U.S. patent application number 10/180399 was filed with the patent office on 2002-12-26 for polymorphic, amorphous and hydrated forms of 5-chloro-3-(4-methanesulfonyl- phenyl)-6'-methyl-[2,3']bipyridinyl.
This patent application is currently assigned to Merck & Co., Inc.. Invention is credited to Crocker, Louis S..
Application Number | 20020198238 10/180399 |
Document ID | / |
Family ID | 22609368 |
Filed Date | 2002-12-26 |
United States Patent
Application |
20020198238 |
Kind Code |
A1 |
Crocker, Louis S. |
December 26, 2002 |
Polymorphic, amorphous and hydrated forms of
5-chloro-3-(4-methanesulfonyl-
phenyl)-6'-methyl-[2,3']bipyridinyl
Abstract
Polymorphic, amorphous and hydrated forms of the title compound
having the following structure: 1 are disclosed. The compound is a
potent and selective cyclooxygenase-2 (COX-2) inhibitor.
Inventors: |
Crocker, Louis S.; (Belle
Mead, NJ) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Assignee: |
Merck & Co., Inc.
|
Family ID: |
22609368 |
Appl. No.: |
10/180399 |
Filed: |
June 26, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10180399 |
Jun 26, 2002 |
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09724522 |
Nov 28, 2000 |
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6441002 |
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60167922 |
Nov 29, 1999 |
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Current U.S.
Class: |
514/334 ;
546/258 |
Current CPC
Class: |
A61K 31/444 20130101;
C07D 213/61 20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/334 ;
546/258 |
International
Class: |
A61K 031/444; C07D
41/02 |
Claims
What is claimed is:
1. A polymorph of Compound A of structural formula: 3selected from
Forms II, III and IV having the physical characteristics described
in the following Table:
3 Form II III IV DSC 134-136.degree. C. 133.degree. C. 134.degree.
C. extrapolated melting temperature onset XRPD (peak 5.6 10.5 8.7
positions, Cu K 9.4 16.1 15.2 alpha) 10.7 22.4 17.1 17.6 19.5 21.7
23.5 23.6
2. A polymorph in accordance with claim 1 which is Form IV.
3. A sesquihydrate of Form I having a DSC of about 134-136.degree.
C., peak m.p. 138.degree. C., an XRPD pattern of 7.1, 9.7, 11.8,
15.5, 20.1, 22.7 and 24.1, and further containing approximately 1.5
mol water per mol of compound A.
4. A polymorph in accordance with claim 1 which is Form IV.
5. A hemihydrate of Form IV in accordance with claim 4 containing
0.5 mol water per mol of compound A.
6. A polymorph in accordance with claim 1 which is Form III.
7. An amorphous form of Compound A in accordance with claim 1
obtained by cooling a molten sample of a crystalline form of
Compound A.
8. A pharmaceutical composition comprised of a polymorph II, III or
IV in accordance with claim 1 in combination with a
pharmaceutically acceptable carrier.
9. A Form II polymorph of Compound A of structural formula: 4having
a DSC extrapolated melting temperature onset of .about.131.degree.
C., and XRPD peak positions, Cu K alpha of 5.6, 9.4, 10.7 and 17.6.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to polymorphic, amorphous and
hydrated forms of the title compound which has the chemical
structure shown below: 2
[0002] The compound is a potent and selective cyclooxygenase-2
(COX-2) inhibitor, useful primarily in the treatment of
inflammation, pain and fever as well as other COX-2 mediated
diseases, such as described in PCT Publication Nos. WO 96/10012 and
WO 96/16934. Compound A is described in U.S. Pat. No. 5,861,419
granted on Jan. 19, 1999 (Example 23) incorporated by reference in
its entirety.
[0003] Bipyridyl compounds generally are highly crystalline, poorly
water soluble and hydrophobic, resulting in difficulties in the
preparation of pharmaceutical formulations and problems associated
with bioavailability. Accordingly, efforts were made to discover
other forms of Compound A and to investigate the properties
thereof. There were discovered three additional polymorphic forms,
an amorphous form and two hydrates.
SUMMARY OF THE INVENTION
[0004] Polymorphic forms of Compound A, for purposes of this
invention, are identified as Form I (onset of melting, m.p.
134-136.degree. C., peak m.p. 138.degree. C.), Form II (onset of
melting, m.p .about.131.degree. C., peak m.p. 133.degree. C.), Form
III (onset of melting, m.p..about.133.degree. C., peak m.p.
