U.S. patent application number 11/208248 was filed with the patent office on 2005-12-29 for novel crystalline forms of gatifloxacin.
This patent application is currently assigned to Teva Pharmaceuticals USA, Inc. for Barbados.. Invention is credited to Amir, Ehud, Niddam-Hildesheim, Valerie, Sterimbaum, Greta, Wizel, Shlomit.
Application Number | 20050288301 11/208248 |
Document ID | / |
Family ID | 30119567 |
Filed Date | 2005-12-29 |
United States Patent
Application |
20050288301 |
Kind Code |
A1 |
Niddam-Hildesheim, Valerie ;
et al. |
December 29, 2005 |
Novel crystalline forms of gatifloxacin
Abstract
Provided are novel crystalline forms of gatifloxacin denominated
forms A, B, C, D, E1, F, G, H, I, and J, and methods for their
preparation. Also provided are methods for making known crystalline
forms of gatifloxacin, in particular forms omega and T2RP.
Inventors: |
Niddam-Hildesheim, Valerie;
(Even-Yeouda, IL) ; Wizel, Shlomit; (Petah Tiqva,
IL) ; Sterimbaum, Greta; (Rishon-Lezion, IL) ;
Amir, Ehud; (Tel Aviv, IL) |
Correspondence
Address: |
KENYON & KENYON
ONE BROADWAY
NEW YORK
NY
10004
US
|
Assignee: |
Teva Pharmaceuticals USA, Inc. for
Barbados.
|
Family ID: |
30119567 |
Appl. No.: |
11/208248 |
Filed: |
August 19, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11208248 |
Aug 19, 2005 |
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10436736 |
May 12, 2003 |
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60379510 |
May 10, 2002 |
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60389093 |
Jun 14, 2002 |
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60401672 |
Aug 6, 2002 |
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60402749 |
Aug 12, 2002 |
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60409860 |
Sep 10, 2002 |
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60423338 |
Nov 1, 2002 |
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60432961 |
Dec 12, 2002 |
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60444812 |
Feb 3, 2003 |
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60448062 |
Feb 15, 2003 |
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Current U.S.
Class: |
514/253.08 ;
544/363 |
Current CPC
Class: |
C07D 215/56
20130101 |
Class at
Publication: |
514/253.08 ;
544/363 |
International
Class: |
A61K 031/496; C07D
043/02 |
Claims
1-75. (canceled)
76. A crystalline form of gatifloxacin characterized by x-ray
reflections at about 7.1.degree., 7.3.degree., 10.8.degree.,
15.7.degree., 16.4.degree., and 18.1.degree..+-.0.2.degree.
2.theta..
77. The crystalline form of claim 76 containing acetonitrile,
water, or mixtures thereof up to about 10% by weight.
78. A method of making the crystalline form of gatifloxacin of
claim 77 comprising the step of treating E1-ACN in a fluidized bed
apparatus.
79. The method of claim 78 wherein the E1-ACN treated with moist
gas at a temperature greater than about 30.degree. C.
80. A method of making the crystalline form of gatifloxacin of
claim 81 comprising the step of exposing E1-ACN to 60% relative
humidity.
81. The crystalline form of gatifloxacin of claim 77, designated E1
hydrate, comprising about 7.5% to 10% by weight water.
82. A method of making the crystalline form of gatifloxacin of
claim 81 comprising the step of treating E1-ACN with moist gas in a
fluidized bed apparatus at a temperature greater than about
30.degree. C.
83. The method of making the crystalline form of gatifloxacin of
claim 82 wherein the gatifloxacin treated is first treated with
moist gas at 20.degree. to 30.degree. C.
84. A method of making the crystalline form of gatifloxacin of
claim 81 comprising the step of exposing E1-ACN to 60% relative
humidity.
85-87. (canceled)
88. A method of making the crystalline form of gatifloxacin a claim
80 comprising the steps of: a) providing a solution of gatifloxacin
in acetonitrile having about 5 wt % or less water at reflux, b)
cooling the solution to a seeding temperature of about 57.degree.
to 70.degree. C., c) seeding the solution at the seeding
temperature, d) cooling the seeded solution, and e) isolating the
crystalline form of gatifloxacin.
89. The method of claim 88 wherein the seeded solution is
maintained at the seeding temperature for a seeding time of at
least about 30 minutes.
90. The method of claim 88 wherein the seeding temperature is about
60.degree. C.
91. The method of claim 88 wherein the seeded solution is cooled to
about 5.degree. C. or below.
92. The method of claim 88 wherein the solution of gatifloxacin in
acetonitrile has about 4.5 mt % or less water.
93. A method of making the crystalline form of gatifloxacin of
claim 80 comprising the step of incubating gatifloxacin in
acetonitrile vapors.
94. A crystalline form of gatifloxacin, denominated E1-ACN, having
up to about 10% acetonitrile and characterized by x-ray reflections
at about 7.1.degree., 7.3.degree., 10.8.degree., 15.7.degree.,
16.4.degree., and 18.1.degree..+-.0.2.degree. 2.theta., wherein the
crystalline form is made by a process comprising the steps of: a)
providing a solution of gatifloxacin in acetonitrile having about 5
wt % or less water at reflux, b) cooling the solution to a seeding
temperature of about 57.degree. to 70.degree. C., c) seeding the
solution at the seeding temperature, d) cooling the seeded
solution, and e) isolating the crystalline form of
gatifloxacin.
95. The crystalline form of gatifloxacin of claim 94 wherein the
solution of gatifloxacin in acetonitrile has about 4.5 wt % or less
water.
96. The crystalline form of claim 94 wherein the seeded solution is
maintained at the seeding temperature for a seeding time of at
least about 30 minutes.
97. The crystalline form of claim 94 wherein the seeding
temperature is about 60.degree. C.
98. The crystalline form of claim 94 wherein the seeded solution is
cooled to about 5.degree. C. or below.
99-107. (canceled)
108. A method of making a hydrated gatifloxacin form E1 comprising
the step of treating gatifloxacin form E1-ACN solvate with a moist
gas at a temperature from ambient temperature to about 60.degree.
C.
109. The method of claim 108 wherein the treating is at about
20.degree. to about 30.degree. C. and the E1 dihydrate has a water
content of about 7.5% to about 10% on a weight basis.
110. The method of claim 108 wherein the moist gas has a relative
humidity between about 55% and about 75%.
111. The method of claim 108 wherein the treating is at about
50.degree. C.
112. The method of claim 108 wherein the treating is effected in a
fluidized bed drying apparatus.
113. A hydrated crystalline form of gatifloxacin having up to about
10% water or a mixture of water and acetonitrile and characterized
by x-ray reflections at about 7.1, 7.3, 10.8, 15.7, 16.4, and
18.1.times.0.2 2, wherein the crystalline form is made by a process
comprising the step of treating gatifloxacin E1-ACN with moist gas
at a temperature from ambient to about 60 C.
114. The crystalline form of gatifloxacin of claim 113 wherein the
treating is at about 20 to about 30 C and the crystalline form
contains about 5% to about 7% water.
115. The crystalline form of claim 113 wherein the relative
humidity of the moist gas is about 55% to about 75%.
116. The crystalline form of gatifloxacin of claim 113 wherein the
treating is at about 50 C.
117. The crystalline form of claim 113 wherein the treating is in a
fludized bed apparatus.
118-131. (canceled)
Description
RELATED APPLICATIONS
[0001] The present application claims the benefit of the filing
date of the following U.S. Provisional Patent Applications:
60/379,510; 60/389,093; 60/401,672; 60/402,749; 60/409,860,
60/423,338; 60/432,961; 60/444,812; and 60/448,062.
FIELD OF THE INVENTION
[0002] The present invent relates to novel polymorphs and
pseudopolymorphs of (.+-.)
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7(3-methyl-1-piper-
azinyl)-4-oxo-3-quinolinecarboxylic acid, commonly known as
gatifloxacin.
BACKGROUND OF THE INVENTION
[0003] Gatifloxacin, known as (.+-.)
1-cyclopropyl-6-fluoro-1,4-dihydro-8--
methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic
acid, has the following structure: 1
[0004] Gatifloxacin, an anti-bacterial agent, is marketed as
Tequin.RTM. by Bristol-Myers Squibb. Tequin.RTM. is available in a
dosage of 200 and 400 mg in the form of a vial or a tablet, which
can be either injected or taken orally.
[0005] Many pharmaceutically active organic compounds can
crystallize in more than one type of molecular packing with more
than one type of internal crystal lattice. That is, the compounds
crystallize in different crystalline forms. The respective
resulting crystal structures (forms) can have, for example,
different unit cells. This phenomenon--identical chemical structure
but different internal structure--is referred to as polymorphism
and the species having different molecular structures are referred
to as polymorphs.
