FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION
"LORNOXICAM SOLVATES AND PROCESSES FOR THEIR
PRODUCTION"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE
MANNER IN WHICH IT IS TO BE PERFORMED


BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to solvates of Lornoxicam, processes for their
preparation and use of the solvates in pharmaceutical compositions.
2. Description of the Related Art
Lornoxicam, also known as 6-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)-2H-
thieno[2,3-e]-l,2-thiazine-l,l-dioxide, is represented by the structure of formula I.

Lornoxicam is a non steroidal anti-inflammatory drug with analgesic properties and
belongs to the class oxicam. The mode of action of lornoxicam is partly based on inhibition of
prostaglandin synthesis (inhibition of the cyclooxygenase enzyme). Lornoxicam is indicated for
the short term treatment of mild to moderate pain associated with extra articular inflammation.
Lornoxicam is also indicated for symptomatic treatment of pain and inflammation in
osteoarthritis and rheumatoid arthritis. Lornoxicam is sold under the brand name Xefo™. See,
e.g., The Merck Index, Thirteenth Edition, 2001, p. 1000, monograph 5603.
U.S. Patent No. 4,180,662 ("the '662 patent"), herein incorporated by reference, discloses
lornoxicam and processes for its preparation. One process for preparing lornoxicam involves
reacting 2-aminopyridine with 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[2,3-
e]-l,2-thiazine-l,l-dioxide by refluxing in xylenes, charcoalizing the reaction mixture, and;
crystallizing the reaction mixture under cool conditions followed by filtration (see Example 8).
Different solvates of an active principle can have different bioavailability, solubility,
stability, color, compressibility, flow ability and workability with consequent modification of the
profiles of toxicological safety, clinical effectiveness and productive efficiency. Because
improved drug formulations showing, for example, better bioavailability or better stability are
consistently sought, there is an ongoing need for new or purer solvate forms of existing drug
molecules. The solvates of lornoxicam described herein are believed to help meet these and
other needs.
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SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, a solvate of lornoxicam is
provided comprising lornoxicam and an organic solvent, wherein the organic solvent is selected
from the group consisting of an amide solvent, a halogenated solvent, and an ether solvent.
In accordance with a second embodiment of the present invention, a solvate of
lornoxicam is provided comprising lornoxicam and an organic solvent, wherein the organic
solvent is selected from the group consisting of N,N-dimethylformamide, 1,2-dichloroethane,
and tetrahydrofuran.
In accordance with a third embodiment of the present invention, a process for the
preparation of a solvate of lornoxicam is provided, the process comprising (a) dissolving
lornoxicam with an organic solvent to form a solvate of lornoxicam and the organic solvent; and
(b) isolating the solvate formed in step (a).
In accordance with a fourth embodiment of the present invention, a substantially pure
solvate of lornoxicam is provided.
In accordance with a fifth embodiment of the present invention, a pharmaceutical
composition is provided comprising a therapeutically effective amount of a solvate of
lornoxicam.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows a powder X-ray diffraction pattern of the solvate of lornoxicam with N,N-
dimethylformamide.
Figure 2 shows a powder X-ray diffraction pattern of the solvate of lornoxicam with
tetrahydrofuran.
Figure 3 shows a powder X-ray diffraction pattern of the solvate of lornoxicam with 1, 2-
dichloroethane.
Figure 4 shows a differential scanning calorimetric pattern of the solvate of lornoxicam
with N,N-dimethylforrnarnide.
Figure 5 shows a differential scanning calorimetric pattern of the solvate of lornoxicam
with tetrahydrofuran.
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Figure 6 shows a differential scanning calorimetric pattern of the solvate of lornoxicam
with 1, 2 dichloroethane.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention contemplates novel solvates of lornoxicam and processes for their
preparation. It has now been found that solvates of lornoxicam exist, whose formation depends
on the solvent under defined conditions, e.g., temperature at which crystallization is carried out,
cooling profile and drying conditions. In one embodiment, the solvates of the present invention
include, but are not limited to, lornoxicam in combination with an organic solvent selected from
the group consisting of an amide solvent, a halogenated solvent, e.g., an aliphatic halogenated
solvent, and ether solvent. In another embodiment, the solvates of the present invention include,
but are not limited to, lornoxicam in combination with an organic solvent selected from the
group consisting of N,N-dimethylformamide, 1,2 dichloroethane, and tetrahydrofuran. These
solvates of lornoxicam can be characterized by methods familiar to those skilled in the art. The
novel solvates of the present invention was characterized by X-ray powder diffraction (Figures
1-3), and differential scanning calorimetry (Figures 4-6).
The X-Ray powder diffraction spectrum for the solvates of lornoxicam was measured by
an X-ray powder Diffractometer equipped with a Cu-anode (X=l.54 Angstrom), X-ray source
operated at 45kV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is
performed using an NIST SRM 640c Si standard. The sample was analyzed using the following
instrument parameters: measuring range=2-50° 20; step width=0.017°; and measuring time per
step-5 sec.
Measurement of differential scanning calorimetry for the solvates of lornoxicam was
obtained on a Mettler Toludo 822e thermal analysis system. Approximately 3 to 5 mg samples
were accurately weighed into a DSC pan. The pans were hermetically sealed and a pinhole was
punched into the pan lid. The use of the pinhole allows for pressure release, but still assures that
the thermal reactions proceed under controlled conditions. The samples were introduced into the
DSC oven and then heated at a rate of 10°C/min, up to a final temperature of 350°C.
The solvates of lornoxicam of the present invention can be obtained by (a) dissolving
lornoxicam with an organic solvent to form a solvate of lornoxicam, wherein the organic solvent
is selected from the group consisting of an amide solvent, a halogenated solvent, and ether
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solvent; and (b) isolating the solvate formed in step (a). In another embodiment, the solvates of
lornoxicam of the present invention can be obtained by (a) dissolving lornoxicam with an
organic solvent to form a solvate of lornoxicam, wherein the organic solvent is selected from the
group consisting of an amide solvent, an aliphatic halogenated solvent, and ether solvent, at the
boiling temperature of the solvent to obtain a clear solution; (b) cooling the solution to room
temperature; (c) stirring the solution at room temperature; and (d) isolating the solvate formed in
step (c), e.g., by filtration.
In one embodiment, a lornoxicam-N,N-dimethylformamide solvate is provided. The
lornoxicam-N, N-dimethylformamide solvate has at least one, and preferably all, of the
following properties:
(a) a powder XRD pattern substantially in accordance with Figure 1;
(b) a DSC spectrum substantially in accordance with Figure 4;
(c) an endothermic peak at 127.97°C and exothermic peak at 236.1°C; and/or
(d) a XRD pattern having characteristic peaks expressed in degrees 2-theta at
approximately the values set forth in tabular form in Table 1 below.
TABLE 1

