Title of Invention

"A CRYSTAL FORM, FORM I, OF 4-{5-(4-FLUROPHENYL)-3-(TRIFLUROMETHYL)-1H-PYRAZOL-1-YL}-BENZENESULOFONAMIDE

Abstract A crystal form, Form I, of 4-(5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-benzenesulfonamide having a powder X-ray diffraction pattern comprising peaks pressed in degrees (± 0.1 degree) of two theta angle of 14.0, 18.9, 21.3, 21.9, and 25.7 obtained using CuKα1 X-ray (wavelength = 1.5406 Angstroms).
Full Text The present invention relates to a crystal form, Form I, of 4-(5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l -yl]-benzenesulfonamide.
FIELD OF THE INVENTION
The present invention relates to crystal forms of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-benzenesulfonamide and methods for preparation, interconversion, and isolation of such crystals.
BACKGROUND OF THE INVENTION Field of Invention
5-Phenylpyrazolyl-l-benzenesulfonamides are a novel synthetic class of compounds with potent COX-2 inhibitory activity useful for the treatment of arthritis and other conditions due to inflammation. 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-benzenesulfonamide is a 5-phenylpyrazolyl-1 -benzenesulfonamide having the following structure:
(Formula Removed)
Formula I Background Art
The compound of Formula I is disclosed in U.S. Pat. Nos. 5,466,823 (Tally et. al.) and 5,521,207 (Graneto). These patents are incorporated herein by reference. Although the preparation of the compound of Formula I is disclosed, the specification is silent as to the isolation and nature of crystal forms of the agent. There is a need to identify polymorphic behavior as a means of ensuring robust processes, avoid tableting problems, tablet failure, crystal growth in suspensions and resultant caking, precipitation from suspensions as well as chemical production problems such as filterability, and to ensure analytical reproducibility (see Analysis of Organic Polymorphs, A Review; Threlfall, T.L., Analyst, 120, pp.2435-2459).
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a crystal, Form I, of 4-[5-(4-
fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-benzenesiilfonainide having a
powder X-ray diffraction pattern comprising peaks expressed in degrees (± 0.1 degree)
of two theta angle of 14.0,18.9,21.3,21.9, and 25.7 obtained using CuKoti X-ray
(wavelength = 1.5406 Angstroms). In another aspect of the invention, a process is
provided for converting crystal Form E of 4-[5-(4-fiuorophenyl)-3-(trifluoromethyl)-
lH-pyrazol-l-yl]-benzenesulfonamide into the crystal Form I comprising i) mixing a
suspension of Form n of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide in a suitable solvent at a temperature from about 0°C to about
60°C; ii) stirring the suspension at a temperature from about 0°C to about 60°C for 24
to 72 hours; and iii) collecting the Form I crystals. In another aspect of the invention,
the solvent in said process is chosen from the group consisting of water, methanol,
ethanol, isopropanol, acetone, acetonitrile, methylene chloride, toluene, and
tetrahydrofuran, and mixtures thereof.
An additional aspect of the invention is process for converting crystal Form n
of4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-benzenesulfonamide
into the crystal Form I comprising (i) dissolving said Form n in a water miscible
solvent in which the solubility of Form n is greater than 2 mg/mL at a temperature
from about 10°C to about 60°C; (ii) precipitating the compound by the addition of
water; (iii) stirring the suspension of step (ii) for 2 to 72 hours at a temperature from
about 15°C to about 45°C; and (iv) collecting the Form I crystals. In another aspect of
the invention, solvent for this process is selected from the group consisting of ethanol,
acetone, acetonitrile, tetrahydrofuran, dioxane, and dimethylformamide.
Li a further aspect, the invention provides a pharmaceutical composition which
comprises a compound of Formula I of crystal Form I. hi another aspect of the
invention, the pharmaceutical composition farther comprises a pharmaceutically
acceptable carrier or excipient. Still another object of the present invention is to
provide a method for preventing or treating inflammatory conditions in animals by using
a therapeutically effective amount of a novel composition of the present invention. A
further object of the present invention is to provide a use of a novel composition of the
present invention in the manufacture of a medicament for the prevention or treatment
of an inflammatory condition in an animal.
A further object of the invention is to prepare crystal Form I of 4-[5-(4-
fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-benzenesulfonamideby:
Step (a) mixing 1.0 to 1.6 moles, or preferably 1.2 to 1.45 moles, or more
preferably 1.25 to 1.35 moles, of alkyl trifluoroacetate per mole of
4-fluoroacetophenone with 1.0 to 1.5 moles, or preferably 1.1 to 1.35 moles, or more
preferably 1.15 to 1.25 moles, of a metal alkoxide per mole of 4-fluoroacetophenone,
and a know quantity of 4-fluoroacetophenone to make a mixture. Optionally, up to
1,3 80 ml, or preferably up to 900 ml, or more preferably up to 490 ml, of a suitable