[0006] Many pharmacologically active organic compounds can also
crystallize in crystalline forms such that second, foreign
molecules, especially solvent molecules, are regularly incorporated
into the crystal structure of the principal pharmacologically
active compound. This phenomenon is sometimes referred to as
pseudopolymorphism and the resulting structures as
pseudopolymorphs. When the second molecule is a solvent molecule,
the pseudopolymorphs can be referred to as solvates.
[0007] However, it is generally not possible to predict whether a
particular organic compound will form different crystalline forms,
let alone predict the structure and properties of the crystalline
forms themselves.
[0008] The discovery of a new crystalline form of a
pharmaceutically useful compound provides an opportunity to improve
the performance characteristics of a pharmaceutical product. It
enlarges the repertoire of materials that a formulation scientist
has available for designing, for example, a pharmaceutical dosage
form of a drug with a targeted release profile or other desired
characteristic. It is clearly advantageous when this repertoire is
enlarged by the discovery of new polymorphs or pseudopolymorphs of
a useful compound. For a general review of polymorphs and the
pharmaceutical applications of polymorphs see G. M. Wall, Pharm
Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm.
Sci., 58, 911 (1969); and J. K. Haleblian, J Pharm. Sci., 64, 1269
(1975), all of which are incorporated herein by reference.
[0009] Crystalline forms can be influenced by controlling the
conditions under which the compound is obtained in solid form.
Solid state physical properties that can differ from one polymorph
to the next include, for example, the flowability of the milled
solid. Various crystalline forms can be more or less hygroscopic.
Absorption of atmospheric moisture by compound in powder form can
impede its ability to flow. Flowability affects the ease with which
the material is handled during processing into a pharmaceutical
product. When particles of the powdered compound do not flow past
each other easily, a formulation specialist must take that fact
into account in developing a tablet or capsule formulation, which
may necessitate the use of glidants such as colloidal silicon
dioxide, talc, starch or tribasic calcium phosphate.
[0010] Another important solid state property of a pharmaceutical
compound that can vary from one polymorph or pseudopolymorph to the
next is its rate of dissolution in aqueous media, e.g., gastric
fluid. The rate of dissolution of an active ingredient in a
patient's stomach fluid can have therapeutic consequences since it
imposes an upper limit on the rate at which an orally-administered
active ingredient can reach the patient's bloodstream. The rate of
dissolution is also a consideration in formulating syrups, elixirs
and other liquid medicaments. The solid state form of a compound
may also affect its behavior on compaction and its storage
stability.
[0011] These practical physical characteristics are influenced by
the conformation, orientation, and packing of molecules in the unit
cell, which characterize a particular polymorphic or
pseudopolymorphic form of a substance. A polymorphic form may have
thermodynamic properties different from those of the amorphous
material or another polymorphic form. Thermodynamic properties can
be used to distinguish between various polymorphs or
pseudopolymorphs. Thermodynamic properties that can be used to
distinguish between polymorphs and pseudopolymorphs can be measured
in the laboratory by such techniques as capillary melting point,
thermogravimetric analysis (TGA), differential scanning calorimetry
(DSC), and differential thermal analysis (DTA).
[0012] A particular crystalline form can also possess distinct
spectroscopic properties that may be detectable by, for example,
solid state .sup.13C NMR spectroscopy and infrared (IR)
spectroscopy. This is particularly so in the case of crystalline
forms that are solvates because of the presence of absorptions or
resonances due to the second, foreign molecule.
[0013]
(.+-.)-1-Cyclopropyl-6-fluoro-1,4-digydro-8-methoxy-7-(3-methyl-1-p-
iperazinyl)4-oxo-3-quinolenecarboxylic acid, commonly known as
gatifloxacin, is a synthetic broad-spectrum antibacterial agent for
oral or intravenous administration.
[0014] U.S. Pat. No. 5,880,283 discloses that gatifloxacin forms a
hygroscopic hemihydrate. The hemihydrate (a pseudopolymorph) is
reported to be easily formed upon crystallization of gatifloxacin
from water-containing organic solvents. The hemihydrate reportedly
has disadvantages for manufacturing of solid oral dosage forms,
e.g., tablets. The patent further discloses a novel pseudopolymorph
of gatifloxacin, the sesquihydrate, and presents thermal analysis
and x-ray diffraction data for this material. The sesquihydrate is
reported to be less hygroscopic and more stable in
manufacturing.
[0015] U.S. Pat. No. 6,413,969 discloses at least 12 different
polymorphs or pseudopolymorphs of gatifloxacin and discloses the
x-ray powder diffraction diagrams of at least 10 of these. The
hexahydrate, pentahydrate and sesquihydrate are crystallized
directly from aqueous solvents. Other crystalline forms are
crystallized from a molten phase or by solid-solid phase
transformations. The pentahydrate form is, according to the
disclosure of U.S. Pat. No. 6,413,969, the most thermodynamically
stable form and has the lowest aqueous solubility at room
temperature. The interrelationships between the twelve identified
crystalline forms are given in the application.
SUMMARY OF THE INVENTION
[0016] In one aspect, the present invention the present invention
relates to crystalline form of gatifloxacin, denominated form A,
characterized by x-ray reflections at about 6.4.degree.,
12.8.degree., 16.4.degree., 17.3.degree., and
19.4.degree..+-.0.2.degree. 2.theta..
[0017] In another aspect the present invention relates to a
crystalline form of gatifloxacin, denominated form B, characterized
by x-ray reflections at about 9.2.degree., 10.6.degree.,
11.9.degree., 18.4.degree., and 25.0.degree..+-.0.2+ 2.theta.; and
to a method for making it, which method includes the steps of
slurrying gatifloxacin in a lower alkanol selected from ethanol and
1-butanol at ambient temperature for a slurry time, especially
about 8 to about 36 hours, and isolating crystalline form B of
gatifloxacin from the slurry.
[0018] In another aspect, the present invention relates to
crystalline form of gatifloxacin, denominated form C, having at
least one characteristic selected from:
[0019] a) x-ray reflections at about 7.2.degree., 10.8.degree.,
15.8.degree., 21.8.degree., and
26.2.degree..+-.0.2.degree.2.theta.,
[0020] b) DSC endotherms at about 173.degree. and 177.degree. C.,
and
[0021] c) FTIR absorption bands at about 805, 1509, 1619, and 1728
cm.sup.-1.
[0022] In a related aspect, the present invention relates to a
method of making gatifloxacin form C including the step of heating
either of gatifloxacin form B or form I at about 40.degree. to
about 70.degree. C., especially 50.degree. C., and atmospheric
pressure for about 25 to about 48 hours.
[0023] In yet another aspect, the present invention relates to a
crystalline form of gatifloxacin, denominated form D, characterized
by x-ray reflections at about 8.2.degree., 14.4.degree.,
19.0.degree., 21.4.degree., 21.9.degree., and
23.1.degree..+-.0.2.degree.2.theta., and to a method of making it,
which method includes the steps of slurrying gatifloxacin in
methanol at ambient temperature for a slurry time, especially about
8 to about 36 hours, and isolating the crystalline form of
gatifloxacin from the slurry.
[0024] In another aspect, the present invention relates to a method
of making form D including the step of incubating gatifloxacin in
vapors of methanol.
[0025] In a further aspect, the present invention relates to a
crystalline form of gatifloxacin, denominated form F, characterized
by x-ray reflections at 8.0.degree., 14.2.degree., 18.7.degree.,
21.8.degree., and 23.0.degree..+-.0.2.degree. 2.theta.; and to a
method of making it, which method includes the steps of
[0026] a) providing a solution of gatifloxacin in a mixture of
methanol and water, 90:10 (v:v),
[0027] b) cooling the solution, especially to ambient temperature
or below, especially about 5.degree. C., and
[0028] c) isolating the crystalline form of gatifloxacin.
[0029] In another aspect, the present invention relates to
crystalline form of gatifloxacin, denominated form G, characterized
by at least one of:
[0030] a) x-ray reflections at about 17.2.degree. and
17.6.degree..+-.0.2.degree. 2.theta., and
[0031] b) FTIR absorption bands at about 1614 cm.sup.-1 and about
1267 cm.sup.-1.
[0032] In a further aspect, the present invention relates to a
method of making gatifloxacin crystalline form G including the step
of drying either of gatifloxacin crystalline forms A or F at
50.degree. C. and atmospheric pressure for at least about 20
hours.
[0033] In yet another aspect, the present invention relates to a
crystalline form of gatifloxacin, denominated form H, characterized
by x-ray reflections at about 6.6.degree., 13.2.degree.,
19.6.degree., and 19.9.degree..+-.0.2.degree.2.theta.; and to a
method of making it, which method includes the steps of:
[0034] a) providing a solution of gatifloxacin in toluene,
especially at reflux
[0035] b) cooling the solution, especially to ambient temperature
or below, especially about -5.degree. C., and
[0036] c) isolating the crystalline form of gatifloxacin.
