WO2013072050A1

WO2013072050A1 - Neramexane mesylate monohydrate and anhydrate

Info

Publication number: WO2013072050A1
Application number: PCT/EP2012/004734
Authority: WO
Inventors: Guenther Quack; Patrick Plitt
Original assignee: Merz Pharma GmbH and Co KGaA
Current assignee: Merz Pharma GmbH and Co KGaA
Priority date: 2011-11-15
Filing date: 2012-11-14
Publication date: 2013-05-23
Anticipated expiration: 2014-05-15
Also published as: JP2015501789A

Abstract

Method of preparing neramexane mesylate monohydrate, comprising one of steps (i) (iii): (i) exposing neramexane mesylate anhydrate to a humid atmosphere; (ii) suspending neramexane mesylate anhydrate in water; (iii) saturating water with neramexane mesylate.

Description

NERAMEXANE MESYLATE MONOHYDRATE AND ANHYDRATE

FIELD OF THE INVENTION

[0001] The invention relates to a hydrate of neramexane mesylate and crystal modifications of neramexane mesylate anhydrate. The invention further relates to a method of preparing said anhydrate from said hydrate, and to the use of said hydrate and anhydrate in medical applications.

BACKGROUND OF THE INVENTION

[0002] Neramexane mesylate is a valuable agent for the continuous therapy of patients suffering from diseases and conditions such as tinnitus or skin diseases such as acne.

[0003] WO 2010/118889 discloses the preparation of neramexane mesylate starting from neramexane and methane sulfonic acid. The product may be obtained by crystallization, respectively re-crystallization, in various solvents and by subsequent drying. Depending on the crystallization conditions, respectively re-crystallization conditions, the product may be obtained in the form of columnar-like or star-shaped or plate-like crystals. These modifications represent a water-free product, i.e., neramexane mesylate anhydrate. Re-crystallization of neramexane mesylate from acetone and dichloromethane may result in solvates.

[0004] Crystalline forms of neramexane mesylate, which can be obtained by crystallization from different solvents, including water, are also known from Steffen Schweizer: "Erstellung eines Praeformulierungskonzeptes fur mittelstandische Pharmaunternehmen unter besonderer Berucksichtigung der physikalisch- chemischen Eigenschaften neuer Arzneistoffe, dargestellt am Beispiel der NMDA- Antagonisten MRZ 2/579 und MRZ 2/576", Dissertation, Johann-Wolfgang-Goethe- Universitat Frankfurt am Main, 2001 , pages 188 - 196.

[0005] It is known that solvates of an agent used in medical applications may have different properties compared to the non-solvated agent. It is further known that different crystal forms of a drug may also provide for different properties.

OBJECTS OF THE INVENTION

[0006] It is an object of the invention to investigate whether neramexane mesylate may be obtained in solvate forms different from solvates with acetone and dichloromethane, respectively whether neramexane mesylate may be obtained in further crystal forms, and whether such solvates and crystal modifications may be used in medical applications.

SUMMARY OF THE INVENTION

[0007] This object is achieved with neramexane mesylate monohydrate and neramexane mesylate anhydrate, wherein the anhydrate is obtained from the monohydrate in the form of needle-like crystals, and the methods of preparing said compounds.

[0008] Accordingly, a first aspect of the invention relates to a method of preparing neramexane mesylate monohydrate, comprising one of steps (i) to (iii):

(i) exposing neramexane mesylate anhydrate to a humid atmosphere;

(ii) suspending neramexane mesylate anhydrate in water;

(iii) saturating water with neramexane mesylate. [0009] In one embodiment of this aspect, said neramexane mesylate monohydrate is obtained in the form of plate-like crystals.

[0010] In a second aspect, the invention relates to neramexane mesylate monohydrate.

[001 1] In a third aspect, the invention relates to a neramexane mesylate monohydrate crystal, wherein the crystal is plate-like.

[0012] In a fourth aspect, the invention relates a method of preparing neramexane mesylate anhydrate, comprising step (i):

(i) dehydrating neramexane mesylate monohydrate.

[0013] In one embodiment of this aspect, said neramexane mesylate anhydrate is obtained in the form of needle-like crystals.

[0014] In one embodiment, the aspect ratio of the needle-like crystals is 15 or more, or 20 or more.

[0015] In one embodiment of this aspect or the foregoing embodiments of this aspect, said method further comprises step (0) prior to step (i):

(0) reacting neramexane with methane sulfonic acid in the presence of water.