solvent, preferably 2-propanol, is added in this step. Optionally, the mixture of step (a)
is heated at a temperature above ambient temperature up to reflux temperature, or
preferably at a temperature of 40°C to 70°C, or more preferably at a temperature of
50°C to 60°C, for 1 to 24 hours, or preferably for 1 to 10 hours; or more preferably for
1 to 4 hours, or more preferably until the reaction is complete. Optionally, after such
heating, the mixture is then cooled to a temperature of-5°C to 30°C, or more
preferably to ambient temperature.
Step (b) The mixture of step (a) is combined with, or preferably added to, a
combination of 415 to 1,245 ml, or preferably 650 to 870 ml, or more preferably 725
to 795 ml, of water per mole of 4-fluoroacetophenone, plus 1.1 to 2.0 moles, or
preferably 1.2 to 1.7 moles, or more preferably 1.3 to 1.5 moles, of concentrated
hydrochloric acid per mole of 4-fluoroacetophenone, plus 0.8 to 1.2 moles, or
preferably 0.9 to 1.1 moles, or more preferably 0.95 to 1.05 moles, of
4-sulfonamidophenylhydrazine hydrochloride per mole of 4-fluorbacetophenone, and
an amount of a suitable solvent, preferably a Ci-Ce alcohol, or more preferably 2-
propanol, so that the total amount of the solvent in the mixture is from 550 to 1,660
ml, or preferably from 600 to 1,000 ml, or more preferably from 650 to 750 ml, per
mole of 4-fluoroacetophenone. Optionally, the mixture of step (b) is heated at a
temperature above ambient temperature up to reflux temperature, or preferably at a
temperature of 40°C to 70°C, or preferably at a temperature of 50°C to 70°C, for 1 to
24 hours, or preferably for 1 to 10 hours; or more preferably for 1 to 4 hours, or more
preferably until the reaction is complete. Optionally, after such heating, the mixture is
then stabilized at a temperature of ambient temperature from 71.5°C, or preferably
from 40 °C to 65 °C, or more preferably from 50°C to 60°C.
Step (c) Then, a seeding amount, or preferably 0.0001% to 50% wt/wt, or more
preferably 0.001% to 5% wt/wt, or more preferably 0.01% to 0.5% wt/wt, of crystals
of Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide relative to 4-fluoroacetophenone is added to the mixture.
Optionally, the mixture of step (c) is heated at a temperature from 40°C to less than
71.5°C, or preferably at a temperature of 50°C to less than 71.5°C, or more preferably
at a temperature of 50°C to 60°C, for 1 to 10 hours, or preferably for 3 to 8 hours; or
more preferably for 5 to 7 hours. Optionally, after such heating, the mixture is then
cooled to a temperature of-5 °C to 30°C, or more preferably to ambient temperature.
Optionally, the mixture is filtered and washed with a suitable solvent, preferably an
alcohol, more preferably 2-propanol, or water or a mixture thereof, Optionally, the
solvent is in an amount of 300 to 1,500 ml, or preferably 600 to 1060 ml, or more
preferably 800 to 860 ml, of per mole of 4-fluoroacetophenone, and the water is in an
amount of 1QO to 700 ml, or preferably 285 to 545 ml, or more preferably 385 to 445
ml, per mole of 4-fluoroacetophenone.
Step (d) The Form I crystals are then collected. Optionally, the Form I crystals are
dried at a temperature of 15°C to 80°C, or preferably at a temperature of 30 °C to 65
°C, more preferably at 50 °C to 60 °C.
In another aspect of the invention, the metal alkoxide of step (a) is chosen
from the group consisting of sodium methoxide, sodium ethoxide, sodium
isopropoxide, sodium tertiary butoxide, lithium methoxide, lithium ethoxide, lithium
isopropoxide, lithium tertiary butoxide, potassium methoxide, potassium ethoxide,
potassium isopropoxide, and potassium tertiary butoxide, and mixtures thereof, or
preferably sodium methoxide.
These, and other objects, will readily be apparent to those skilled in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. Presented in Figure 1 is the experimental powder X-ray diffraction (PXRD)
pattern of Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide.
Figure 2. Presented in Figure 2 is the calculated powder X-ray diffraction (PXRD)
pattern of Form I of 4^[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide.
Figure 3. Presented in Figure 3 is the powder X-ray diffraction (PXRD) pattern of
Form n of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyraz6l-l-yl]-
benzenesulfonamide.
Figure 4. Presented in Figure 4, is the differential scanning calorimetry (DSC) data of
Forms I and n of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide.
DETAILED DESCRIPTION OF THE INVENTION
The selective COX-2 inhibitor 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lHpyrazol-
1 -yl]-benzenesulfonamide (Formula 1)
has been described in U.S.Patent Nos. 5,466,823 and 5,521,207. The description
describes a synthesis of the compound, but is silent with respect to the crystalline form
which is obtained. As described in the examples, following the procedure given in
these patents leads to crystals of Form n, which has been demonstrated by powder X--
ray diffraction (PXRD) patterns. The inventors have found that this crystal form is
unstable with respect to another form, Form I, at ambient temperature and pressure.
The forms can be distinguished by their PXRD (powder X-ray diffraction) patterns.