[0037] In another aspect, the present invention relates to
gatifloxacin toluene solvate.
[0038] In another aspect, the present invention relates to a method
of making gatifloxacin crystalline form H including the steps
of:
[0039] a) slurrying gatifloxacin in toulene at ambient temperature
for a slurry time, especially about 8 to about 36 hours, and
[0040] b) isolating the crystalline form of gatifloxacin from the
slurry.
[0041] In a further aspect, the present invention relates to a
crystalline form of gatifloxacin, denominated form I, characterized
by x-ray reflections at 6.5.degree., 7.1.degree., 12.8.degree.,
17.2.degree., 19.3.degree., and 21.0.degree..+-.0.2.degree., and to
a method of making it, which method includes the steps of:
[0042] a) providing a solution of gatifloxacin in 1-butanol,
especially at reflux
[0043] b) cooling the solution, especially to ambient temperature
or below, especially about -5.degree., and
[0044] c) isolating the crystalline form of gatifloxacin from the
suspension.
[0045] In still yet another aspect, the present invention relates
to a crystalline form of gatifloxacin that exists in various
solvated forms, denominated form J, characterized by a x-ray
reflection at about 6.7.degree., 11.3.degree., 13.8.degree., and
16.4.degree..+-.0.2.degree. 2.theta.. Form J can exist at least as
an iso-propanol solvate, that can be made by an incubation process
or a crystallization process; a methyl ethyl ketone solvate that
can be made by an incubation process; an acetone solvate that can
be made by an incubation process or slurry process; a 1-butanol
solvate that can be made by a crystallization process; or as a
tetrahydrofuran solvate that can be made by a slurry process.
[0046] In still yet another aspect, the present invention relates
to a crystalline form of gatifloxacin, denominated form E1,
characterized by x-ray reflections at about 7.1.degree.,
7.3.degree., 10.8.degree., 15.7.degree., 16.4.degree., and
18.1.degree..+-.0.2.degree. 2.theta.; and to methods for making it.
Form E1 contains acetonitrile, water, or a mixture of acetonitrile
and water at up to about 10 wt %.
[0047] In another aspect, the present invention relates to a
crystalline form of gatifloxacin, E1-ACN, and to methods of making
it. E1-ACN has the crystallographic characteristics of E1, namely
x-ray reflections at about 7.1.degree., 7.3.degree., 10.8.degree.,
15.7.degree., 16.4.degree., and 18.1.degree..+-.0.2.degree.
2.theta.; and contains up to about 10% acetonitrile.
[0048] Gatifloxacin E1-ACN can be made by a process including the
steps of:
[0049] a) providing a solution of gatifloxacin in acetonitrile
having about 5 wt % or less water, especially about 4.5 wt % or
less water, at reflux,
[0050] b) cooling the solution to a seeding temperature of about
57.degree. to 70.degree. C., especially about 60.degree. C.,
[0051] c) seeding the solution at the seeding temperature and,
optionally, maintaining the seeded solution at the seeding
temperature for a seeding time of about 30 minutes or more,
[0052] d) cooling the seeded solution, especially to ambient
temperature or below, especially 5.degree. C. or below, and
[0053] e) isolating the crystalline E1-ACN gatifloxacin.
[0054] In still a further aspect, the present invention relates to
a hydrate form E1 having a water content of about 7.5 to about 10
weight percent (wt %). In a particular aspect, the present
invention relates to a hydrated form of gatifloxacin that is a
dihydrate (E1 dihydrate) having about 9.3 weight percent water. The
hydrated E1 of the present invention, regardless of water content,
is substantially free of prior-art sesquihydrate and is
characterized by x-ray reflections at about 7.1.degree.,
7.3.degree., 10.8.degree., 15.7.degree., 16.4.degree., and
18.1.degree..+-.0.2.degree. 2.theta..
[0055] In a further aspect, the present invention relates to
methods of making hydrated E1, which method includes the step of
treating gatifloxacin form E1-ACN solvate with a moist gas,
especially moist gas of about 55% to about 75% relative humidity at
a temperature from ambient temperature to about 60.degree. C.,
especially about 20.degree. to 30.degree. C.; although treating at
50.degree. C. can be advantageous.
[0056] In still a further-aspect, the present invention relates to
a method of making prior-art crystalline form of gatifloxacin,
denominated form omega (.OMEGA.), including the steps of:
[0057] a) providing, at reflux, a filtered solution of gatifloxacin
in acetonitrile, wherein the solution has a water content of about
5% or less, especially about 4.5 wt % or less,
[0058] b) cooling the solution to a seeding temperature of about
50.degree. to about 56.degree. C.
[0059] c) seeding the solution with gatifloxacin at the seeding
temperature and, optionally, maintaining the seeded solution at the
seeding temperature for a seeding time of at least about 30
minutes,
[0060] d) cooling the seeded solution, especially to ambient
temperature or below, especially about 5.degree. C., and
[0061] e) isolating the crystalline gatifloxacin crystalline form
omega from the suspension.
[0062] In still a further aspect, the present invention relates to
method of making prior-art crystalline form of gatifloxacin T2RP.
In one such method, >200 g (especially >1000 g) of
gatifloxacin E1-ACN are slurried with ethanol and the solid
isolated from the slurry is treated with moist gas, especially in a
fluidized bed apparatus. Other methods including the step of
treating novel forms of gatifloxacin are also disclosed.
[0063] In another aspect, the present invention relates to a method
of making about 200 g or less of gatifloxacin form T2RP including
the steps of slurrying about 200 g or less of gatifloxacin E1-ACN
in ethanol, isolating the solid from the slurry, and drying the
isolated solid at about 50.degree. C.
[0064] In another aspect, the present invention relates to
gatifloxacin having an average particle size less than about
100.mu., especially less than about 50.mu., wherein the
gatifloxacin is in a crystalline form selected from forms A, B, C,
D, hydrated E1, F, G, H, I, and J.
[0065] In yet still another aspect, the present invention relates
to pharmaceutical compositions containing a hydrated form of
gatifloxacin form E1, especially E1 dihydrate, that are
substantially free of sesquihydrate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0066] FIG. 1 shows a representative x-ray diffraction diagram of
gatifloxacin form A.
[0067] FIG. 2 shows a representative DSC thermogram of gatifloxacin
form A.
[0068] FIG. 3 shows a representative TGA thermogram of gatifloxacin
form A.
[0069] FIG. 4 shows a representative x-ray diffraction diagram of
gatifloxacin form B.
[0070] FIG. 5 shows a representative DSC thermogram of gatifloxacin
form B.
[0071] FIG. 6 shows a representative TGA thermogram of gatifloxacin
form B.
[0072] FIG. 7 shows a representative x-ray diffraction diagram of
gatifloxacin form C.
[0073] FIG. 8 shows a representative FTIR spectra for gatifloxacin
form C.
[0074] FIG. 9 shows a representative DSC thermogram of gatifloxacin
form C.
[0075] FIG. 10 shows a representative TGA thermogram of
gatifloxacin form C.
[0076] FIG. 11 shows a representative x-ray diffraction diagram of
gatifloxacin form D.
[0077] FIG. 12 shows a representative DSC thermogram of form D.
[0078] FIG. 13 shows a representative TGA thermogram of form D.
[0079] FIG. 14a through 14g show representative x-ray diffraction
diagrams of gatifloxacin form E1.
[0080] FIG. 15 shows a representative TGA thermogram of
gatifloxacin form E1 dihydrate.
[0081] FIG. 16 shows a representative TGA thermogram of
gatifloxacin form E1 as its acetonitrile solvate.
[0082] FIG. 17 shows a representative x-ray diffraction diagram of
gatifloxacin form F.
[0083] FIG. 18 shows a representative DSC thermogram of form F.
[0084] FIG. 19 shows a representative TGA thermogram of form F.
[0085] FIG. 20 shows a representative x-ray diffraction diagram of
gatifloxacin form G.
[0086] FIG. 21 shows a representative FTIR spectrum of gatifloxacin
form G.
[0087] FIG. 22 shows a representative DSC thermogram of
gatifloxacin form G.
[0088] FIG. 23 shows a representative TGA thermogram of
gatifloxacin form G.
[0089] FIG. 24 shows a representative x-ray diffraction diagram of
gatifloxacin form H toluene solvate.
[0090] FIG. 25 shows a representative DSC thermogram of
gatifloxacin form H toluene solvate.
[0091] FIG. 26 shows a representative TGA thermogram of
gatifloxacin form H toluene solvate.
[0092] FIG. 27 shows a representative x-ray diffraction diagram of
gatifloxacin form I.
[0093] FIG. 28 shows a representative DSC thermogram of
gatifloxacin form I.