135.degree. C.) and Form IV (onset of melting,
m.p..about.134.degree. C., peak m.p. 136.degree. C). Forms I
through IV are anhydrous. An amorphous form and two hydrates have
also been identified.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] The invention is described in connection with the appended
drawings in which:
[0006] FIG. 1 is the X-ray powder diffraction (XRPD) pattern of
Form I;
[0007] FIG. 2 is the XRPD pattern of Form II;
[0008] FIG. 3 is the XRPD pattern of Form III;
[0009] FIG. 4 is the XRPD pattern of Form IV;
[0010] FIG. 5 is the XRPD pattern of the hemihydrate;
[0011] FIG. 6 is the XRPD pattern of the sesquihydrate;
[0012] FIG. 7 is a thermogravimetric (TG) scan of the hemihydrate,
and
[0013] FIG. 8 is a TG scan of the sesquihydrate.
DETAILED DESCRIPTION
[0014] Polymorphic forms of Compound A, for purposes of this
invention, are identified as Form I (onset of melting, m.p.
134-136.degree. C., peak m.p. 138.degree. C.), Form II (onset of
melting, m.p .about.131.degree. C., peak m.p. 133.degree. C.), Form
III (onset of melting, m.p..about.133.degree. C., peak m.p.
135.degree. C.) and Form IV (onset of melting,
m.p..about.134.degree. C., peak m.p. 136.degree. C.). Forms I
through IV are anhydrous. An amorphous form and two hydrates have
also been identified.
[0015] The polymorphs of the present invention are synthesized in
accordance with the following examples which are illustrative.
Preparative Example 1
[0016] The starting material compound A is made in accordance with
Example 23 of U.S. Pat. No. 5,861,419 granted on Jan. 19, 1999.
EXAMPLE 1
Form II
[0017] Form II is obtained by crystallizing compound A obtained in
accordance with Preparative Example 1 from ethyl acetate.
[0018] Differential Scanning Calorimetry showed an extrapolated
onset of melting at 131.+-.1.degree. C., and a peak melting point
of 132.5.+-.0.1.degree. C.
EXAMPLE 2
Form I
[0019] Form I was obtained by recrystallizing Form II obtained as
described in Example 1 from a solvent mixture of
isopropanol/hexane.
EXAMPLE 3
Form IV
[0020] Form IV appeared spontaneously in batches of compound A
prepared as in Preparative Example 1.
[0021] Form IV is alternatively prepared by contacting Form I as
described in Example 2 with an organic solvent, e.g., toluene and
heptane, and then recrystallizing at a temperature less than
45.degree. C., such as about 15.degree. C.
[0022] Form IV is also alternatively prepared by dissolving Form II
in an organic solvent, such as toluene and heptane, and then
recrystallizing at a temperature less than 45.degree. C., such as
about 15.degree. C.
EXAMPLE 4
Form III
[0023] Form III was prepared by stirring Form IV from Example 3 in
water for 1 day, and then dehydrating at 90.degree. C. in vacuo
until Form III is present. The melting temperature onset was ca.
133.degree. C. with an enthalpy of fusion of approximately 24
kJ/mol. The peak melting temperature was 135.degree. C.
[0024] Alternatively, using the hemihydrate of Example 5,
conducting a temperature XRPD of the hemihydrate at 130.degree. C.
resulted in the production of Form III.
EXAMPLE 5
Hemihydrate
[0025] The hemihydrate form of compound A is produced by stirring
Form IV obtained in accordance with Example 3 in water for at least
1 day. XRPD analysis of the solid produced a diffractogram
identical to previous hemihydrate samples obtained for Form II.
Thermogravimetry confirmed that Form IV had converted to the
hemihydrate form, exhibiting a sharp weight loss of 2.45% on
heating,which corresponds to a mole ratio of water to drug of
0.50%.
EXAMPLE 6
Sesquihydrate
[0026] The sesquihydrate of compound A is obtained by combining
Form I in accordance with Example 2 and water (approximately 1.5
mol/mol compound).
EXAMPLE 7
Amorphous
[0027] The amorphous form of compound A is obtained by heating any
polymorph to above its melting temperature (for example to
145.degree. C.) under nitrogen, followed by quench cooling to room
temperature under a dry atmosphere.