Definitions
As referred to in the present application, "water miscible" means capable of
being mixed with or dissolved in water at all proportions.
As referred to in the present application, "anhydrous crystalline" refers to a
crystal that does not contain substantial amounts of water. The water content can be
determined by methods known in the art including, for example, Karl Fischer
titrations. Preferably an anhydrous crystalline form contains at most about 1% by
weight water, more preferably at most about 0.5% by weight water, and most
preferably at most about 0.1% by weight water.
As referred to in the present application, "stable" in bulk drug stability tests
means that at least about 90% by weight, preferably at least about 95% by weight, and
more preferably at least about 99% by weight of the bulk drug remains unchanged
after storage under the indicated conditions for the indicated tune.
"DSC" means differential scanning calorimetry.
The term alkyl, unless otherwise specified, where used either alone or with
other terms such as "trifluoroacetate", embraces linear or branched having one to four
carbon atoms, or preferably, two carbon atoms. Non-limiting examples include groups
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, and sec-butyl.
"Metal alkoxides" are metal salts of an alcohol. Generally, the metal alkoxides
contain sodium, lithium, or potassium as the metal. In this invention they are used in
the form of an alcohol solution. Generally, the alcohol corresponds to the alcohol of
the alkoxide. Non-limiting examples of metal alkoxides include sodium methoxide,
sodium ethoxide, sodium isopropoxide, sodium tertiary butoxide, lithium methoxide,
lithium ethoxide, lithium isopropoxide, lithium tertiary butoxide, potassium
methoxide, potassium ethoxide, potassium isopropoxide, potassium tertiary butoxide,
and mixtures thereof.
Seeding is a technique of using a single crystal or more to induce the formation
of more crystals from a mixture, solution, or suspension. A seeding amount is the
amount of material that, when added to a mixture, solution, or suspension, is able to
cause the formation of the desired form of a compound. While in theory, this amount
can be very small, in practice, a larger amount is used. This amount can be any
amount that can be reasonably handled and is sufficient to cause the formation of the
desired form of a compound. As a non-limiting example, amounts of 0.0001% to
50% wt/wt of the seeding compound based on a reference compound can be used as a
seeding amount.
The term "C" when used in reference to temperature means centigrade or
Celsius.
"Ambient temperature" is the air temperature surrounding an object. It is the
temperature inside a room, which generally is from 15 to 25 degrees centigrade.
Reflux is a technique used in chemistry to apply energy to reactions over an
extended period of time. For this technique, a liquid reaction mixture is placed in a
vessel open only at the top. This vessel is connected to a vertical condenser, such that
any vapors given off are>cooled back to liquid, and fell back into the reaction vessel.
The vessel is then heated vigorously for the course of the reaction. The advantage of
this technique is that it can he left for a long period of time without the need to add
more solvent or fear of the reaction vessel boiling dry. In addition because a given
solvent will always boil at a certain temperature, the reaction will proceed at the same
temperature. Because different solvents boil at different temperatures,, by careful
choice of solvent, the temperature of the reaction can be controlled. "Reflux
temperature" as used herein refers to the temperature at which a particular solvent
boils during the reflux technique. For example, 2-propanol has a boiling point of
82°C; methanol has a boiling point of 65°C at sea level.
In reference to step (a), "reaction completion" is determined by confirming
that the amount of 4-fluoroacetophenone left in the mixture is less than or equal to 2%
w/w relative to the input charge of 4-fluoroacetophenone by using the following
HPLC method:
Column: Discover HS F5, 5u, 250 X 4.6 mm Supelco Cat # 567517-U
Mobile Phase (Gradient):
Time
0
15.0
15.1
20.0
20.1
27.0
A:
B:
% Mobile Phase A
60
60
20
20
60
60
% Mobile Phase B
40
40
80
80
40
40
0.05% (v/v) TFA in Water
0.05% (v/v) TFA in Acetonitrile
Flow Rate:
Injection:
Detection:
1 ml/min
20ul
247 ran
hi reference to step (b), "reaction completion" is determined by confirming
that the amount of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide formed is greater than 90% by using the following HPLC
method:
Column: Zorbax Eclipse XDB Phenyl, 3.5 um, 150 x 4.6 mm
Mobile Phase: 55/45 v/v Methanol/ 25 mM HaPCU at pH 2,5 (pH adjusted with NaOH)
Run time: 30 mins
Column temperature: 35°C
Flow rate: l.Oml/min
Injection volume: 15 ul
Detection: UV at 254 nm
Sample concentration: 0.4 mg/ml
"Therapeutically effective amount" refers to that amount of the compound
being administered which will prevent a condition (eg, an inflammatory condition), or
will relieve to some extent one or more of the symptoms of the disorder being treated.