[0094] FIG. 29 shows a representative TGA thermogram of
gatifloxacin form I.
[0095] FIG. 30 shows a representative FTIR spectrum of gatifloxacin
form J.
[0096] FIG. 31 shows a representative DSC thermogram of
gatifloxacin form J.
[0097] FIG. 32 shows a representative TGA thermogram of
gatifloxacin form J.
DETAILED DESCRIPTION OF THE INVENTION
[0098] Gatifloxacin, (.+-.)
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-
-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, is a
known anti-bacterial. The present invention provides novel
crystalline forms (polymorphs, pseudopolymorphs) of this useful
drug.
[0099] Unless otherwise specified or required by the context,
gatifloxacin refers to the compound in any crystalline form, which
may or may not be a solvated crystalline form, or in an amorphous
form.
[0100] As used herein, gatifloxacin form omega (.OMEGA.), form
T1RP, and form T2RP refer to the crystalline forms disclosed under
those designations in U.S. Pat. No. 6,413,969. Gatifloxacin
sesquihydrate refers to the crystalline form of gatifloxacin
denominated as such in U.S. Pat. No. 5,880,283.
[0101] As used herein, the phrase, "having at least one
characteristic of GTF form `#`," where "#" is an arabic letter or
numeral or a roman numeral, or any combinatiuon of these denoting a
crystalline form of gatifloxacin, refers to a crystalline form of
gatifloxacin that exhibits at least the characteristic powder x-ray
diffraction (PXRD) reflections (or peaks), or the characteristic
DSC endo- or exotherms, or, where applicable, the characteristic
FTIR absorption bands of form `#`.
[0102] As used herein in connection with a measured quantity, the
term, "about," refers to that variation in the measured quantity as
would be expected by the skilled artisan making the measurement and
exercising a level of care commensurate with the objective of the
measurement and the precision of the measuring equipment used.
[0103] As used herein, the term ambient temperature is a
temperature between about 18.degree. and about 30.degree. C.
[0104] As used herein, ambient pressure is about 760 mmHg.
[0105] As used herein in connection with drying procedures, drying
under vacuum (in vacuo) implies drying at a reduced pressure of
about 10 to about 20 mm Hg.
[0106] As used herein in connection with a multi-component mixture
of liquids, the term % v/v refers to the ratio of the volume of the
named component to the sum of the volumes of all components used to
make the mixture, times 100. Thus, a mixture of approximately equal
volumes of A and B is referred to as "50 vol-% A" (or 50 vol-% B).
Alternatively, this mixture can be referred to as "a mixture of A
and B, 50:50 (v:v)".
[0107] As used herein, lower alkanol refers to an alcohol of
formula C.sub.nH.sub.2n+1OH, where n is 6 or less.
[0108] X-ray reflections reported herein were determined by the
powder diffraction technique (PXRD). X-ray powder diffraction
analysis was performed using a Scintag powder diffractometer with
variable goniometer, a Cu source, and a solid state detector. A
standard round aluminum sample holder with zero background quartz
plate was used. Samples were scanned from 2.degree. to 40.degree.
2.theta. at 3.degree. per minute. Reflections are reported as peak
maxima in the Intensity vs. 2.theta. plots, and are subject to the
normal experimental error (uncertainty) of .+-.0.2.degree.. Wet
samples were promptly analyzed "as is," i.e., without drying or
grinding prior to the analysis.
[0109] Fourier transform infra-red spectra (FTIR) were obtained on
Nujoll mulls using a Perkin Elmer SpectrumOne spectrophotometer.
Sixteen scans were recorded from 4000 to 400 cm.sup.-1 at a
resolution of 4 cm.sup.-1.
[0110] Differential scanning calorimetric (DSC) analysis was
performed with a Mettler Toledo DSC 821.sup.e calorimeter. Samples
of about 3 to about 5 milligrams, held in a vented (3-hole)
crucible, were analyzed at a heating rate of 10.degree. per
minute.
[0111] Thermogravimetric analysis (TGA) was performed using a
Mettler TG50 thermobalance. Samples of 7 to 15 milligrams were
analyzed at a heating rate of 10.degree. C. per minute in the
temperature range between about 25.degree. C. and about 200.degree.
C.
[0112] The water content (wt-% water) of crystalline forms of
gatifloxacin reported herein was determined by the Karl-Fisher
method. Water content of solutions was likewise determined by the
Karl-Fisher method.
[0113] In particular embodiments, a novel crystalline form of the
present invention is made by a crystallization (precipitation)
process in which a particular crystalline form of gatifloxacin is
crystallized from a solution in an organic solvent. The solvent can
be a single component (i.e., a single organic compound normally
liquid at ambient temperature), or it can be multi-component (i.e.,
a mixture of organic compounds normally liquid at ambient
temperature). One of the components of a multi-component solvent
can be a poor solvent for gatifloxacin. Crystallization can be
induced by changing the solubility of gatifloxacin in the solvent.
The solubility can be altered by, for example, lowering the
temperature of the solution, or by adding an "anti-solvent" to the
solution.
[0114] In particular embodiments, filtration of the solution from
which the crystalline form of gatifloxacin is to be crystallized
has been found to be an important step. Although an understanding
of the theory of the importance of this filtration step is
unnecessary to the practice of the present invention, the present
inventors speculate that filtration, especially hot filtration,
removes and promotes control of the temperature at which nucleation
can be sustained and crystallization begins. Both of these are
parameters capable of influencing the crystalline form of
gatifloxacin obtained.
[0115] The temperature of the solution can be lowered in one or
more steps. For making certain crystalline forms, it is
advantageous to lower the temperature in steps and-to maintain the
temperature at each step for a holding time (i.e., a first holding
time at the temperature at the end of the first cooling step, a
second holding time at the temperature at the end of the second
cooling step, etc.). Step-wise lowering of the temperature can be
advantageous when seeding is employed. Seeding is a well-known
technique for inducing crystallization of a compound from its
solution. When seeding is employed, the solution is cooled into a
seeding temperature in a first cooling step. The temperature at
which the solution is seeded is denoted the seeding temperature and
the holding time at that temperature is known as a seeding time. It
is sometimes necessary to carefully control the cooling rate of any
cooling step, depending on the crystalline form of gatifloxacin
being sought.
[0116] The skilled artisan will appreciate that in any method of
the present invention in which a solution of gatifloxacin is
provided, the solution can be provided by any means; for example by
dissolving gatifloxacin in the solvent or, where the solvent does
not interfere with the reaction, by preparing gatifloxacin in the
presence of the desired solvent, or in the presence of one
component of a multi-component solvent system whereafter other
component(s) are introduced.
[0117] An anti-solvent is an organic compound, normally a liquid at
ambient temperature, that is a poor solvent for the compound to be
crystallized (here gatifloxacin).
[0118] The solubility of the compound to be crystallized from the
combination of solvent and anti-solvent is lower than the
solubility of the compound in the original solvent. In particular
embodiments, crystallization is induced through use of an
anti-solvent and by lowering the temperature of the solution.
[0119] The crystalline form of gatifloxacin is then isolated by
standard means.
[0120] In other embodiments, a novel crystalline form of
gatifloxacin of the present invention is made in a slurry
(suspension) process in which gatifloxacin is slurried (suspended),
with agitation, in a slurry solvent, usually at ambient
temperature, for a slurry time. As long as there is sufficient
slurry solvent to wet and suspend the gatifloxacin, the ratio of
gatifloxacin to slurry solvent is not critical and will be dictated
by practical considerations, for example, ease of handling. The
slurry time is not critical and will usually be between about 8 and
about 36 hours. The skilled artisan will know to adjust the slurry
time by routine optimization by, for example, isolating the solid
from a small aliquot of the slurry and determining the crystalline
form of the solid by an appropriate technique, for example x-ray
diffraction, differential scanning calorimetry, or Fourier
transform infra-red spectroscopy.
[0121] At the end of the slurry time, the crystalline form of
gatifloxacin is isolated by standard techniques, for example
filtration (gravity or suction) or centrifugation, to mention just
two.
[0122] In other embodiments, a novel crystalline form of
gatifloxacin of the present invention is made by treating a vapor
incubation process wherein gatifloxacin is exposed to (i.e.,
incubated with) vapors of an organic solvent, usually at ambient
temperature, for an incubation time. Any suitable chamber capable
of holding the sample and containing the solvent vapors can be
used. The incubation time is not critical and will generally be
between about 2 and about 20 days.
[0123] In those embodiments that yield a crystalline form of
gatifloxacin that is a solvate, care should be taken to analyze the
material without drying that might remove the solvent.
[0124] One or more of the foregoing methods, and other methods such
as thermal treatment (heating, drying) described hereinbelow, are
adapted to the preparation of the novel crystalline forms of
gatifloxacin of the present invention.
