexane mesylate anhydride, which is plate-like when prepared and / or crystallized from an organic solvent according to the method disclosed in WO 2010/118889. .

FIG. 2 shows an optical microscope image of neramexane mesylate monohydrate, where the crystals are plate-like.

FIG. 3 shows neramexane mesylate anhydrate obtained from neramexane mesylate monohydrate by drying the monohydrate in air, where neramexane mesylate anhydrate is formed. The optical microscope image of is shown.

4, Bruker D8 Advance diffractometer in Bragg-Brentano reflection geometry; Cu K _alpha radiation; 40 kV / 40 mA; variable divergence slit; 3 ° LynxEye detector equipped with a window; step size 0.02 ° 2 [Theta]; step time 2 shows a powder X-ray diffraction pattern of neramexane mesylate anhydrate using 2 seconds at 37 seconds, scanning range 2θ). The sample was rotated (0.5 rps) during the measurement. The sample was prepared to obtain a flat surface without any special treatment other than slight pressure. Measurements were performed in laboratory environmental conditions in silicone single crystal sample holders of 0.1 or 1 mm depth.

FIG. 5 shows the powder X-ray diffraction pattern of each neramexane mesylate monohydrate.

FIG. 6 shows neramexane mesylate anhydrate obtained from neramexane mesylate monohydrate by drying monohydrate in air, where neramexane mesylate anhydrate is formed. Fig. 3 shows another optical microscope image of.

DETAILED DESCRIPTION OF THE INVENTION According to a first aspect, the present invention relates to a method for preparing neramexane mesylate monohydrate.

  The term “neramexane” means 1-amino-1,3,3,5,5-pentamethylcyclohexane. This definition, and other definitions used herein, mean definitions as used in the meaning of the present invention.

  The term “neramexane mesylate” means 1-amino-1,3,3,5,5-pentamethylcyclohexane methanesulfonate.

  The term “neramexane mesylate monohydrate” includes the product of 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate combined with water. In particular, the term “monohydrate” includes products in which one molecule of neramexane mesylate is combined with one molecule of water or about one molecule of water.

  The term “about” includes products having 3-8 wt% or 4-7 wt% water based on the total weight of neramexane mesylate monohydrate to 100 wt%.

  In one embodiment, the term “neramexane mesylate monohydrate” includes neramexane mesylate, in which water is incorporated onto the lattice sites of the crystal lattice of neramexane mesylate.

  In another embodiment, the term “neramexane mesylate monohydrate” includes products in which water is attached to neramexane mesylate without being incorporated onto lattice sites.

  Neramexane mesylate monohydrate may be prepared starting from neramexane mesylate anhydride, for example, obtained according to one of the methods disclosed in WO 2010/118889.

  The term “neramexane mesylate anhydride” includes neramexane mesylate without water.

  The term “water free” includes a moisture content of less than 3% by weight, based on the total amount of water and anhydride.

  In one embodiment of the method, neramexane mesylate anhydrate is exposed to a humid atmosphere, such as humid air, or any other humid gas, such as humid nitrogen.

  The term “humid” includes a relative humidity of 80-100%, or 85-100%, or 90-100%, or 95-100%, or 95-97%. The relative humidity may be determined according to known methods, for example using a hygrometer. The term “humid” is used synonymously with the term “moist”.

  In one embodiment, the relative humidity means a relative humidity at room temperature. In one embodiment, the temperature is in the range of 15-30 ° C, or 20-25 ° C.

  Under such a humid atmosphere, neramexane mesylate anhydride can absorb water and form a monohydrate. Monohydrate formation can be detected by known methods of measuring dynamic vapor adsorption (DVS). The method is a gravimetric method that measures how quickly and how much water has been absorbed by a sample, for example, a dry powder of neramexane mesylate anhydrous. Herein, the vapor concentration surrounding the sample is varied and the resulting mass change is measured. When doing so, neramexane mesylate monohydrate can be identified. This can be further characterized, for example, by X-ray diffraction analysis.

  DVS measurements reveal that water uptake is reversible depending on humidity and / or temperature. When neramexane mesylate monohydrate is exposed to an atmosphere having a relatively low humidity, water will desorb from the monohydrate and an anhydride will be formed.

  The term “relatively low humidity” includes less than 70%, or less than 60%, or less than 50%.

  In another embodiment of the method, neramexane mesylate anhydride may be recrystallized or crystallized from water, thereby forming a monohydrate.

  In one embodiment of the method, the term “recrystallization” or “crystallization” as used herein comprises suspending neramexane mesylate in water, where the mesylic acid absorbs water. Monohydrate crystals are formed. After filtration, neramexane mesylate monohydrate can be obtained.

  In another embodiment of the method, the term “recrystallization” as used herein includes dissolving neramexane mesylate in water, eg, saturating water with mesylic acid. The monohydrate can then initiate precipitation and can be isolated by filtration. If necessary, precipitation may be aided by the removal of some water.