Pharmaceutical compositions suitable for use in the present invention include
compositions wherein the active ingredients are contained in an amount sufficient to
achieve the intended purpose. Determination of a therapeutically effective amount is
well within the capability of those skilled in the art, especially in light of the detailed
disclosure provided herein.
Animals that are suitable recipients of the compounds of the present invention
include but are not limited to humans or other mammals or animals, for example, farm
animals including cattle, sheep, pigs, horses, goats and poultry (e.g., chickens, turkeys,
ducks and geese) and other birds, and companion animals such as dogs, cats, and
exotic and/or zoo animals. Treatment of both rodents and non-rodent animals is
contemplated.
In practice, the amount of the compound to be administered ranges from about
0.001 to 100 mg per kg of animal body weight, such total dose being given at one time
or in divided doses. It may be administered alone or in combination with one or more
other drugs. Generally, it will be administered as a formulation in association with one
or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to
describe any ingredient other than the compound(s) of the invention. The choice of
excipient will to a large extent depend on factors such as the particular mode of
administration, the effect of the excipient on solubility and stability, and the nature of
the dosage form.
Pharmaceutical compositions suitable for the deb'very of compounds of the
present invention and methods for their preparation will be readily apparent to those
skilled in the art. Such compositions and methods for their preparation may be found,
for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing
Company, 1995).
For use as an anti-inflammatory agent in animals the inventive composition
may be administered either orally or by injection. Where it is desired to administer
the inventive composition in a dry, solid unit dosage form, capsules, boluses or tablets
containing the desired amount of active compounds usually are employed. These
dosage forms are prepared by intimately and uniformly mixing the active ingredient
with suitable finely divided diluents such as starch, lactose, talc, magnesium stearate,
vegetable gums, and the like. Such unit dosage formulations may be varied widely
with respect to their total weight and content of the anti-inflammatory agent
depending upon factors such as the type of host animal to be treated, the severity and
type of uiflammation, and the weight of the host. The formulation of tablets is
discussed in Pharmaceutical Dosage Forms: Tablets. Vol. 1, by H. Lieberman and L.
Lachman (Marcel Dekker, New York, 1980).
Alternatively, the anti-inflammatory compositions of the present invention
may be administered to animals parenterally, for example, by mtraruminal,
intramuscular, or subcutaneous injection in which event the active ingredients are
dissolved or dispersed in a liquid carrier vehicle. For parenteral administration, the
active materials are suitably admixed with an acceptable vehicle, preferably of the
vegetable oil variety such as peanut oil, cottonseed oil, and the like. Other parenteral
vehicles such as organic preparations using solketal, propylene glycol, glycerol
formal, and aqueous parenteral formulations are also used, often in combination in
various proportions. The active compound or compounds are dissolved or suspended
in the parenteral formulation for administration; such formulations generally contain
from 0.005 to 5% by weight of the active compound.
Detailed Description of the Invention
In the following description of the invention, specific embodiments in which
the invention maybe practiced are described. These embodiments are described in
sufficient detail to enable those skilled in the art to practice the invention. Other
embodiments may be utilized, and logical and other changes may be made without
departing from the scope of the invention. The following detailed description is,
therefore, not to be taken in a limiting sense, and the scope of the invention is defined
only by the appended claims, along with the full scope of equivalents to which such
claims are entitled.
Form n is the crystal form obtained from the procedure described in U.S. Pat.
No. 5,466,823. Methods for obtaining crystal Form I are illustrated by the following
non-limiting descriptions and examples.
hi one method, 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide of crystal Form n may be suspended and mixed in suitable
i
solvent in which the concentration of drug is higher than the saturation point, at a
temperature from about 0°C to about 60°C. A suitable solvent is one in which the
solubility of the drug is greater than about 1 mg/mL and less than about 800 mg/mL.
Examples of suitable solvents include but are not limited to water, methanol, ethanol,
isopropanol, acetone, acetonitrile, methylene chloride, toluene, and tetrahydroraran,
and mixtures thereof. The suspension is stirred at a temperature from about 0°C to
about 60°C for 24 to 72 hours. The Form I crystals are collected by filtration.
In another procedure, the crystal Form I can be prepared by precipitation from