[0125] In one embodiment, the present invention provide a
crystalline form of gatifloxacin, denominated form A, which is
characterized by x-ray reflections at about 6.4.degree.,
12.8.degree., 16.4.degree., 17.3.degree., and
19.4.degree..+-.0.2.degree. 2.theta.. A typical x-ray diffraction
diagram of form A is shown in FIG. 1. A typical DSC thermogram of
form A is shown in FIG. 2. The loss on drying of form A, as
determined by TGA, can be as high as 65%. A typical TGA thermogram
of form A is shown in FIG. 3.
[0126] Form A can be made by a slurry process including the steps
of slurrying gatifloxacin in iso-propanol (IPA) at ambient
temperature and isolating the crystalline form A.
[0127] Form A can be converted to form J by, for example, drying at
50.degree. C. The skilled artisan will know to adjust the drying
time according to, for example, sample size and drying equipment
used. Generally, a time of about 12 to about 18 hours is sufficient
to effect the conversion.
[0128] In another embodiment, the present invention provides a
novel crystalline form of gatifloxacin, denominated form B,
characterized by x-ray diffraction reflections at
2.theta.=9.2.degree., 10.6.degree., 11.9.degree., 18.4.degree., and
25.0.degree.. A typical x-ray diffraction diagram for form B is
shown in FIG. 4. A typical DSC thermogram of form B is shown in
FIG. 5. A typical TGA thermogram of form B is shown in FIG. 6.
[0129] Gatifloxacin crystalline form B can be made in a slurry
process including the steps of slurrying gatifloxacin at ambient
temperature in either 1-butanol or ethanol and recovering the
gatifloxacin form B.
[0130] In still another embodiment, the present invention provides
a novel crystalline form of gatifloxacin, denominated form C, that
can be characterized by one or more of
[0131] a) x-ray reflections at about 7.2.degree., 10.8.degree.,
15.8.degree., 21.8.degree., and
26.2.degree..+-.0.2.degree.2.theta.,
[0132] b) DSC endotherms at about 173.degree. and 177.degree. C.,
and
[0133] c) FTIR absorption bands at about 805, 1509, 1619, and 1728
cm.sup.-1.
[0134] A typical x-ray diffraction diagram of form C is shown in
FIG. 7. A typical FTIR spectrum for form C is shown in FIG. 8. A
typical DSC thermogram of form C is shown in FIG. 9. A typical TGA
thermogram of form C is shown in FIG. 10.
[0135] Form C can be made by, for example, drying form B, described
above, at ambient pressure and about 60.degree. C., or at about
50.degree. C. and 10 to 20 mm Hg. Form C can also be made by drying
form I, described hereinbelow, at about 50.degree. to about
60.degree. C.
[0136] In another embodiment, the present invention provides a
novel crystalline form of gatifloxacin, denominated form D,
characterized by x-ray reflections at about 8.2.degree.,
14.4.degree., 19.0.degree., 21.4.degree., 21.9.degree., and
23.1.degree..+-.0.2.degree. 2.theta.. A typical x-ray diffraction
diagram for form D-is shown in FIG. 11. A typical DSC thermogram of
form D is shown in FIG. 12. Form D has a loss on drying of about 13
wt %. A typical TGA thermogram of form D is shown in FIG. 13.
[0137] Form D can be made by either a slurry process or a vapor
incubation process. The slurry process for making form D includes
the steps of slurrying gatifloxacin with methanol and isolating
gatifloxacin form D. In the vapor incubation process, gatifloxacin
is incubated in vapors of methanol.
[0138] In still a further embodiment, the present invention
provides a novel crystalline form of gatifloxacin, denominated form
E1. Form E1 can be characterized by x-ray reflections at about
7.1.degree., 7.3.degree., 10.8.degree., 15.7.degree., 16.4.degree.,
and 18.1.degree..+-.0.2.degree. 2.theta.. Typical x-ray diffraction
diagrams for different batches of form E1 are shown in FIGS. 14a
through 14g, which suggest that small changes in the x-ray pattern
may be observed in different batches, especially in the range of
19.degree. to 30.degree. 2.theta..
[0139] Form E1 contains up to about 10% acetonitrile, water, or
mixtures thereof. Form E1-ACN containing 8% to 10% acetonitrile can
be referred to as monosolvate. The crystallographic properties of
E1 are essentially insensitive to the presence of the solvent. The
solvent can be driven-off by heating.
[0140] In a particular embodiment, the present invention provides a
crystalline form of gatifloxacin, denominated E1-ACN, that has the
crystallographic properties of E1 and contains up to about 10%
acetonitrile. A typical TGA thermogram of E1-ACN is shown in FIG.
16. Drying of E1-ACN at 70.degree. to 170.degree. C. for at least
about 30 minutes yields gatifloxacin form omega (.OMEGA.).
[0141] E1-ACN can be made by a crystallization process including
the steps of providing, at reflux, a solution of gatifloxacin in
acetonitrile, wherein the water content of the solution is about 5
wt % or less, preferably 4.5 wt % or less, cooling the solution to
a seeding temperature between about 57.degree. to 70.degree. C.,
preferably about 60.degree. C, seeding the solution with
gatifloxacin, optionally maintaining the seeded solution at the
seeding temperature for a seeding time of about 30 minutes or more,
cooling the seeded solution to a temperature at which E1-ACN
crystallizes, especially to ambient temperature or below,
preferably about 5.degree. C. or below, and isolating the
gatifloxacin E1-ACN. Typically, E1-ACN is isolated from a
suspension.
[0142] The water content of the solution prior to seeding should be
about 5 wt % or less, preferably 4.5 wt % or less, as determined by
Karl-Fisher analysis. If necessary, the water content can be
reduced by distilling-off acetonitrile-water azeotrope
(replenishing acetonitrile as required).
[0143] E1-ACN can also be made by a vapor incubation method in
which gatifloxacin is incubated with vapors of acetonitrile for
about 5 to about 20 days.
[0144] In another embodiment, the present invention provides a
hydrate form of gatifloxacin having the crystallographic properties
of form E1. The hydrated form can but preferably does not also
contain acetonitrile, with the proviso that the total amount of
water and acetonitrile is about 10% or less. In a preferred
embodiment, the hydrated form contains about 7.5% to about 10%
water and is a dihydrate. A typical TGA thermogram of form E1
dihydrate is shown in FIG. 15.
[0145] The crystallographic characteristics of hydrated form E1 are
those of E1-ACN. Hydrated form E1 has a water content (Karl-Fisher)
between about 5% and about 10%, preferably 7.5% to 10%. In a
particular embodiment, the hydrated form of E1 is form E1 dihydrate
and contains about 9% water.
[0146] Hydrated form E1 can be made in a treating process including
the step of treating E1-ACN with a moist gas, such as air,.
nitrogen, or a noble gas. Preferably, the moisture content of the
gas is such that the gas has a relative humidity between about 55%
and 75%. The treating can be at any temperature from ambient up to
about 60.degree. C. Preferably, the treating is at about 20.degree.
to 30.degree. C., most preferably 25.degree. C.
[0147] Treating E1-ACN solvate with a moist gas at higher
temperature than 30.degree. C. results in hydrated E1 that can
contain 5% to 7% water. By treating the E1 product which contains
5% to 7% water with a moist gas (55% -75% relative humidity) at
20.degree. to 30.degree. C., preferably 25.degree. C., hydrated E1
(water content of 7.5% to 10%) is obtained. In preferred
embodiments, E1 dihydrate of 9.3% water content is obtained.
[0148] Any apparatus that allows for circulation or percolation of
moist gas around and between particles of the E1-ACN can be used.
Fluidized bed apparatus, well known in the art, is particularly
well suited for the treating.
[0149] The skilled artisan will know to adjust, within the limits
discussed above, the time and temperature to achieve the desired
water content. If the water content of a particular treated batch
is lower than desired (or the acetonitrile content higher than
desired), the batch can simply be treated further to achieve the
desired levels of water and acetonitrile.
[0150] The hydrated E1, especially E1 dihydrate, obtained in this
or any other embodiment of the present invention is substantially
free of prior-art sesquihydrate. By substantially free is meant
that the dihydrate contains about 5% or less of sesquihydrate.
[0151] A suitable method to determine the presence of gatifloxacin
sesquihydrate in gatifloxacin form E1 is x-ray powder diffraction.
Determination of presence of sesquihydrate in form E1 is feasible
in the region 7.degree. to 9.degree. 2.theta., where a peak of
sesquihydrate appears at about 7.8.degree. 2.theta..
[0152] Moreover, the dihydrate of the present invention is stable
against transformation to the sesquihydrate when exposed at ambient
temperature to 60% relative humidity for one week. A sample is
considered stable if the sesquihydrate content does not rise by an
amount detectable by PXRD, described above, upon storage.