Angle 20 Relative Intensity
(%)
8.71 94.4
10.96 50.3
13.64 22.49
17.45 93.49
17.74 45.89
21.92 30.86
25.81 16.71
26.02 100.00
26.3 43.29
28.35 15.99
The lornoxicam-N, N-dimethylformamide solvate of the present invention can be
obtained by dissolving lornoxicam in N,N-dimethylformamide. The amount of solvent can vary
about 70 to about 80 volumes with respect to the lornoxicam. The temperature for dissolution
will ordinarily range from about 125°C to about 140°C and preferably from about 130°C to
about 135°C. If desired, a portion of the N,N-di methyl form amide may be recovered to facilitate
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the crystallization. Atter recovery, the mass may then be cooled, e.g., to room temperature, to
produce a precipitate. The time required to cool to room temperature can range from about 1
hour to about 1.5 hours.
The precipitated mass can be stirred at room temperature for complete crystallization.
The time period can range from about 7 hours to about 10 hours and preferably from about 8
hours to about 9 hours. The crystallized product can then be isolated and dried to obtain a
lornoxicam-N, N-dimethylformamide solvate.
In another embodiment, a lornoxicam-tetrahydrofuran solvate is provided. The
lornoxicam-tetrahydrofuran solvate has at least one, and preferably all, of the following
properties:
(a) a powder XRD pattern substantially in accordance with Figure 2;
(b) a DSC spectrum substantially in accordance with Figure 5;
(c) an endothermic peak at 115.06°C and exothermic peak at 235.65°C; and/or
(d) a XRD pattern having characteristic peaks expressed in decrees 2-theta at
approximately the values set forth in tabular form in Table 2 below.
TABLE 2