[0016] In a fifth aspect, the invention relates to a neramexane mesylate anhydrate crystal, wherein the crystal is needle-like. [0017] In one embodiment, the aspect ratio of the needle-like crystals is 15 or more, or 20 or more.

[0018] In a sixth aspect, the invention relates to neramexane mesylate monohydrate for use as a medicament.

[0019] The sixth aspect also pertains to a pharmaceutical composition comprising an effective amount of neramexane mesylate monohydrate.

[0020] In a seventh aspect, the invention relates to neramexane mesylate monohydrate for use in the treatment of tinnitus or acne.

[0021] The seventh aspect also pertains to the use of neramexane mesylate monohydrate for the manufacture of a pharmaceutical composition for the treatment of tinnitus or acne.

[0022] The seventh aspect also pertains to a method of treating a patient suffering from tinnitus or acne, comprising: administering to said patient an effective amount of neramexane mesylate monohydrate.

[0023] In one embodiment of the sixth or seventh aspect, the neramexane mesylate monohydrate is in the form of plate-like crystals.

[0024] In an eighth aspect, the invention relates to neramexane mesylate anhydrate for use as a medicament, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals. [0025] The eighth aspect also pertains 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.

[0026] In one embodiment, the aspect ratio of the needle-like crystals is 15 or more, or 20 or more.

[0027] In a ninth aspect, the 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.

[0028] The ninth aspect also pertains 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.

[0029] The ninth aspect also pertains to a method of treating a patient suffering from tinnitus or acne, comprising: administering to said patient an effective amount of neramexane mesylate anhydrate, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals.

[0030] In one embodiment, the aspect ratio of the needle-like crystals is 15 or more, or 20 or more.

BRIEF DESCRIPTION OF THE FIGURES

[0031] Figure 1 shows a light microscopic image of neramexane mesylate anhydrate, wherein the crystals are plate-like when prepared and / or crystallized from an organic solvent according to methods disclosed in WO 2010/118889.

[0032] Figure 2 shows a light microscopic image of neramexane mesylate monohydrate, wherein the crystals are plate-like.

[0033] Figure 3 shows light microscopic images of neramexane mesylate anhydrate obtained from neramexane mesylate monohydrate by drying the monohydrate in air, wherein needle-like crystals are formed.

[0034] Figure 4 shows a powder X-ray diffraction diagram of neramexane mesylate anhydrate using: a Bruker D8 Advance diffractometer in Bragg-Brentano reflection geometry; Cu K_a radiation; 40 kV/40 mA; variable divergence slit; LynxEye detector with 3° window; step size 0.02° 2Θ; step time, 37 s, scanning range 2-50° in 2Θ. The samples are rotated (0.5 rps) during the measurement. The samples are prepared without any special treatment other than slight pressure to get a flat surface. The measurement is performed at ambient laboratory conditions in a silicon single crystal sample holder, 0.1 or 1 mm deep.

[0035] Figure 5 shows the respective powder X-ray diffraction diagram of neramexane mesylate monohydrate.

[0036] Figure 6 shows another light microscopic image of neramexane mesylate anhydrate obtained from neramexane mesylate monohydrate by drying the monohydrate in air, wherein needle-like crystals are formed. DETAILED DESCRIPTION OF THE INVENTION

First Aspect

[0037] According to a first aspect, the invention relates to a process for preparing neramexane mesylate monohydrate.

[0038] The term "neramexane" refers to 1-amino-1 ,3,3,5,5-pentamethylcyclohexane. This definition as well as the other definitions used herein refer to definitions as used in the meaning of the invention.

[0039] The term "neramexane mesylate" refers to 1-amino-1 ,3,3,5,5- pentamethylcyclohexane methane sulfonate.

[0040] The term "neramexane mesylate monohydrate" encompasses a product, in which 1-amino-1 ,3,3,5,5-pentamethylcyclohexane mesylate is associated with water. Specifically, the term "monohydrate" encompasses a product in which one molecule of neramexane mesylate is associated with one molecule of water, or with approximately one molecule of water.

[0041] The term "approximately" encompasses a product having a water content of from 3 to 8 wt.-% or 4 to 7 weight % based on the total weight of neramexane mesylate monohydrate which refers to 100 wt %.

[0042] In one embodiment, the term "neramexane mesylate monohydrate" comprises neramexane mesylate in which water is incorporated on lattice sites of the crystal lattice of neramexane mesylate. [0043] In another embodiment, the term "neramexane mesylate monohydrate" encompasses a product in which water adheres to neramexane mesylate without being incorporated on lattice sites.