a solution of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide in a suitable water miscible solvent in which the compound
solubility is greater than 2 mg/mL, by the addition of water at a temperature from
about 10°C to about 60°C. Examples of suitable solvents for the preparation of Form I
from Form n include ethanol, acetone, acetonitrile, tetrahydrofuran, dioxane, and
dimethylformamide. Subsequent to the initial precipitation with water, the suspension
is stirred for 24 to 72 hours at a temperature from about 15°C to about 45°C, and the
Form I crystals are collected by filtration.
Preparation 1. Preparation of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lHpyrazol-
l-yl]-benzenesulfonamide, Form IL
The following procedure is essentially identical to that of Example 1 of U.S.
Patent No. 5,521,207 with the non-critical variation of using 4-fluroacetophenone
instead of 4-chloroacetophenone as a starting material.
Step 1: Preparation of4,4,4-trifluoro-l-[4-(fluoro)phenyl]-butane-l,3-dione.
Ethyl trifiuoroacetate (2.35 g, 1.66 mmol) was placed in a 50 mL round
bottom flask, and dissolved in methyl tert-butyl ether (7.5 mL). To the stirred solution
was added 25 weight % sodium methoxide (4.0 mL, 17.7 mmol) via an addition
funnel over a 2 minute period. Next, 4'-fluoroacetophenone (2.1g, 15 mmol) was
dissolved in methyl tert-butyl ether (2 mL), and added to the reaction dropwise over 5
minutes. After stirring overnight (15.75 hours), 3N HC1 (7.0 ml,) was added. The
organic layer was collected, washed with brine (7.5 mL), dried over MgS04, filtered,
and concentrated in vacuo to give 3.2 g of pale-orange solid. The solid was
recrystallized from iso-octane to give 2.05 g of the dione.
Step 2: Preparation of4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide
4-Sulphonamidophenyl hydrazine hydrochloride (982 mg, 4.4 mmol) was
added to a stirred solution of 4,4,4-trifluoro-l-[4-(fluoro)phenyl]-butane-l,3-dione
(0.936 g, 4.0 mmol) in ethanol (50 mL). The reaction was heated to reflux and stirred
for 20 hours. After cooling to room temperature, the reaction mixture was
concentrated in vacuo. The residue was taken up in ethyl acetate and washed with
water and brine and dried over MgSCU, filtered, and concentrated in vacuo to give a
brown solid which was recrystallized from ethyl acetate and iso-octane to give the 4-
[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-benzenesulfonamide 0.8 g.
MSm/eES-(M-H)384
m.p. 167-171 °C.
Preparation 2. Preparation of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lHpyrazol-
l-yl]-benzenesulfonamide, Form I without isolating the crystal Form n.
The following procedure describes a general method of preparing the crystal
Form I of 4-[5-(4-fiuorophenyl)-3-(trifluoromethyl)-lH-pvrazol-l-yl]-
benzenesulfonamide without isolating the crystal Form n.
Part A. 4-fluoroacetophenone (1 molar equivalent) is combined with a
mixture of alkyl trifluoroacetate (1.0-1.6 molar equivalents), a metal alkoxide (1.0-1.5
molar equivalents) and optionally a suitable solvent (up to 10 litres per kilogram of 4-
fluoroacetophenone). This mixture may be heated at temperatures of up to reflux (to
effect completion of reaction). A "suitable solvent" for this part A is a Ci-Ce saturated
aliphatic alcohol, including linear, branched chain, and cyclic alcohols. Non-limiting
examples of suitable solvents include alcohols such as methanol, ethanol, isopropanol,
and the like, and mixtures thereof.
Part B. The mixture from Part A is combined with a mixture of 4-
sulfonamidophenylhydrazine hydrochloride (0.8-1.2 molar equivalents based upon 4-
fluoroacetophenone) and aqueous hydrochloric acid (1.1-2.0 molar equivalents based
upon 4-fluoroacetophenone) in water (3-9 litres per kilogram of 4-
fluoroacetophenone). If required, a suitable solvent maybe added such that the total
amount of the solvent present in Part B lies within the range of 4-12 litres per
kilogram of 4-fluoroacetophenone. The reaction may be heated at temperatures of up
to reflux (to effect completion of reaction). Following the reaction period, the mixture
is seeded with the crystals of Form I (0.0001% wt/wt based upon 4-
fluoroacetophenone or more) at temperatures of below 71.5°C. The solids are isolated
by filtration and may be washed and/or reslurried with a suitable solvent. The product
may be dried at temperatures up to 80°C. A "suitable solvent" for this part B is a Ci-
Ce saturated aliphatic alcohol, including linear, branched chain, and cyclic alcohols,
and water, and mixtures thereof.
The following procedure describes a preferred method of preparing the crystal
Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide without isolating the crystal Form IL 2-propanol (70 ml) and
ethyl trifluoroacetate (27.15 g, 0.191 moles) are added to a first vessel, followed by a
line wash of 2-propanol (10 ml). Next, 25% sodium methoxide in methanol (37.5 g,
0.174 moles) is added to the vessel, followed by a line wash of 2-propanol (10 ml).
Next, 4-fluoroacetophenone (20g, 0.145 moles) is added followed by a line wash of 2-
propanol (10 ml). The contents of vessel are heated to 55°C and held at that