Angle 29 Relative Intensity
(%)
8.34 45.06
10.62 31.10
13.92 12.45
15.16 12.27
15.62 11.42
16.65 100.00
21.43 18.88
23.23 15.21
25.06 23.56
25.47 52.20
26.89 11.42
The Lornaxicam-tetrahydrofuran solvate of the present invention can be obtained by
dissolving of lornoxicam in tetrahydrofuran. The amount of Solvent used can vary from about
200 to about 300 volumes with respect to lornoxicam. The temperature for dissolution will
ordinarily range from about 70°C to about 90°C and preferably from about 80°C to about 85°C.
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Next, the solution may be cooled, e.g., to room temperature, to produce a precipitate. The time
required to cool to room temperature can range from about 1 hour to 1.5 hours. The precipitated
mass can be stirred at room temperature for complete crystallization. The time period can range
from about 7 hours to 10 hours and preferably from about 8 hours to about 9 hours. The
crystallized product can then be isolated and dried to obtain a lornoxicam-tetrahydrofuran
solvate.
In another embodiment, a lonoxicam-l,2-dichloroethane solvate is provided. The
Ionoxicam-1, 2-dichJoroethane solvate has at least one, and preferably all, of the following
properties:
(a) a powder XRD pattern substantially in accordance with Figure 2;
(b) a DSC spectrum substantially in accordance with Figure 5;
(c) an endothermic peak at 122.46°C and exothermic peak at 236.72°C; and/or
(d) a XRD pattern having characteristic peaks expressed in degrees 2-theta at
approximately the values set forth in tabular form in Table 3 below.
TABLE 3

Angle 26 Relative Intensity
(%)
7.84 20.74
12.34 21.74
14.01 14.23
15.62 24.73
17.83 49.65
20.82 88.12
23.32 100.00
25.88 64.58
30.02 15.33
The Lornaxicam -1,2-dichloroethane solvate of the present invention can be obtained by
dissolving lornoxicam in 1,2-dichloroethane. The amount of solvent used can vary from about
150 to about 200 volumes with respect to lornoxicam. The temperature for dissolution can range
from about 70°C to about 90°C and preferably from about 80°C to about 85°C. The solution
may be cooled, e.g., to room temperature, to produce a precipitate. The time required to cool to
room temperature can range from about 1 hour to about 1.5 hours. The precipitated mass can be
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stirred at room temperature for complete crystallization. The time required can range from about
0.5 hours to 1.5 hours and preferably about 1 hour to about 1.5 hours. The crystallized product
can then be isolated and dried to obtain a lornoxicam-1,2-dichloroethane solvate.
Yet another aspect of the present invention is directed to pharmaceutical compositions
containing at least one or more of the solvates of lornoxicam of the present invention. Such
pharmaceutical compositions may be administered to a mammalian patient in any dosage form,
e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for
administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal
routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets,
suspensions, powders, lozenges, elixirs and the like. The novel solvates of lornoxicam disclosed
herein also may be administered as suppositories, ophthalmic ointments and suspensions, and
parenteral suspensions, which are administered by other routes. The dosage forms may contain
the novel solvates of lornoxicam of the present invention as is or, alternatively, may contain the
solvates of lornoxicam as part of a composition. The pharmaceutical compositions may further
contain one or more pharmaceutically acceptable excipient.
Capsule dosages will contain the novel solvates of lornoxicam within a capsule which
may be coated with gelatin. Tablets and powders may also be coated with an enteric coating.
The enteric-coated powder forms may have coatings containing, for example, phthalic acid
cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate,
carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of
methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be
employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating
on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-
coating.
Tableting compositions may have few or many components depending upon the tableting
method used, the release rate desired and other factors. For example, the compositions of the
present invention may contain diluents such as cellulose-derived materials like powdered
cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl
cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch;
inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to
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one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose)
and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as
pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include, but are not limited to,
binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders
used in wet and dry granulation and direct compression tableting processes; disintegrants such as
sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others;
lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings;
sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
In one embodiment, the solvates of lornoxicam disclosed herein for use in the
pharmaceutical compositions of the present invention can have a D50 and D90 particle size of less
than about 400 microns, preferably less than about 200 microns, more preferably less than about
150 microns, still more preferably less than about 50 microns and most preferably less than about
15 microns. The particle sizes of the solvates of lornoxicam can be obtained by, for example,
any milling, grinding micronizing or other particle size reduction method known in the art to
bring the solid state solvates of lornoxicam into any of the foregoing desired particle size range.
The following examples are provided to enable one skilled in the art to practice the
invention and are merely illustrative of the invention. The examples should not be read as
limiting the scope of the invention as defined in the features and advantages.
EXAMPLE 1
Preparation of Iornoxicam-N, N-dimethylformamide solvate
Lornoxicam (2.0 g) was dissolved in N, N-dimethylformamide (140.0 ml) at a
temperature of about 130°C. The N, N-dimethylformamide was distilled under reduced pressure
to about 70.0 ml. The solution was cooled to room temperature and stirred overnight at room
temperature. The solution was filtered, and the product was dried at a temperature ranging from
about 50°C to about 55°C. Dry Wt. - 1.1 gm.
The XRD pattern and DSC of the final compound are set forth as Figures 1 and 4,
respectively, and was recorded and identified as the N, N-dimethylformamide solvate of
lornoxicam.
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EXAMPLE 2
Preparation of lornoxicam-tetrahydrofuran solvate
Lomoxicam (2.0 g) was dissolved in tetrahydrofuran (500.0 ml) at reflux. The solution
was then cooled to room temperature and stirred overnight at room temperature. The solution
was filtered, and the product was dried at a temperature ranging from about 50°C to about 55°C.
Dry Wt.-1.9gm
The XRD pattern and DSC of the final compound are set forth as Figures 2 and 5,
respectively, and was recorded and identified as the tetrahydrofiiran solvate of lomoxicam.
EXAMPLE 3
Preparation of lornoxicam-1, 2-dichloroethane solvate
Lomoxicam (2.0 g) was dissolved in 1, 2-dichloroethane (400.0 ml) at reflux. The
solution was cooled to room temperature gradually. Next the solution was stirred for 1 hour at
room temperature. The solution was filtered, and the product was dried at a temperature ranging
from about 50°C to about 55°C. Dry Wt. - 1.9 gm
The XRD pattern and DSC of the final compound are set forth as Figures 3 and 6,
respectively, and was recorded and identified as the 1, 2-dichloroethane solvate of lomoxicam
It will be understood that various modifications may be made to the embodiments
disclosed herein. Therefore the above description should not be construed as limiting, but
merely as exemplifications of preferred embodiments. For example, the functions described
above and implemented as the best mode for operating the present invention are for illustration
purposes only. Other arrangements and methods may be implemented by those skilled in the art
without departing from the scope and spirit of this invention. Moreover, those skilled in the art
will envision other modifications within the scope and spirit of the features and advantages
appended hereto.
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WE CLAIM:
1. A solvate of Iornoxicam.
2. Lomoxicam-N, N-dimethylformamide solvate.
3. Lornoxicam-N, N-dimethylformamide solvate as claimed in claim 2, having at least
one of the following properties:

(a) a powder XRD pattern substantially in accordance with Figure 1;
(b) a DSC spectrum substantially in accordance with Figure 4;
(c) an endothermic peak at 127.97°C and exothermic peak at 236.1 °C; and/or
(d) a XRD pattern having characteristic peaks expressed in degrees 2-theta at
approximately the values set forth in tabular form in Table 1 below.
TABLE 1

Angle 29 Relative Intensity
8.71 94.4
10.96 50.3
13.64 22.49
17.45 93.49
17.74 45.89
21.92 30.86
. 25.81 16.71
26.02 100.00
26.3 43.29
28.35 15.99
4. Lornoxicam-tetrahydrofuran solvate.
5. Lornoxicam-tetrahydrofuran solvate as claimed in claim 4, having at least one of the
following properties:

(a) a powder XRD pattern substantially in accordance with Figure 2;
(b) a DSC spectrum substantially in accordance with Figure 5;
(c) an endothermic peak at 115.06°C and exothermic peak at 235.65°C; and/or
(d) a XRD pattern having characteristic peaks expressed in degrees 2-theta at
approximately the values set forth in tabular form in Table 2 below.
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TABLE 2

Angle 29 Relative Intensity
(%)
8.34 45.06
10.62 31.10
13.92 12.45
15.16 12.27
15.62 11.42
16.65 100.00
21.43 18.88
23.23 15.21
25.06 23.56
25.47 52.20
26.89 11.42
6. Lonoxicam-l,2-dichloroethane solvate.
7. Lonoxicam-ls2-dichloroethane solvate as claimed in claim 6, having at least one of
the following properties:

(a) a powder XRD pattern substantially in accordance with Figure 2;
(b) a DSC spectrum substantially in accordance with Figure 5;
(c) an endothermic peak at 122.46°C and exothermic peak at 236.72°C; and/or
(d) a XRD pattern having characteristic peaks expressed in degrees 2-theta at
approximately the values set forth in tabular form in Table 3 below.
TABLE 3

Angle 2θ Relative Intensity
(%)
7.84 20.74
12.34 21.74
14.01 14.23
15.62 24.73
17.83 49.65
20.82 88.12
23.32 100.00
25.88 64.58
30.02 15.33
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8. A pharmaceutical composition comprising a therapeutically effective amount of the
solvates as defined in claims 1-7.
9. A process for the preparation of a solvate of lornoxicam as claimed in claim 1, the
process comprising (a) dissolving lornoxicam with an organic solvent to form a solvate of
lornoxicam and the organic solvent; and (b) isolating the solvate formed in step (a).
10. The process as claimed in claim 9, wherein the organic solvent is selected from the
group consisting of N,N-dimethylformamide, 1,2 dichloroethane, and 1,2 dichloroethane.
Dated this Fifteenth (15th) day of February, 2007

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