[0044] The neramexane mesylate monohydrate may be prepared starting from neramexane mesylate anhydrate as e.g. obtained according to one of the methods disclosed in WO 2010/118889.

[0045] The term "neramexane mesylate anhydrate" encompasses neramexane mesylate which is free of water.

[0046] The term "free of water" encompasses a water content below 3 % by weight based on the total amount of water and anhydrate.

[0047] 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.

[0048] The term "humid" encompasses a relative humidity of from 80 to 100 %, or from 85 to 100 %, or from 90 to 100 %, or from 95 to 100 %, or from 95 to 97 %. The relative humidity may be determined according to known methods, e.g. with a hygrometer. The term "humid" is synonymously used to the term "moist".

[0049] In one embodiment, said relative humidity relates to the relative humidity at ambient temperature. In one embodiment, the temperature is in the range of from 15 to 30 °C, or from 20 to 25 °C. [0050] In such humid atmosphere, neramexane mesylate anhydrate may absorb water and may form the monohydrate. The formation of the monohydrate may be detected by the known method of measuring the dynamic vapor sorption (DVS). Said method is a gravimetric technique that measures how quickly and how much of water is absorbed by a sample, such as by a dry powder of neramexane mesylate anhydrate. Herein, the vapor concentration surrounding the sample is varied and the change in mass which this produces is measured. In doing so, the monohydrate of neramexane mesylate may be identified. It may be further characterized by e.g. X-ray diffraction analysis.

[0051] The DVS measurements reveal that the water uptake is reversible depending on the humidity and / or the temperature. If neramexane mesylate monohydrate is exposed to an atmosphere having a relatively low humidity, water is desorbed from the monohydrate and the anhydrate is formed.

[0052] The term "relatively low humidity" encompasses a humidity below 70 %, or below 60 %, or below 50 %.

[0053] In another embodiment of the method, neramexane mesylate anhydrate may be re-crystallized or crystallized from water, whereby the monohydrate is formed.

[0054] In one embodiment of the method, the term "re-crystallized" or "crystallized" as used within this context encompasses the suspending of neramexane mesylate in water, wherein the mesylate absorbs water to form monohydrate crystals. After filtration, neramexane mesylate monohydrate may be obtained.

[0055] In another embodiment of the method, the term "re-crystallized" as used within this context encompasses the dissolving of neramexane mesylate in water such as to saturate the water with the mesylate. Subsequently, the monohydrate may start precipitating and may be isolated by filtration. If necessary, the precipitation may be supported by the removal of some of the water.

[0056] Accordingly, in one embodiment, the invention relates to a method of preparing neramexane mesylate monohydrate, the method comprising step (i) or step (ii) or step (iii), or consisting of step (i) or step (ii) or step (iii):

(i) exposing neramexane mesylate anhydrate to a humid atmosphere to allow the anhydrate to absorb water and to form the neramexane mesylate monohydrate; or

(ii) suspending neramexane mesylate anhydrate in water to allow the anhydrate to absorb water and to form the neramexane mesylate monohydrate, and subsequently isolating the monohydrate, e.g. by filtration; or

(iii) saturating water with neramexane mesylate and isolating crystallizing product, e.g. by filtration.

[0057] In one embodiment, the neramexane mesylate monohydrate obtained in the method according to step (i) or step (ii) or step (iii) crystallizes in the form of plate-like crystals.

[0058] The inventors' discovery that a neramexane mesylate monohydrate is formed from neramexane mesylate anhydrate in the presence of water, e.g. in step (iii), is surprising in view of the above Schweizer-reference that explicitly teaches at page 196 that the process of recrystallizing neramexane mesylate in water does not lead to the formation of a hydrate form. Second aspect

[0059] In a second aspect, the invention relates to neramexane mesylate monohydrate.

Third aspect

[0060] In a third aspect, the invention relates to neramexane mesylate monohydrate in the form of solid material, i.e., in the form of crystals.

[0061] In one embodiment, the neramexane mesylate monohydrate is in the form of plate-like crystals.

Fourth aspect

[0062] In a fourth aspect, the invention relates to a method of preparing neramexane mesylate anhydrate. This method encompasses the removal of water from neramexane mesylate monohydrate.

[0063] Accordingly, in one embodiment, the method comprises step (i) or consists of step (i):

(i) dehydrating neramexane mesylate monohydrate wherein neramexane mesylate anhydrate is obtained.