temperature for 2 hours, then cooled to ambient temperature. Water (110 ml),
concentrated hydrochloric acid (20.0 g, 0.203 moles), and
4-sulfonamidophenylhydrazine hydrochloride (32.4 g, 0.145 moles) are added to a
second vessel, followed by a line wash of water (10 ml). The contents of the first
vessel are added to the second vessel, followed by a line wash of 2-propanol (60 nil).
The combined contents are heated at 70°C for 2 hours, then cooled to 55° C and
seeded with 10 mg (0.05% wt/wt relative to 4-fluoroacetophenone) of Form I of 4-[5-
(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-benzenesulfonamide. The
contents are held at 55°C for 6 hours, then cooled to ambient temperature and filtered.
The product is washed with 50% aqueous 2-propanol (120 ml) and water (60 ml), then
dried under vacuum at 55°C to give 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lHpyrazol-
l-yl]-benzenesulfonamide of the desired Form I polymorph (44.8 g, 80%).
The invention is described in greater detail by the following non-limiting
examples.
EXAMPLES
Example 1.
De-ionized water, 1 mL, was mixed well with isopropyl alcohol, 1 mL, in a 20
mL glass vial. 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide, Form n, (258.6 mg) was added to the vial. A magnetic stirring
bar was introduced and the vial capped tightly. The suspension was stirred at ~ 200
rpm for about 30 min. A thick paste-like suspension was observed. The stirring was
stopped and the vial was allowed to stand for 3 days. A portion of the suspension was
removed and dried on absorbent paper. The powder X-ray pattern of this solid is
shown in Figure 1. The melting point of some isolated crystals observed under a hot
stage microscope was 148-152°C. However, this range may not be reproducibly
observed because of the transition of Form I to Form n at between 140 to 155°C.
Example 2.
380 mg of Form n was suspended in 2 mL of ethanol. Part of the compound
was dissolved but some excess solid compound suspended in the solution. The
resulting suspension was stirred with a magnetic stirring bar at a temperature from
about 20°C to about 30°C for 2 weeks. At the end of the period, the solid was filtered
and identified by PXRD to be Form L
Example 3.
1.5 g of Form n was added to 2 mL of acetonitrile to afford a suspension. The
suspension was stirred with a magnetic stirring bar at a temperature from about 20*C
to about 30"C for 2 weeks. At the end of the period, the solid was filtered and
identified by PXRD to be Form I.
Example 4.
0.5 g of Form n was added to 2 mL of methanol + water mixture (1:1, v:v) to
afford a suspension. The suspension was stirred with a magnetic stirring bar at a
temperature from about 20°C to about 30'C for 4 weeks. At the end of the period, the
solid was filtered and identified by PXRD to be Form I.
Example 5.
81.5 kg 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-
benzenesulfonamide was completely dissolved in 81.5 Kg of ethanol (6 volumes) at
40°C and filtered while hot. 154 L of water (9 volumes) was added to the solution
over a period of 1 hr while the temperature was maintained at 40°C followed by
cooling down to 20°C. The slurry was stirred at 20 C for 24 hrs, and filtered to
pro\dde4-[5-(4-fluorophenyl)-3-(trifluoromelhyl)-lH-pvrazol-l-yl3-
benzenesulfonamide as Form I.
Example 6. Powder X-ray diffraction.
Powder X-ray diffraction was performed using a Scintag X2 Advanced
Diffraction System (controlled by Scintag DMS/NT 1.30a and Microsoft Windows
NT 4.0 software). The system uses a Copper X-ray source {45 kV and 40 mA) to
provide CuKcti emission of 1.5406A and a solid-state Peltier cooled detector. The
beam aperture was controlled using tube divergence and anti-scatter slits of 2 and 4
mm and detector anti-scatter and receiving slits of 0,5 and 0.2 mm width. Data were
collected from 2 to 35° (two-theta) using a step scan of 0.03"/step with a counting
time of one second per step. Scintag round, top loading aluminum sample holders
with a 12 mm diameter cavity were utilized for the experiments. Powders were
packed into the holder and were gently pressed by a glass slide to ensure coplanarity
between the sample surface and the surface of the sample holder.
As will be appreciated by the skilled crystallographer, the relative intensities of
the various peaks within Tables given below may vary due to a number of factors such
as for example orientation effects of crystals hi the X-ray beam or the purity of the
material being analysed or the degree of crystallinity of the sample. The peak positions
may also shift for variations in sample height but the peak positions will remain
substantially as defined in given Tables.
The skilled crystallographer will also appreciate that measurements using a
different wavelength will result in different shifts according to the Bragg equation - nX
= 2d sin 6.
Such further PXRD patterns generated by use of alternative wavelengths are
considered to be alternative representations of the PXRD patterns of the crystalline
materials of the present invention and as such are within the scope of the present
invention.
For Form 1,2-theta Angles, d spacings and relative intensities were calculated