Accordingly, in one embodiment, the present invention is a method of preparing neramexane mesylate monohydrate, comprising step (i) or step (ii) or step (iii):
(I) exposing neramexane mesylate anhydride to a humid atmosphere, allowing the anhydride to absorb water and forming neramexane mesylate monohydrate; or (ii) suspending neramexane mesylate anhydride in water. Clouding, allowing the anhydride to absorb water and forming neramexane mesylate monohydrate and then isolating the monohydrate, for example by filtration; or (iii) saturating the water with neramexane mesylate And, for example, comprising the step of isolating the crystallized product by filtration or consisting of step (i) or step (ii) or step (iii).

  In one embodiment, neramexane mesylate monohydrate obtained in the method of step (i) or step (ii) or step (iii) crystallizes in the form of plate-like crystals.

  Our discovery that neramexane mesylate monohydrate is formed from neramexane mesylate anhydrate in the presence of water, for example in step (iii), indicates that the process of recrystallizing neramexane mesylate in water It is surprising in light of the above Schweizer document that clearly teaches on page 196 that it does not lead to the formation of hydrate forms.

Second aspect In a second aspect, the present invention relates to neramexane mesylate monohydrate.

Third Aspect In a third aspect, the present invention relates to neramexane mesylate monohydrate in the form of a solid substance, ie in the form of crystals.

  In one embodiment, the neramexane mesylate monohydrate is in the form of plate-like crystals.

Fourth Aspect In a fourth aspect, the present invention relates to a method for preparing neramexane mesylate anhydride. This method involves the removal of water from neramexane mesylate monohydrate.

Thus, in one embodiment, the method comprises step (i):
(I) Neramexane mesylate anhydride is obtained, or includes a step of dehydrating neramexane mesylate monohydrate, or comprises step (i).

  In one embodiment, removal of water from neramexane mesylate monohydrate, i.e. dehydration or desorption of water, as already mentioned in the respective embodiments of the first aspect, has an atmosphere with low humidity. May be achieved by providing neramexane mesylate monohydrate.

  In another embodiment, removal of water from neramexane mesylate monohydrate, ie, dehydration or desorption of water, is accomplished by subjecting neramexane mesylate monohydrate to elevated temperature and / or reduced pressure. May be.

  The term “increased temperature” includes temperatures that are sufficient to remove water but are insufficient to decompose the formed neramexane mesylate anhydride.

  In one embodiment, the temperature is 30-200 ° C, or 30-180 ° C.

  The term “reduced pressure” includes pressures below 1 bar.

Thus, in one embodiment, the present invention provides a method of preparing neramexane mesylate monohydrate from neramexane mesylate monohydrate, wherein step (i) comprises steps (j) to (jjj):
(J) exposing neramexane mesylate monohydrate to a humid atmosphere, eg, humid air where the relative humidity of the atmosphere is less than 70%;
(Jj) exposing neramexane mesylate monohydrate to an elevated temperature wherein the temperature is in the range of 30-200 ° C;
(Jjj) exposing neramexane mesylate monohydrate to reduced pressure, wherein the pressure is less than 1 bar;
The method includes one, two, or three steps, or includes one, two, or three steps of steps (j) to (jjj).

  The neramexane mesylate anhydride obtained in the method of the fourth aspect is obtained in the form of needle-like crystals. Since the crystallographic tendency of neramexane mesylate anhydride obtained in the method of WO 2010/118889, which is a prior art in which an organic solvent is used for crystallization or recrystallization, is columnar or star-like or plate-like, This is surprising.

  In principle, the dimensions that should be ideally used to completely define the tendency of a crystal are width, thickness and length, all orthogonal to each other. However, since only two dimensions can be accurately quantified with a microscope, the simplest system of trend description involves quantifying the length-to-width ratio, which can be easily done with a microscope. The length is always defined as the longest dimension and the width as the shortest dimension. Thus, the “aspect ratio” is defined herein as the ratio of crystal length to crystal width.

  The term “needle-like crystal” used in this disclosure means a crystal having an aspect ratio of 15 or more. In one embodiment, the aspect ratio is 20 or greater. In yet another embodiment, the aspect ratio is 30 or greater, or 40 or greater, or 50 or greater.

  In one embodiment, the upper aspect ratio limit may be up to 1,000, or up to 500, or up to 400, or up to 300, or up to 200, or up to 100.

  In one embodiment, the aspect ratio is 15 to 1,000 or 20 to 1,000 or 30 to 1,000, or 40 to 1,000 or 50 to 1,000; or 15 to 500 or 20 to 500. Or 30-500, or 40-500 or 50-500; or 15-400 or 20-400 or 30-400, or 40-400 or 50-400; or 15-300 or 20-300 or 30-300, or 40-300 or 50-300; or 15-200 or 20-200 or 30-200; or 40-200 or 50-200; or 15-100 or 20-100 or 30-100; or 40-100 or 50- 100.

  The aspect ratio is determined with a scanning electron microscope (SEM). Such methods are known in the art. A typical method involves spreading the sample on a pure aluminum support and then sputter coating with a thin layer of Pd / Au having a thickness in the nanometer range. A sputter coating apparatus SCD 030 (Balzers) may be used. Images may be acquired at a magnification of, for example, 150 times using, for example, a JSM 6400 scanning electron microscope (JEOL, Japan) at an acceleration voltage of 20 keV and a working distance of 15 mm. Electrical filtering and thresholding may be used to improve the separation of particles in the binary image from the background. Commercially available analysis software such as Analysis, SIS, Muenster, Germany may be used for image analysis. The software automatically detects and evaluates the particles in the image and classifies them according to the aspect ratio.