[0064] In one embodiment, the removal of water from neramexane mesylate monohydrate, i.e., the dehydration or the desorption of water, may be effected by subjecting neramexane mesylate monohydrate to an atmosphere which has a low humidity as already referred to in the respective embodiments of the first aspect.

[0065] In another embodiment, the removal of water from neramexane mesylate monohydrate, i.e., the dehydration or desorption of water, may be effected by subjecting neramexane mesylate monohydrate to elevated temperature and / or to reduced pressure.

[0066] The term "elevated temperature" encompasses a temperature which is sufficient to remove water but is insufficient to decompose the formed neramexane mesylate anhydrate.

[0067] In one embodiment, the temperature is from 30 to 200 °C, or from 30 to 180

°C.

[0068] The term "reduced pressure" encompasses a pressure below 1 bar.

[0069] Accordingly, in one embodiment, the invention relates to a method of preparing neramexane mesylate anhydrate from neramexane mesylate monohydrate, wherein step (i) comprises one or two or three steps of steps (j) to (jjj). or consisting of one or two or three steps of steps (j) to (jjj):

(j) exposing neramexane mesylate monohydrate to a humid atmosphere such as humid air, wherein the relative humidity of the atmosphere is below 70 %;

Gj) exposing neramexane mesylate monohydrate to an elevated temperature, wherein the temperature is in the range of from 30 to 200 °C;

Gjj) exposing neramexane mesylate monohydrate to a reduced pressure, wherein the pressure is below 1 bar.

[0070] The neramexane mesylate anhydrate obtained in the method according to the fourth aspect is obtained in the form of needle-like crystals. This is surprising since the crystal habitus of neramexane mesylate anhydrate as obtained in the methods according to the prior art WO 2010/1 18889, wherein organic solvents are used for crystallization or recrystallization, is columnar-like or star-shaped or plate-like.

[0071] In principal the dimension which should ideally be used in completely defining a crystal's habit are width, thickness and length, all being orthogonally to each other. However, since only two dimensions can be accurately quantified microscopically, the simplest system of habit description involves quantifying the length to the width ratio which is readily attainable microscopically. The length is always defined as the longest dimension and the width as the shortest dimension. Thus, the "aspect ratio" referred to herein is defined as the ratio of the length of the crystal to the width of the crystal.

[0072] The term "needle-like crystals" as used in this disclosure refers to crystals having an aspect ratio of 15 or more. In one embodiment, the aspect ratio is 20 or more. In still another embodiment, the aspect ratio is 30 or more or 40 or more or 50 or more.

[0073] In one embodiment, the upper limit of the aspect ratio 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.

[0074] In one embodiment, the aspect ratio is from 15 to 1 ,000 or from 20 to 1 ,000 or from 30 to 1 ,000, or from 40 to 1 ,000 or from 50 to 1 ,000; or from 15 to 500 or from 20 to 500 or from 30 to 500, or from 40 to 500 or from 50 to 500; or from 15 to 400 or from 20 to 400 or from 30 to 400, or from 40 to 400 or from 50 to 400; or from 15 to 300 or from 20 to 300 or from 30 to 300, or from 40 to 300 or from 50 to 300; or from 15 to 200 or from 20 to 200 or from 30 to 200, or from 40 to 200 or from 50 to 200; or from 15 to 100 or from 20 to 100 or from 30 to 100, or from 40 to 100 or from 50 to 100. [0075] The aspect ratio is determined by means of scanning electron microscopy (SEM). Such method is known in the art. A typical method comprises the spreading of a sample onto a pure aluminum support and the subsequent sputter-coating with a thin layer of Pd/Au, wherein the thickness is in the nanometer range. A sputter coater SCD 030 (Balzers) may be used. Images may be taken at e.g. 150-fold magnification using e.g. a JSM 6400 Scanning Electron Microscope (JEOL, Japan) at an acceleration voltage of 20 keV and a working distance of 15 mm. Electronic filtering and thresholding may be used to improve the separation of particles in binary images from the background. For image analysis, commercially available analysis software may be used, e.g. Analysis, SIS, Muenster, Germany. The software detects and assesses particles in the image automatically and classifies them according to the aspect ratio.

[0076] Such needle-like crystals provide for higher surface areas as e.g. compared to plate-like crystals. As a result, the dissolution rates of said needle-like crystals are higher as compared to the dissolution rates of plate-like crystals. Due to this, the needle-like crystals may be advantageously used in pharmaceutical formulations where a high dissolution rate is required, i.e., where neramexane mesylate is to be rapidly dissolved.