from the single crystal structure using the "Reflex Powder Diffraction" module of
Accelrys Materials Studio™ [version 2.2]. Pertinent simulation parameters were in
each case:
Wavelength -1.540562 A (Cu Ka)
Polarisation Factor = 0.5
Pseudo-Voigt Profile (U = 0.01, V = -0.001, W = 0.002)
The experimental and the calculated PXRD patterns for Form I and the
experimental pattern for Form n are given in Figures 1,2 and 3, respectively. The
main PXRD peaks of Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lh-pyrazol-
1-ylj-benzenesulfonamide are presented hi Table 1. The main peaks of Form I of 4-
[5-(4-fluorophenyl)-3-(trifluoromemyl)-lh-pyrazol-l-yl]-benzenesulfonamidefrom
the calculated PXRD pattern are presented hi Table 2. Form I displays unique
diffraction peaks at 14.0,18.9,21.3,21.9, and 25.7 degrees of two theta-angle± 0.1
degree.
(Table Removed) Example 7. Differential scanning calorimetry (DSC).
Differential scanning calorimetry (DSC) data were obtained using a DSC
calorimeter (TA Instruments 2920). Powder (1-5 mg) was packed in an aluminum
DSC pan. An aluminum lid was placed on top of the pan and was crimped. The
crimped pan was placed in the sample cell along with an empty pan as a reference.
Temperatures were increased to 250°C from 30°C at a rate of 10°C/min unless
otherwise specified. The thermal cell was purged with dry nitrogen at 50 mL/min.
The TA Instruments Thermal Solutions™ for NT (version 1.3L) was used for data
collection and Universal Analysis™ for NT (version 2.4F) was used for data analysis.
As can be seen in Figure 4, the DSC of Form I shows an endothermal phase transition
from Form I to Form H at 140°C to 155°C.
Example 8. Thermodynamic Relationship between Forms I and II.
In this Example, the transition temperature between Forms I and II is
described. Form I and Form n are enantiotropic, which means that one polymorph is
stable at temperatures below a transition temperature, Tt, but the other polymorph is
stable at temperatures above Tt. The two solid phases have equal free energies at the
transition temperature. Knowledge of the thermodynamic stability relationship is
necessary for the selection of suitable crystallization conditions to produce Form I,
and for formulation development and commercial manufacturing. It is important to
determine T, for the preparation and processing of bulk drug.
Materials And Methods.
Materials. The Form I sample used in this study was 100% pure when tested
by HPLC. Form n was prepared by heating Form I to 155 °C for 3 days in a dry oven
and cooled to room temperature. This Form II sample was free of chemical
degradation when tested by HPLC.
Methods. Suspension crystallization. The relative stability relationship
between Forms I and II at a specific temperature was bracketed by suspending a
mixture of the two polymorphs in toluene in a closed glass vial that was equilibrated
at the temperature of interest. Excess solid of one polymorph was first added to
saturate toluene in a glass vial at the chosen temperature. The other polymorph was
added at least half an hour later. The suspension was stirred continuously for at least
three days. A portion of the suspension was withdrawn and immediately filtered. The
filtered solid was analyzed using PXRD to identify the equilibrium solid at tiiat
temperature. The equilibrium polymorph is thermodynamically more stable at the
specific temperature. By repeating the experiment at different temperatures, the Jt was
bracketed.
Results.
Suspension Crystallization. The results from suspension crystallization
showed that at greater than 71.5° C, a mixture of Forms I and II always converted to
Form n, but at less than 71.0° C, Form I was the equilibrium solid phase. Therefore,
Form I is thermodynamically more stable at less than 71.0° C, and Form II is more
stable at greater than 71.5° C. The 71 must be between 71.0 and 71.5° C.
Discussion.
It is important to determine the T\ for the preparation and processing of bulk
drug. For example, a step comprising crystallization from solution is often involved
prior to the final isolation of the bulk drug. If T\ for the desired form lies below the
crystallization temperature, it might be difficult to crystallize the drug consistently as a
pure phase. Another example is the drying of drug-containing granules after wetgranulation.
If the drying temperature is higher than T\ uncontrolled polymorph
changes of the drug may occur. The changes in turn may affect the subsequent
processing, quality, and performance of final products. The transition temperature, Tt»
was determined to be approximately 71° C using suspension crystallization. Because
Form I is more stable at temperatures below about 71 °C and becomes metastable
with respect to Form n at temperatures above ~71 °C, Form I crystal should maintain
its solid-state stability through the normal range of temperatures for crystallization and
storage, as long as the temperature is below 71° C.
The present invention has been described in detail and by reference to various
specific and preferred embodiments and techniques. However, it should be understood
that many variations and modifications can be made while remaining within the scope
of the invention.