[0153] The E1 dihydrate of the present invention is stable against
transformation to sesquihydrate when stored at 30.degree. C. and
60% relative humidity for 3 months.
[0154] In another embodiment, the present invention provides a
novel crystalline form of gatifloxacin, denominated form F,
characterized by x-ray reflections at 8.0.degree., 14.2.degree.,
18.7.degree., 21.8.degree., and 23.0.degree..+-.0.2.degree.
2.theta.. A typical x-ray diffraction diagram of form F is shown in
FIG. 17. A typical DSC thermogram of form F is shown in FIG. 18. A
typical TGA thermogram of form F is shown in FIG. 19.
[0155] Form F can be made by a crystallization method including the
steps of providing a solution, about 25% solids, of gatifloxacin in
a mixture of methanol and water, 90:10 (v:v); cooling the solution,
especially to ambient temperature or below; and isolating the
crystalline form of gatifloxacin from the suspension. Drying form F
yields form G, described herein below.
[0156] In still a further embodiment, the present invention
provides a novel crystalline form of gatifloxacin, denominated form
G, characterized by at least one of:
[0157] a) x-ray reflections at about 17.2.degree. and
17.6.degree..+-.0.2.degree. 2.theta., or
[0158] b) FTIR absorption bands at about 1614 cm.sup.-1 and about
1267 cm.sup.-1.
[0159] A typical x-ray diffraction diagram of form G is shown in
FIG. 20. A typical FTIR spectrum of form G is shown in FIG. 21. A
typical DSC thermogram of form G is shown in FIG. 22. A typical TGA
thermogram of form G is shown in FIG. 23.
[0160] Form G can be made by, for example, drying either of form A
or form F at about 50.degree. C. and atmospheric pressure for at
least about 20 hours.
[0161] In a further embodiment, the present invention provides a
novel crystalline form of gatifloxacin, denomonated form H. Form H
is characterized by x-ray reflections at about 6.6.degree.,
13.2.degree., 19.6.degree., and
19.9.degree..+-.0.2.degree.2.theta.. A typical x-ray diffraction
diagram of form H toluene solvate is shown in FIG. 24. A typical
DSC-thermogram of form H toluene solvate is shown in FIG. 25. A
typical TGA thermogram of form H toluene solvate is shown in FIG.
26.
[0162] Form H can be made by a crystallization method including-the
steps of: providing a solution of gatifloxacin in toluene,
preferably at reflux; cooling the solution to a temperature at
which form H crystallizes, especially to ambient temperature or
below, preferably 5.degree. C. or below, and isolating the
crystalline form of gatifloxacin from the suspension.
[0163] Form H can also be prepared by a slurry method including the
steps of slurrying gatifloxacin in toluene at ambient temperature
for a slurry time and isolating the crystalline form of
gatifloxacin from the slurry. Preferred slurry times are between
about 8 and about 36 hours.
[0164] In a further embodiment, the present invention provides a
novel crystalline form of gatifloxacin, denominated form I and
characterized by x-ray reflections at 6.5.degree., 7.1.degree.,
12.8.degree., 17.2.degree., 19.3.degree., and
21.0.degree..+-.0.2.degree.2.theta.. A typical x-ray diffraction
diagram of form I is shown in FIG. 27. A typical DSC thermogram of
form I is shown in FIG. 28. A typical TGA thermogram of form I is
shown in FIG. 29.
[0165] Form I can be made by a crystallization method including the
steps of:
[0166] a) providing a solution of gatifloxacin in 1-butanol,
[0167] b) cooling the solution to a temperature at which form I
crystallizes, especially to ambient temperature or below to obtain
a suspension, and
[0168] c) isolating the crystalline form of gatifloxacin from the
suspension.
[0169] Form I converts to hereinbelow described form J upon
drying.
[0170] In still another embodiment, the present invention provides
a novel crystalline form of gatifloxacin, denominated form J, that
exists as multiple solvates. Regardless of solvation, form J is
characterized by x-ray reflections at about 6.7.degree.,
11.3.degree., 13.8.degree., and 16.4.degree..+-.0.2.degree.
2.theta.. A typical FTIR spectrum of form J is shown in FIG. 30. A
typical DSC thermogram of form J is shown in FIG. 31. A typical TGA
thermogram of form J is shown in FIG. 32.
[0171] Form J as its iso-propanol solvate can be made by incubating
gatifloxacin in vapors of iso-propanol, or by a crystallization
method that includes the steps of:
[0172] a) providing a solution of gatifloxacin in iso-propanol,
[0173] b) cooling the solution to a temperature at which form J
crystallizes, especially ambient temperature or below, and
[0174] c) isolating the crystalline form of gatifloxacin.
[0175] Form J as its iso-propanol solvate can also be made by
heating gatifloxacin form A at about 40.degree. to about 70.degree.
C., preferably about 50.degree. C. and atmospheric pressure.
[0176] Form J as its methyl ethyl ketone solvate can be made by
incubating gatifloxacin in vapors of methyl ethyl ketone.
[0177] Form J as its acetone solvate can be made by a slurry
process including the steps of slurrying gatifloxacin in acetone at
ambient temperature, and isolating the crystalline acetone solvate
form J gatifloxacin from the slurry.
[0178] Form J as its tetrahydrofuran solvate can be made by a
slurry process including the steps of slurrying gatifloxacin in
tetrahydrofuran at ambient temperature, and isolating the
crystalline form J tetrahydrofuran solvate.
[0179] Form J as its 1-butanol solvate can be made by a
crystallization method including the steps of:
[0180] a) providing a solution of gatifloxacin in 1-butanol,
preferably at reflux
[0181] b) cooling the solution to a temperature at which form J
crystallizes, especially ambient temperature or below, especially
about 5.degree. C., and
[0182] c) isolating the crystalline gatifloxacin form J 1-butanol
solvate.
[0183] Total loss-on-drying (LOD) values, step weight-losses, and
water contents for form J as several of its solvates are summarized
in Table I below.
1TABLE I LOD, KF and Corresponding Solvate Formulas of form J
Samples Total Weight Weight loss Karl Corresponding Loss step
(.apprxeq.80- Fisher Solvate Solvent By TGA (%) 145.degree. C.)
(wt-%) Formula IPA 8.7 4.1 4.01 GTF:IPA (4:1) (Theoretical value:
3.8%) 1-BuOH 10.4 7.6 2.79 GTF:n-BuOH (5:2) (Theoretical value:
7.3%) IPA 8.7 6.4 2.42 GTF:IPA (5:2) (Theoretical value: 6.0%) IPA
8.3 4.9 4.84 GTF:IPA (3:1) (Theoretical value: 5.0%) Acetone 8.9
4.3 3.45 GTF:Acetone (3:1) (Theoretical value: 4.9%) IPA 11.4 7.8
3.13 GTF:IPA (2:1) (Theoretical value: 7.4%)
[0184] In still further embodiments, the present invention provides
methods of making the prior-art crystalline form of gatifloxacin
denominated form omega (.OMEGA.).
[0185] In one such embodiment, the present invention provides a
crystallization method of making gatifloxacin form omega including
the steps of:
[0186] a) providing a filtered solution of gatifloxacin in
acetonitrile, wherein the solution has a water content of about 5%
or less, preferably about 4.5 wt % or less, at a temperature of
about 80.degree. C. or higher, preferably
[0187] b) cooling the solution to a seeding temperature of about
50.degree. to about 56.degree. C.
[0188] c) seeding the solution with gatifloxacin at the seeding
temperature and, optionally, maintaining the seeded solution at the
seeding temperature for a seeding time of about 30 minutes or
more,
[0189] d) cooling the seeded solution to a temperature at which
form omega crystallizes, preferably to ambient temperature or
below, most preferably about 5.degree. C., and
[0190] e) isolating the gatifloxacin crystalline form omega.
[0191] As discussed in relation to for E1, the water content of the
hot-filtered solution can be adjusted to the desired range by
distilling off water-acetonitrile azeotrope.
[0192] In another embodiment, the present invention provides a
method of making gatifloxacin form omega including the step of
heating form J to about 90.degree. to about 170.degree. C.,
preferably about 120.degree. C., at atmospheric pressure.
[0193] In a further embodiment, the present invention provides a
method of making gatifloxacin form omega including the steps of
heating form E1 at about 70.degree. to 170.degree. C. for at least
about 30 minutes.
[0194] In yet still a further embodiment, the present invention
provides a method of making gatifloxacin form omega including the
steps of heating gatifloxacin form G at about 120.degree. C. In yet
other embodiments, the present invention provides a method of
making the prior art hemihydrate crystalline form of gatifloxacin,
denominated T2RP, via the novel gatifloxacin E1. Thus in one
embodiment, useful when the amounts of gatifloxacin are about 200 g
or less, the present invention provides a method of making T2RP
including the steps of slurrying gatifloxacin E1 with ethanol,
isolating the solid from the slurry, and drying the solid in vacuo
to obtain gatifloxacin T2RP.