[0077] In another embodiment of the method, neramexane mesylate anhydrate in the form of needles may not only be prepared starting from neramexane mesylate monohydrate, but may also be obtained in a process starting from neramexane and methane sulfonic acid as referred to in WO 2010/118889, provided the process is run in the presence of water such as to allow the formation of neramexane mesylate monohydrate.

[0078] In one embodiment, water is incorporated within the methane sulfonic acid. [0079] In another embodiment, water is added separately from methane sulfonic acid.

[0080] In one embodiment, the monohydrate is isolated prior to step (i). In another embodiment, the monohydrate is not isolated as such but obtained as intermediate which is subjected to the above dehydration or desorption conditions.

[0081] Accordingly, in one embodiment, the method comprises prior to step (i) step (0):

(0) reacting neramexane with methane sulfonic acid in the presence of water. Fifth aspect

[0082] In a fifth aspect, the invention relates to a neramexane mesylate anhydrate crystal, wherein the crystal is needle-like.

Sixth aspect

[0083] In a sixth aspect, the invention relates to neramexane mesylate monohydrate for use as a medicament.

Seventh aspect

[0084] In a seventh aspect, the invention relates to neramexane mesylate monohydrate for use in the treatment of tinnitus or a skin disease such as acne.

[0085] In one embodiment of the sixth or the seventh aspect, the monohydrate is used in the form of plate-like crystals. Eighth aspect

[0086] In an eighth aspect, the invention relates to neramexane mesylate anhydrate for use as a medicament, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals.

Ninth aspect

[0087] In a ninth aspect, the invention relates to neramexane mesylate anhydrate in the form of needle-like crystals for use in the treatment of tinnitus or a skin disease such as acne.

EXAMPLES

Example 1

[0088] Approximately 200 mg of neramexane mesylate anhydrate are placed in an aluminum crucible which is then placed into an instrument for determining dynamic vapor sorption. The reactive humidity is increased to 95 to 97 % relative humidity at ambient temperature for two days until deliquescence is observed. Subsequently, the material is stored at 75 % relative humidity at ambient temperature for one day until the material recrystallizes. The absorbed amount of water corresponds to the monohydrate. The product may be characterized by X-ray powder diffraction (Fig. 5). The water uptake is reversible as may be shown by dynamic vapor sorption experiments.

Example 2

[0089] 100 mg of neramexane mesylate are dissolved in water to prepare a saturated solution. Precipitating crystals are isolated and are characterized as the monohydrate.

Example 3

[0090] Plate-like crystals of neramexane mesylate monohydrate are stored at a relative humidity below 50 %. Upon dehydration or desorption of water, neramexane mesylate anhydrate is formed. The crystals have a needle-like habit.

Example 4

[0091] A saturated solution of neramexane mesylate in water is placed on a glass slide. Upon evaporation of the solvent at ambient conditions crystals are formed which have a needle-like habit. The product is neramexane mesylate anhydrate.

Claims

1. Method of preparing neramexane mesylate monohydrate, comprising one of steps (i) to (iii):

(i) exposing neramexane mesylate anhydrate to a humid atmosphere;

(ii) suspending neramexane mesylate anhydrate in water;

(iii) saturating water with neramexane mesylate.

2. Method of claim 1 , wherein said neramexane mesylate monohydrate is obtained in the form of plate-like crystals.

3. Neramexane mesylate monohydrate.

4. Neramexane mesylate monohydrate crystal, wherein the crystal is plate-like.

5. Method of preparing neramexane mesylate anhydrate, comprising step (i): (i) dehydrating neramexane mesylate monohydrate.

6. Method of claim 5, wherein the neramexane mesylate anhydrate is obtained in the form of needle-like crystals, wherein the aspect ratio is 15 or more, or 20 or more.

7. Method of claim 5 or 6, further comprising step (0) prior to step (i):

(0) reacting neramexane with methane sulfonic acid in the presence of water;

8. Neramexane mesylate anhydrate crystal, wherein the crystal is needle-like, wherein the aspect ratio is 15 or more, or 20 or more.

9. Neramexane mesylate monohydrate for use as medicament.

10. 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.

12. Neramexane mesylate anhydrate for use as medicament, wherein the neramexane mesylate anhydrate is in the form of needle-like crystals, wherein the aspect ratio is 15 or more, or 20 or more.

13. 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, wherein the aspect ratio is 15 or more, or 20 or more.