We claim:
1. A process for converting a crystal form, Form II, of 4-(5-(4-fluorophenyl)-3-
(trifluoromethyl)-lH-pyrazol-l-yl}-benzenesulfonamide into the crystal Form I, of 4-{5-
(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-benzenesulfonamide comprising:
(a) mixing a suspension of Form II of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-benzenesulfonamide in a suitable solvent at a temperature from about 0°C to about 60°C;
(b) stirring the suspension at a temperature from about 0°C to about 60°C for 24 to 72 hours; and
(c) collecting the Form I crystals.
2. The process as claimed in claim 1 wherein the solvent is chosen from the group
consisting of water, methanol, ethanol, isopropanol, acetone, acetonitrile, methylene
chloride, toluene, and tetrahydrofuran and mixtures thereof.

Documents:

4992-delnp-2006-Abstract-(15-03-2010).pdf

4992-delnp-2006-abstract.pdf

4992-delnp-2006-Claims-(15-03-2010).pdf

4992-DELNP-2006-Claims-(19-05-2010).pdf

4992-delnp-2006-claims.pdf

4992-delnp-2006-Correspondence-Others (19-11-2009).pdf

4992-DELNP-2006-Correspondence-Others-(12-10-2009).pdf

4992-delnp-2006-Correspondence-Others-(15-03-2010).pdf

4992-DELNP-2006-Correspondence-Others-(18-03-2010).pdf

4992-DELNP-2006-Correspondence-Others-(19-05-2010).pdf

4992-delnp-2006-correspondence-others.pdf

4992-delnp-2006-Description (Complete)-(15-03-2010).pdf

4992-delnp-2006-description (complete).pdf

4992-delnp-2006-Drawings (19-11-2009).pdf

4992-delnp-2006-drawings.pdf

4992-delnp-2006-Form-1-(15-03-2010).pdf

4992-delnp-2006-form-1.pdf

4992-delnp-2006-form-13.pdf

4992-delnp-2006-form-18.pdf

4992-delnp-2006-Form-2-(15-03-2010).pdf

4992-delnp-2006-form-2.pdf

4992-DELNP-2006-Form-3-(12-10-2009).pdf

4992-delnp-2006-Form-3-(15-03-2010).pdf

4992-DELNP-2006-Form-3-(18-03-2010).pdf

4992-delnp-2006-form-3.pdf

4992-delnp-2006-form-5.pdf

4992-delnp-2006-GPA-(15-03-2010).pdf

4992-delnp-2006-gpa.pdf

4992-delnp-2006-pct-210.pdf

4992-delnp-2006-pct-304.pdf

4992-delnp-2006-pct-402.pdf

4992-delnp-2006-pct-409.pdf

4992-delnp-2006-pct-416.pdf

4992-delnp-2006-Petition 137-(15-03-2010).pdf


Patent Number 242174
Indian Patent Application Number 4992/DELNP/2006
PG Journal Number 34/2010
Publication Date 20-Aug-2010
Grant Date 18-Aug-2010
Date of Filing 30-Aug-2006
Name of Patentee PHARMACIA & UPJOHN COMPANY LLC .,
Applicant Address 301 Henrietta Street, Kalamazoo, MICHIGAN 49001 (USA)
Inventors:
# Inventor's Name Inventor's Address
1 CHANGQUAN CALVIN SUN, Pfizer Global Research & Development, 301 Henrietta Street, Kalamazoo, MICHIGAN 49001 (USA)
2 O'CONNOR GARRY, Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, England.
PCT International Classification Number C07D 231/12
PCT International Application Number PCT/IB2005/000735
PCT International Filing date 2005-03-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/558,469 2004-04-01 U.S.A.