Characterization of Polymorphs
[0028] The polymorphic forms of compound A are characterized using
the following procedures.
[0029] X-Ray Powder Diffraction Pattern Analysis
[0030] Polymorph I is crystalline by XRPD using a Scintag XDS-2000,
Si(Li) Peltier-cooled solid state detector using a Cu K alpha
source at 45 kV and 40 mA, and divergent beam (2 mm and 4 mm) and
receiving beam slits (0.5 mm and 0.2 mm). Peak positions were
calibrated using a standard silicon disk (97.5% pure).
[0031] Temperature XRPD studies were carried out under nitrogen,
using a gold-plated copper stage with a Beryllium window on the
cover. A Micristar temperature controller monitored and controlled
the temperatures.
[0032] Temperature XRPD studies demonstrated that the compound did
not undergo any transitions prior to melting, which was complete at
140.degree. C., and that there was no conversion to a different
polymorphic form. Similar results were obtained for Form II. The
material remained amorphous and did not recrystallize.
[0033] Table 1 below lists the XRPD peak locations for Forms I, II,
III and IV.
1TABLE 1 X-ray Crystalline Reflections in .degree. 2 theta That Are
Characteristic of Polymorphs I, II, III and IV using Cu K alpha
Form I Form II Form III Form IV 7.1 5.6 8.7 9.7 9.4 10.5 11.8 10.7
16.1 15.5 17.6 15.2 20.1 17.1 19.5 22.7 22.4 21.7 24.1 23.5
23.6
[0034] XRPD patterns for Forms I-IV are shown in FIGS. 1-4. XRPD
patterns for the two hydrate forms are shown in FIGS. 5 and 6.
[0035] Differential Scanning Calorimetry (DSC)
[0036] The extrapolated melting temperature onset of Form I was
134.0.+-.0.6.degree. C. with an enthalpy of fusion of 27.2.+-.0.9
kJ/mol at 10 deg/min under nitrogen in crimped aluminum pans (FIG.
1). The peak melting temperature was 138.degree. C.
[0037] When measured using a TA Instruments DSC2910 instrument, at
10.degree. C./min under a nitrogen atmosphere in an open aluminum
pan, the onset of melting was 136.degree. C. and the peak melting
temperature was as described above. There were no significant
changes with DSC scanning rate other than the expected shift in
peak temperature. DSC thermal behaviour of Form I in crimped sample
pans under nitrogen (60 mL/min) was measured using a Seiko robotic
DSC (RDC-220) at 2, 10 and 20 deg/min. The DSC was calibrated for
temperature and heat flow with gallium, indium and tin.
[0038] The melting temperature onset and enthalpy of fusion of Form
I were slightly higher than those observed for Form II. These
polymorphic forms do not recrystallize upon cooling from the melt
nor do they recrystallize on reheating. The glass transition
temperature of the amorphous form (mid-point, 10K/min, crimped
aluminum pan) is 55.degree. C.
[0039] Table 2 provides a comparison of the extrapolated melting
temperature onset, T.sub.0, and the enthalpy of fusion, .DELTA.H,
for Forms I, II, III and IV.
2TABLE 2 Extrapolated melting temperature onset, T.sub.o, and
Enthalpy of Fusion obtained by DSC at 10K/min in crimped pans under
nitrogen Polymorphic form T.sub.o (.degree. C.) Enthalpy of fusion,
kJ/mol Form I 134.0 .+-. 0.6 27.2 .+-. 0.9 Form II 131 .+-. 1 25.8
.+-. 0.2 Form III 133 22.7 Form IV 134.0 .+-. 0.1 27.9 .+-. 0.2
[0040] The DSC thermogram for Form IV, obtained at a scanning rate
of 10.degree. C./min under nitrogen in crimped aluminum pans,
consisted of a single symmetrical endotherm with a mean onset
melting point of 134.0.+-.0.1.degree. C. and a heat of fusion of
27.9 kJ/mol. A scanning rate of 2.degree. C./min confirmed that the
observed endotherm was due to a single endothermic transition. The
enthalpy of fusion of the different polymorphs are also
similar.
[0041] Forms I and IV have similar solubilities. Form IV is
slightly less soluble and slightly more stable at temperatures
below 45.degree. C. Forms I and IV are enantiotropic with Form IV
converting to Form I at temperatures greater than 45.degree. C.
when in contact with organic solvents.
* * * * *