[0195] In a related embodiment, useful with >200 gram quantities
of gatifloxacin or more, the present invention provides a method of
making gatifloxacin form T2RP including the steps of slurrying
kilogram quantities of gatifloxacin in ethanol isolating the solid
from the slurry, and treating the isolated solid with moist air, as
is done in making E1 dihydrate from E1-ACN.
[0196] In another embodiment, the present invention provides a
method of making form T2RP including the step of heating, at
atmospheric pressure, the prior-art sesquihydrate at about
80.degree. to about 150.degree. C., preferably 120.degree. C.
[0197] In another embodiment, the present invention provides a
method of making hemihydrate T2RP including the step of heating, at
atmospheric pressure, novel gatifloxacin form G about 80.degree. to
about 130.degree. C., preferably 120.degree. C. to effect the
conversion.
[0198] In still yet another embodiment, the present invention
provides novel crystalline gatifloxacin forms A, B, C, D, E1, F, G,
H, I, and J having an average particle size of 100 .mu.m or less,
preferably 50 .mu.m or less.
[0199] The present invention provides a plurality of particles of
any of the gatifloxacin forms A, B, C, D, E1, F, G, H, I, and J
having the diameter of all particles in the plurality equal to or
less than about 100 .mu.m; preferably, equal to or less than about
50 .mu.m. Particles of the plurality will vary in characteristics
and the characteristics of no individual or small proportion of the
particles will materially affect the advantages afforded by this
invention which may include more rapid dissolution and the
potential for improved bioavailability. Rather, the characteristics
of the pharmaceutical composition are determined from a
statistically significant sampling of the composition and
measurement of bulk, or average, properties of the sample.
Statistically significant measurements include those with a
statistical sampling error of about 2% or less. The "average
particle diameter" refers to the equivalent spherical diameter as
determined by well-known methods, e.g., laser light scattering
method, or sieving methods.
[0200] Gatifloxacin of the above-defined defined particle diameter
may be produced by known methods of particle size reduction
starting with crystals, powder aggregates and coarse powder of
gatifloxacin of one or more of crystalline forms A, B, C, D, E1, F,
G, H, I, and J. The principal operations of conventional size
reduction are milling of a feedstock material and sorting of the
milled material by size.
[0201] A fluid energy mill, or micronizer, is an especially
preferred type of mill for its ability to produce particles of
small size in a narrow size distribution. As those skilled in the
art are aware, micronizers use the kinetic energy of collision
between particles suspended in a rapidly moving fluid (typically
air) stream to cleave the particles. The suspended particles are
injected under pressure into a recirculating particle stream.
Smaller particles are carried aloft inside the mill and swept into
a vent connected to a dust collector. The feedstock may be
pre-milled to about 150 to 850 .mu.m.
[0202] Examples of a useful micronizers include a fluid energy mill
such as Microgrinding MC-300 KX, (Microgrinding Ltd., 6995
Molinazzo di Monteggio, CH), Alpine-Hosokawa Fluidized bed opposed
jet mill, model AFG (Alpine-Hosokawa, Peter Dorfler Strs., D-8900,
DE) and Sturtavent micronizer jet mill (Sturtavent, 348 Circuit
St., Hanover, Mass., USA). Alternatively, a pinmill such as Alpine
UPZ 160 or similar equipment can be used.
[0203] The feed material to the micronizer can have an average PSD
about 100-200 microns. The material is fed into the micronization
system in a controlled feed rate by means of a screw feeder or a
vibratory feeder. The air jet mill is operated with controlled air
pressures. For the Microgrinding MC-300 KX, the feed rate is 40-60
kg/hr, the feed air pressure is 6-8.5 bar and the grinding air is
3-6 bar.
[0204] The material is fed into the mill system in a controlled
feed rate by means of a screw feeder or a vibratory feeder. The
mill is operated with controlled speed. For the Alpine UPZ 160, the
feed rate is 60-75 kg/hr, the mill speed is 7000-15,000 rpm.
[0205] The novel crystalline forms of the present invention, as a
plurality of particles of particle size .ltoreq.100 .mu.m,
especially .ltoreq.50 .mu.m, are particularly useful for the
preparation of pharmaceutical compositions.
[0206] Thus, in still yet a further embodiment, any of the novel
crystalline forms of gatifloxacin, forms A, B. C. D. E1. F.G, H, I,
or J described hereinabove, alone or in any combination, are
formulated into a pharmaceutical composition, preferably an oral
solid dosage form or a dosage form for parental administration.
Preferably, the crystalline form of the gatifloxacin used in making
the pharmaceutical composition has a maximum particle size of 100
.mu.m or less, preferably 50 .mu.m or less.
[0207] The pharmaceutical composition can be in the form of a solid
oral dosage form (e.g., compressed tablets or capsules), or it can
be in the form of a liquid oral dosage form (e.g., a solution or
oral suspension). It was found that E1 is also stable in
formulations at 30.degree. C. for at least 3 months.
[0208] Compressed tablets can be made by dry or wet granulation
methods as is known in the art. In addition to the pharmaceutically
active agent or drug, compressed tablets contain a number of
pharmacologically inert ingredients, referred to as excipients.
Some excipients allow or facilitate the processing of the drug into
tablet dosage forms. Other excipients contribute to proper delivery
of the drug by, for example, facilitating disintegration.
[0209] Excipients can be broadly classified according to their
intended function. This classification is sometimes arbitrary and
it is known that a particular excipient can function in more than
one way or serve more than one purpose in a formulation.
[0210] Diluents increase the bulk of a solid pharmaceutical
composition and may make a pharmaceutical dosage form containing
the composition easier for the patient and caregiver to handle.
Diluents for solid compositions include, for example,
microcrystalline cellulose (e.g., AVICEL.RTM., microfine cellulose,
lactose, starch, pregelatinized starch, calcium carbonate, calcium
sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium
carbonate, magnesium oxide, maltodextrin, mannitol,
polymethacrylates (e.g., EUDRAGIT.RTM.), potassium chloride,
powdered cellulose, sodium chloride, sorbitol and talc.
[0211] Solid pharmaceutical compositions that are compacted into a
dosage form like a tablet may include excipients whose functions
include helping to bind the active ingredient and other excipients
together after compression. Binders for solid pharmaceutical
compositions include acacia, alginic acid, carbomer (e.g.,
carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose,
gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl
cellulose, hydroxypropyl cellulose (e.g., KLUCEL.RTM.),
hydroxypropyl methyl cellulose (e.g., METHOCEL.RTM.), liquid
glucose, magnesium aluminum silicate, maltodextrin,
methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON.RTM.,
PLASDONE.RTM.), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical
composition in the patient's stomach may be increased by the
addition of a disintegrant to the composition.
[0212] Disintegrants include alginic acid, carboxymethylcellulose
calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL.RTM.,
PRIMELLOSE.RTM.), colloidal silicon dioxide, croscarmellose sodium,
crospovidone (e.g., KOLLIDON.RTM., POLYPLASDONE.RTM.), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose, polacrilin potassium, powdered cellulose, pregelatinized
starch, sodium alginate, sodium starch glycolate (e.g.,
EXPLOTAB.RTM.) and starch.
[0213] Glidants can be added to improve the flow properties of
non-compacted solid compositions and improve the accuracy of
dosing. Excipients that may function as glidants include colloidal
silicon dioxide, magnesium trisilicate, powdered cellulose, starch,
talc and tribasic calcium phosphate.
[0214] When a dosage form such as a tablet is made by compaction of
a powdered composition, the composition is subjected to pressure
from a punch and die. Some excipients and active ingredients have a
tendency to adhere to the surfaces of the punch and die, which can
cause the product to have pitting and other surface irregularities.
A lubricant can be added to the composition to reduce-adhesion and
ease release of the product from the die. Lubricants include
magnesium stearate, calcium stearate, glyceryl monostearate,
glyceryl palmitostearate, hydrogenated castor oil, hydrogenated
vegetable oil, mineral oil, polyethylene glycol, sodium benzoate,
sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc
and zinc stearate.
[0215] Flavoring agents and flavor enhancers make the dosage form
more palatable to the patient. Common flavoring agents and flavor
enhancers for pharmaceutical products that may be included in the
composition of the present invention include maltol, vanillin,
ethyl vanillin, menthol, citric acid, fumaric acid ethyl maltol,
and tartaric acid.
[0216] Solid and liquid compositions may also be colored using any
pharmaceutically acceptable colorant to improve their appearance
and/or facilitate patient identification of the product and unit
dosage level.