  Such needle-like crystals provide a high surface area compared to, for example, plate-like crystals. As a result, the dissolution rate of the needle-like crystal is higher than the dissolution rate of the plate-like crystal. For this reason, needle-like crystals can be advantageously used in pharmaceutical formulations where a high dissolution rate, ie neramexane mesylate, is required to dissolve rapidly.

  In another embodiment of the method, neramexane mesylate anhydrate in the form of a needle can be prepared starting from neramexane mesylate monohydrate, but the process can also be carried out in the presence of water neramexane mesylate. It can also be obtained in a process starting from neramexane and methanesulfonic acid, as mentioned in WO 2010/118889, which makes it possible to form a monohydrate.

  In one embodiment, water is incorporated into methanesulfonic acid.

  In another embodiment, water is added separately from methanesulfonic acid.

  In one embodiment, the monohydrate is isolated prior to step (i). In another embodiment, the monohydrate is not isolated but is obtained as an intermediate subject to the dehydration or desorption conditions described above.

Thus, in one embodiment, the method comprises step (0) prior to step (i):
(0) including a step of reacting neramexane with methanesulfonic acid in the presence of water.

Fifth Aspect In a fifth aspect, the invention relates to neramexane mesylate anhydrous crystals, wherein the crystals are needle-like.

Sixth aspect In a sixth aspect, the present invention relates to neramexane mesylate monohydrate for use as a medicament.

Seventh Aspect In a seventh aspect, the present invention relates to neramexane mesylate monohydrate for use in the treatment of tinnitus or skin diseases such as acne.

  In one embodiment of the sixth or seventh aspect, the monohydrate is in the form of a plate-like crystal.

Eighth aspect In an eighth aspect, the present invention relates to neramexane mesylate anhydrate for use as a medicament, wherein neramexane mesylate anhydrate is in the form of needle-like crystals.

Ninth aspect In a ninth aspect, the present invention relates to neramexane mesylate anhydrate in the form of needle-like crystals for use in the treatment of tinnitus or skin diseases such as acne.

Example 1
About 200 mg of neramexane mesylate anhydride is placed in an aluminum crucible and then placed in an apparatus for dynamic vapor adsorption. The reaction humidity is increased to 95-97% relative humidity at room temperature for 2 days until dissolution is observed. The material is then stored at 75% relative humidity for 1 day at room temperature until the material recrystallizes. The amount of water absorbed corresponds to the monohydrate. The product can be characterized by X-ray powder diffraction (Figure 5). Water uptake is reversible as shown by dynamic vapor adsorption experiments.

Example 2
100 mg of neramexane mesylate was dissolved in water to prepare a saturated solution. The precipitated crystals are isolated and characterized as a monohydrate.

Example 3
Plate-like crystals of neramexane mesylate monohydrate are stored at a relative humidity of less than 50%. Dehydration or elimination of water forms neramexane mesylate anhydride. Crystals have a needle-like tendency.

Example 4
A saturated solution of neramexane mesylate in water is placed on a glass slide. At ambient conditions, as the solvent evaporates, crystals with a needle-like tendency are formed. The product is neramexane mesylate anhydride.

Claims (13)

A method for preparing neramexane mesylate monohydrate, comprising steps (i) to (iii):
(I) a step of exposing neramexane mesylate to a humid atmosphere (ii) a step of suspending neramexane mesylate in water (iii) including one of the steps of saturating neramexane mesylate with neramexane mesylate ,Method.   The process according to claim 1, wherein the neramexane mesylate monohydrate is obtained in the form of plate-like crystals.   Neramexane mesylate monohydrate.   Neramexane mesylate monohydrate crystals, wherein the crystals are plate-like. A process for preparing neramexane mesylate anhydride, comprising step (i):
(I) A method comprising the step of dehydrating neramexane mesylate monohydrate.   6. The method according to claim 5, wherein the neramexane mesylate anhydride is obtained in the form of needle-like crystals having an aspect ratio of 15 or more or 20 or more. Step (0) before step (i):
The method according to claim 5 or 6, further comprising a step of reacting neramexane with methanesulfonic acid in the presence of water.   Neramexane mesylate anhydride crystals, wherein the crystals are needle-like and the aspect ratio is 15 or 20 or more.   Neramexane mesylate monohydrate for use as a medicament.   Neramexane mesylate monohydrate for use in the treatment of tinnitus or acne.   11. Neramexane mesylate monohydrate for use according to claim 9 or 10, wherein the neramexane mesylate monohydrate is in the form of plate-like crystals.   Neramexane mesylate anhydrate crystal for use as a medicament, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals and the aspect ratio is 15 or greater or 20 or greater.   Neramexane mesylate anhydrate for use in the treatment of tinnitus or acne, wherein the neramexane mesylate is in the form of needle-like crystals and the aspect ratio is 15 or 20 or more.

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