FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
Crystal modification of 5-substituted-2-oxazolidone derivative and its process
thereof
2. APPLICANT (S)
(a) NAME: FDC Ltd.
(b)NATIONALITY: Indian company incorporated under the Companies
Act 1956
(c) ADDRESS: B-8, MIDC Industrial Estate, Waluj - 431136, Maharashtra,
India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it is to be performed.


Technical Field:
The invention relates to novel crystalline Polymorphic Form 1 of 5- (3,5-
Dimethylphenoxymethyl)-2-oxazolidinone (Metaxalone), to process for the preparation
thereof and to its pharmaceutical compositions containing this crystal form.
Background and Prior Art:
5-Aryloxymethyl-2-oxazolidinones are a group of compounds, which are well-known for
exhibiting activity as depressants of central synaptic transmission.
Among the leading active skeletal muscle relaxants of the class,
5-Aryloxymethyl-2-oxazolidinones is 5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone
genetically known as Metaxalone is indicated for the relief of discomforts associated with
acute, painful musculoskeletal conditions. It acts on the central nervous system (CNS) to
produce the muscle relaxant effects.
United States Patent No, 3062827 refers to 5- (3', 5'-dialkylphenoxymethyl)-2-
oxazolidinone and by way of an example describes preparation of 5-(3',5'-
dimethylphenoxyfnethyl)-2-oxazolidinone.
United States Patent No. 3446814 claims a method of preparing 5-(3,5-
dimethyIphenoxymethyl)-2-oxazolidinone.
WO2003061552 claims a novel process for the preparation of 5- (3, 5-
dimethylphenoxymethyl)-2-oxazolidinone and also claims a process for purifying 5- (3, 5-
dimethylphenoxy methyl)-2-oxazolidinone by crystallizing 5- (3, 5- dimethylphenoxy
methyl)-2-oxazolidinone from a mixture of organic solvents. It further claims that the
crystallized 5- (3, 5- dimethylphenoxy methyl)-2-oxazolidinone thus obtained is substantially
pure form having purity greater than 99.5% and none of the individual impurity is more than
0.05%.
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None of the prior art references reveal about the existence of polymorph of 5- (3, 5-
dimethylphenoxy methyl)-!-oxazolidinone nor do they claim the process of making any
particular polymorph of 5- (3, 5- dimethylphenoxy methyl)-2-oxazolidinone.
The occurrence of different crystalline forms of the same compound is termed as
polymorphism. The physical properties vary with crystal structure, hence polymorphism can
influence many important properties of pharmaceuticals such as bioavailability, dissolution
rate, compressibility, solubility, stability, etc. The melting points and the X-ray diffraction
pattern also differ.
Differential scanning calorimetry and X-ray diffraction spectroscopy and some other physical
methods are used to distinguish between the polymorphic forms.
The aim of the present invention is to provide a stable crystalline Polymorphic Form of
metaxalone which is useful in stable pharmaceutical preparations. Hence the present
invention is aimed to provide a crystalline Polymorphic Form of metaxalone referred herein
further as Polymorph Form I, which has many advantageous properties like stability,
solubility, enhanced bioavailability, compressibility and better dissolution rate.
Objects of the Invention:
An object of the invention is to provide a stable crystalline Polymorphic Form-1 of the
Compound, 5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone.
Another object of the invention is to provide Polymorphic Form -I of compound, 5- (3, 5-
dimethylphenoxymethyl)-2-oxazolidinone with various advantageous properties which is
useful to pharmacist.
Yet another object of the invention is to provide processes for the preparation of crystalline
Polymorphic Form -I of 5- (3, 5- dimethylphenoxymethyI)-2-oxazolidinone.
Further object of the invention is to provide a process, which is economical and commercially
viable to prepare the said Polymorphic Form.
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Yet another object is to provide Polymorphic Form -I of a compound, 5- (3, 5-
dimethylphenoxymethyl)-2-oxazolidinone which has better thermal stability. The improved
thermal stability of the Polymorphic Form I provide substantial therapeutic benefit to the
patients through use of dosage forms, compositions and combinations thereof.
Summary of the Invention:
The present invention discloses a novel crystalline Polymorphic Form I of a compound, 5- (3,
5- dimethylphenoxymethyl)-2-oxazolidinone, which provide substantial therapeutic benefit to
the patients through use of dosage forms, compositions and combinations thereof. The
present invention also discloses processes for preparation of the said Polymorphic Form I of
5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone. The process which comprises dissolving
amorphous form or a mixture containing Polymorphic Form 1 and amorphous form of 5- (3,
5-dimethylphenoxymethyl)-2-oxazolidinone in a polar solvent, charcoalising the solution
thus obtained, filtering, adding an anti solvent to the filtrate, optionally heating to clarity;
cooling to 5°C - 10°C under stirring and filtering to obtain the crystalline Polymorphic Form
I.
Description of the drawings:
Figure 1: Thermal Analysis Result of Crystal form Polymorphic Form I.
Figure 2; XRPD data of Crystal form Polymorphic Form I.
Detailed Description of the Invention:
According to one embodiment of the invention there is provided a crystalline form of the
compound of formula (1), which is referred herein as Polymorphic Form I. This Polymorphic
Form I has better thermal stability. The improved thermal stability of the Polymorphic Form I
provide substantial therapeutic benefit to the patients through use of dosage forms,
compositions and combinations thereof
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Formula (t)
In the X-ray diagram, the angle of refraction 2theta is plotted on the horizontal axis (X-axis)
and the relative line intensity (counts) on the vertical (Y-axis). X-ray diffraction diagram is
recorded on film using PC-APD Diffraction Software (Diffractometer type PW -1710 based)
is depicted in Figure 2.
The Polymorphic form I is characterized by x-ray diffraction pattern having peaks at 10.355,
14.285,18.625, 19.030, 20.810 and 22,475± 0.30 degrees 2 theta angle.
The crystalline Polymorphic Form 1 which comprises at least 95% by weight of crystals of
the Polymorphic Form I; remains essentially dry in a glass climatic chamber at 40°C and
relative humidify up to75 %. The crystalline Polymorphic Form I which comprises at least
99% by weight of crystals of Polymorphic Form I remains dry in a glass climatic chamber at
40% relative humidity and at 75°C. This analytical data and observation proves conclusively
that Polymorphic Form I has substantially improved thermal stability, thereby enabling the
Polymorphic Form 1 to contribute substantial therapeutic benefits not only to the molecule as
such but also to the dosage forms thereof.
In accordance, figure 2 provides following angles of refraction 2theta with % relative
intensities
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Polymorphic Form I

Angle (20) % Relative intensity
7.915 13.4
10.355 100.00
14.125 29.7
14.285 26.1
18.265 13.7
18,625 18.3
18.890 19.2
19.030 21.4
20.810 33.2
21.655 19.9
22.475 24.4
24.575 11.1
29.720 10.5
Melting point is determined by means of a DSC thermogram using a Shimadzu DSC -60.
(Differential Scanning Calorimetry) is the technique used in determining the melting point
that can be measured by heating the samples until a thermal i.e. an endothermic or
exothermic reaction is detected by means of ultra sensitive sensors. The melting point is
determined using about 3.0 to 4.0 mg of the sample in an aluminium crucible with a
perforated plate under a quiescent atmosphere of air at a heating rate of 2°C per minute.
The invention relates to crystal form Polymorphic Form I of a compound of formula (1)
having irregular, elongated rod shaped crystals.
The invention relates to essentially pure crystal form, referred to hereinafter as the
Polymorphic Form 1 of a compound of formula (1).
The new crystal form, the Polymorphic Form I, has the following properties.
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i) The melting point of the Polymorphic Form I form in the DSC thermogram has a
mehing point less than 125°C, especially between 121° to 125° C as indicated in
Figure 1.
ii) The X-ray diffraction diagram of the Polymorphic Form I as indicated in Figure 2.
iii) Crystalline Polymorphic Form I of the compound of formula (1) has a melting point
less than 125°C,especially between 122.5°Cand I24°C.
iv) Preference is for the crystalline Polymorphic Form I of the compound of formula (1)
which shows the peak marked in Figure 2.
(v) Still more preference is for the crystalline Polymorphic Form I of compound of the
formula (1) which shows an X-ray diffraction diagram of the type shown in Fig 2.
In all cases, Polymorphic Form I of the compound of formula (1) comprising the
corresponding above-mentioned crystal form is also taken to be meant in a wider
aspect of the invention..
The Polymorphic Form 1 of a compound of formula (1) is prepared by
a) dissolving an amorphous form or a mixture containing crystal and amorphous form of
the compound of formula (1) in a suitable polar solvent at reflux temperature,
b) adding activated charcoal to the solution of step (a) generally at a temperature ranging
from 50- 65 °C and preferably at 60-65 °C under stirring for a suitable period of time;
c) filtering the solution through hyflo and washing with suitable polar solvent;
d) adding an anti solvent to step (c) solution , optionally heating to clarity, cooling to
25°~C to 35 °C under stirring for about 12 hours,
e) cooling the solution of step( d) further to a temperature of 5°C-10°~C,and
f) filtering the solution to isolate the polymorphic Form I of the compound of formula
0).
The polar solvent is selected from the group consisting of methanol, ethanol and isopropanol.
One preferred solvent is methanol.
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The anti solvent is a hydrocarbon solvent, selected from the group consisting of pet. ether,
ethyl acetate, ether, dh'sopropyl ether, n-hexane, toluene, xylene and benzene. The preferred
solvent is toluene.
In the above condition on the selective preparation of the crystal form, parameter such as the
weight ratio of a compound of formula (1) to the solvent can be varied. It is also possible to
vary the time needed for the preparation of the Polymorphic Form I.
The Polymorphic Form I of the present invention can be used in pharmaceutical preparations
such as tablets, capsules, solutions, suspensions etc. The present invention also describes the
use of the said polymorphic form of metaxalone in the treatment of depression of central
synaptic transmissions.
The invention is further illustrated with the following examples and should not be construed
to limit the scope of the present invention. The features of the present invention will become
more apparent from the following description of the inventive concept and the description of
the preferred embodiments and appended claims.
Examples
Example I:
An amorphous form of 5-(3,5-Dimethylphenoxy-) methyl)-2-oxazolidinone(20 gms)was
heated with methanol(70ml) to a clear solution at reflux temperature . To it added(lgm)
charcoal in methanol slurry and further heated to reflux. Charcoal!sed solution was filtered
through hyflo at 60-65^, added toluene(lOml) to the filtered solution, heated to clarity. The
solution was cooled to 25-30°C under stirring for 12 hours and further cooled to
a temperature of about 5-10°C. The product Polymorphic Form I obtained was
filtered, washed with methanol (20ml) and dried at 65 to 70°C.
Yield-(16.8gms)
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Example II:
A mixture containing amorphous and Polymorphic Form I of 5-(3,5-dimethylphenoxy-)
methyl)-2-oxazolidinone(10 gms) was heated with methanol (35 ml )to a clear solution at
reflux temperature .To it added charcoal (0.5 gm) in methanol slurry and further heated to
reflux. Charcoalised solution was filtered through hyflo at 60-65°C,added toluene( 5ml) to the
filtered solution, heated to clarity. The solution was cooled to 25-30°Cunder stirring for
12 hours and further cooled to a temperature of about 5°-10°C.The product Polymorphic Form 1
obtained was filtered, washed with methanol(lOml) and dried at 65 to 70°C.
Yield-(8.3g)
The polymorph obtained in examples I and II showed sharp melting point at 123°C and the
DSC pattern shows sharp peak at 123.56°C. The X-Ray powder diffraction study confirms
the crystalline nature of Polymorphic Form..

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We Claim,
1) A novel Polymorphic Form I of 5-(3,5-Dimethyiphenoxymethyl) -2-oxazoIidinone
compound of formula (1) with improved thermal stability, which is characterized by

Formula (1)
x-ray diffraction pattern having peaks at 30.355, 14.285,18.625, 19.030, 20.810 and 22.475±
0.30 degrees 2 theta angle as in Fig 2.
2) The crystalline Polymorphic Form 1 according to claim 1, characterized to possess
improved thermal stability, comprising at least 95% by weight of crystals of the Polymorphic
Form I which remains essentially dry in a glass climatic chamber at 40°C and relative
humidity up to75 % .
3) The crystalline Polymorphic Form I according to claim 1, characterized to possess
improved thermal stability, which comprises at least 99% by weight of crystals of
Polymorphic Form I which remains essentially dry in a glass climate chamber at 40%
relative humidity and 75°C.
4) The crystalline Polymorphic Form I according to claim 1, characterized to have a
melting point in the range of 122.5 - 124 ° C, and more precisely a melting point of 123.75°
C, as detected in the Differential Scanning Calorimetry thermogram as in Fig 1.
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5) The crystalline Polymorphic Form I having improved thermal stability according to
claims 1 to 4 for preparation of medicaments useful in the treatment of depression of central
synaptic transmissions.
6) A pharmaceutical composition comprising crystalline Polymorphic Form I having
improved thermal stability according to claims 1 to 4 and a pharmaceutically acceptable
carrier for preparation of dosage forms thereof.
7) Process for the preparation of crystalline Polymorphic Form I of a compound of formula
(1) characterized by XRPD and DSC, wherein said process comprising the steps of:
a) dissolving an amorphous form or any other crystal form of compound of formula(l) in a
suitable polar solvent at reflux temperature,
b) adding activated charcoal to the solution of step (a) at a temperature ranging between 50
-65 °C and preferably 60-65 °C under stirring for a suitable period of time;
c) filtering the above solution through hyflo and washing with suitable polar solvent,
d) adding anti solvent to step (c) solution;
e) optionally heating to reflux temperature and cooling to 25°C to 35 °C under stirring for
about 12 hours,

f) cooling further the solution of step( e) to a temperature of 5°C-10°C and
g) filtering the solution to isolate the Polymorphic Form I of the compound of formula (1).

8) The process of claim 7, wherein the polar solvent used in step (a), is selected from
methanol, ethanol and isopropanol.
9) The process of claim 7, wherein the anti solvent used in step(d) is a hydrocarbon solvent.
10) The process of claim 9, wherein said hydrocarbon solvent is selected from the group
consisting of pet. Ether, ethyl acetate, ether, di-isopropyl ether, n-hexane, toluene, xylene
and benzene.
11) The process of claim 10, wherein the preferred hydrocarbon solvent is toluene.
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12) A polymorphic Form I of compound of formula (1) having improved thermal stability
according to claiml, process for its preparation, pharmaceutical compositions comprising
it and its use in the treatment of depression of central synaptic transmissions.
Dated this 23rd day of January 2006

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