[0217] Of course, wet or dry granulate can also be used to fill
capsules, for example gelatin capsules. The excipients chosen for
granulation when a capsule is the intended dosage form may or may
not be the same as those used when a compressed tablet dosage form
is contemplated.
[0218] Selection of excipients and the amounts to use may be
readily determined by the formulation scientist based upon
experience and consideration of standard procedures and reference
works in the field.
[0219] In liquid pharmaceutical compositions of the present
invention, one of GTF forms A, B, C, D, E1, F, G, H, I, and J, or
mixtures thereof, and any other solid excipients are dissolved or
suspended in a liquid carrier such as water, vegetable oil,
alcohol, polyethylene glycol, propylene glycol or glycerin.
[0220] Liquid pharmaceutical compositions can contain emulsifying
agents to disperse uniformly throughout the composition an active
ingredient or other excipient that is not soluble in the liquid
carrier. Emulsifying agents that can be useful in liquid
compositions of the present invention include, for example,
gelatin, egg yolk, casein, cholesterol, acacia, tragacanth,
chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol
and cetyl alcohol.
[0221] Liquid pharmaceutical compositions of the present invention
can also contain a viscosity enhancing agent to improve the
mouth-feel of the product and/or coat the lining of the
gastrointestinal tract. Such agents include, for example, acacia,
alginic acid, bentonite, carbomer, carboxymethylcellulose calcium
or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose,
gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol,
povidone, propylene carbonate, propylene glycol alginate, sodium
alginate, sodium starch glycolate, starch tragacanth and xanthan
gum.
[0222] Sweetening agents such as sorbitol, saccharin, sodium
saccharin, sucrose, aspartame, fructose, mannitol and invert sugar
can be added to improve the taste.
[0223] Preservatives and chelating agents such as alcohol, sodium
benzoate, butylated hydroxy toluene, butylated hydroxyanisole and
ethylenediamine tetraacetic acid can be added at levels safe for
ingestion to improve storage stability.
[0224] A liquid composition according to the present invention can
also contain a buffer such as gluconic acid, lactic acid, citric
acid or acetic acid, sodium gluconate, sodium lactate, sodium
citrate or sodium acetate.
[0225] The solid compositions of the present invention include
powders, granulates, aggregates and compacted compositions. The
dosages include dosages suitable for oral, buccal, rectal,
parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant and ophthalmic administration. The most
suitable route in any given case will depend on the nature and
severity of the condition being treated. The dosages can be
conveniently presented in unit dosage form and prepared by any of
the methods well-known in the pharmaceutical arts.
[0226] Dosage forms include solid dosage forms like tablets,
powders, capsules, suppositories, sachets, troches and losenges as
well as liquid syrups, suspensions and elixirs.
[0227] The active ingredient and excipients can be formulated into
compositions and dosage forms according to methods known in the
art.
[0228] A composition for tableting or capsule filling can be
prepared by wet granulation. In wet granulation some or all of the
active ingredients and excipients in powder form are blended and
then further mixed in the presence of a liquid, typically water,
which causes the powders to clump up into granules. The granulate
is screened and/or milled, dried and then screened and/or milled to
the desired particle size. The granulate can then be tableted or
other excipients can be added prior to tableting, such as a glidant
and/or a lubricant.
[0229] A tableting composition can be prepared conventionally by
dry blending. For instance, the blended composition of the active
ingredients and excipients can be compacted into a slug or a sheet
and then comminuted into compacted granules. The compacted granules
can be compressed subsequently into a tablet.
[0230] As an alternative to dry granulation, a blended composition
can be compressed directly into a compacted dosage form using
direct compression techniques. Direct compression produces a more
uniform tablet without granules. Excipients that are particularly
well-suited to direct compression tableting include
microcrystalline cellulose, spray dried lactose, dicalcium
phosphate dihydrate and colloidal silica. The proper use of these
and other excipients in direct compression tableting is known to
those in the art with experience and skill in particular
formulation challenges of direct compression tableting.
[0231] A capsule filling of the present invention can comprise any
of the aforementioned blends and granulates that were described
with reference to tableting, only they are not subjected to a final
tableting step.
[0232] Capsules, tablets and lozenges and other unit dosage forms
may be administered in various dosages depending on the need.
[0233] The present invention can be further illustrated with the
following non-limiting examples.
EXAMPLES
Example 1
Form A
[0234] 3 g of gatifloxacin were slurried in 20 mL of iso-propanol
(IPA). The mixture was slurried at ambient temperature for a slurry
time of 24 hours with a magnetic stirrer. The mixture was filtered
under vacuum, rinsed with iso-propanol (IPA) (10 mL) and analyzed
by XRD analysis and showed to be form A.
Example 2
Form B
[0235] 3 g of gatifloxacin were slurried in 20 mL of 1-butanol. The
mixture was stirred at ambient temperature for a slurry time of 24
hours with a magnetic stirrer. Then the mixture was filtered under
vacuum, the isolated solid rinsed with 1-butanol (10 mL), and
analyzed by XRD analysis.
[0236] A second portion of the solid obtained after filtration was
dried under vacuum at 50.degree. C. for 24 hours. This resulted in
a partially amorphous form B.
Example 3
Form B
[0237] 3 g of gatifloxacin were slurried in 20 mL of EtOH absolute.
The mixture was stirred at ambient temperature for a slurry time of
24 hours with a magnetic stirrer. Then the mixture was filtered
under vacuum, the isolated solid rinsed with absolute EtOH (10 mL),
and analyzed by XRD. The product was partially amorphous form
B.
Example 4
Form C
[0238] 3 g of gatifloxacin were slurried in 20 mL of 1-butanol. The
mixture was stirred at ambient temperature for a slurry time of 24
hours with a magnetic stirrer. The mixture was then filtered under
vacuum, the isolated solid rinsed with 1-butanol (10 mL), and dried
at atmospheric pressure in an oven at 60.degree. C. for 24
hours.
Example 5
Form C
[0239] 5 g of gatifloxacin were suspended in 40 mL of 1-butanol.
The mixture was heated to reflux temperature until complete
dissolution of the material. The solution was then stirred at this
temperature for 5 minutes, cooled to ambient temperature, and then
to 5.degree. C. The stirring was maintained at this temperature for
one hour and then the mixture was filtered under vacuum. The solid
obtained was put in an atmospheric oven at 60.degree. C. for 40
hours. The sample was analyzed by PXRD and found to be form C.
Example 6
Form D
[0240] 3 g of gatifloxacin were slurried in 20 mL of methanol. The
mixture was stirred at ambient temperature for a slurry time 24
hours with a magnetic stirrer. Then the mixture was filtered under
vacuum, the isolated solid rinsed with methanol (10 mL) and
analyzed by XRD.
Example 7
Form D
[0241] 2 g of gatifloxacin were put in a beaker. This beaker was
put open in a bottle-containing methanol. Then this bottle was
hermetically closed for 15 days in order to create an atmosphere
saturated with methanol vapors. The sample was then analyzed by XRD
analysis.
Example 8
Form F
[0242] 5 g of gatifloxacin were put in suspension in 20 mL of a
aqueous solution of MeOH 90%. The mixture was heated to reflux
temperature and a solution of MeOH 90% (109 mL) was added to
complete the dissolution of the material. The solution was then
stirred at this temperature for 5 minutes, cooled to ambient
temperature, and then to 5.degree. C. The mixture was maintained at
this temperature for one hour and then was filtered under vacuum.
The sample was analyzed by PXRD, with no further drying, and found
to be form F.
Example 9
Form G
[0243] 5 g of gatifloxacin were put in suspension in 20 mL of a
aqueous solution of MeOH 90%. The mixture was heated to reflux
temperature and a solution of MeOH 90% (109 mL) was added to
complete the dissolution of the material. The solution was then
stirred at this temperature for 5 minutes, cooled to ambient
temperature, and then to 5.degree. C. The mixture was maintained at
this temperature for one hour and then was filtered under vacuum.
The sample was dried in an atmospheric oven at 60.degree. C. for 24
hours. These samples were analyzed by XRD analysis and found to be
form G.
Example 10
Form H
[0244] 3 g of gatifloxacin were slurried in 20 mL of toluene. The
mixture was stirred at ambient temperature for a slurry time of 24
hours with a magnetic stirrer. Then the mixture was filtered under
vacuum, the isolated solid rinsed with toluene (10 mL). The sample
was analyzed by PXRD analysis with no further drying.
Example 11
Form H
[0245] 5 g of gatifloxacin were put in suspension in 50 mL of
toluene equipped with a condenser and a Dean-Stark trap. The
mixture was heated to reflux until complete dissolution of the
material. After 10 minutes of a strong reflux the solution was
cooled to ambient temperature, and then to 5.degree. C. The mixture
was maintained at this temperature for one hour and then was
filtered under vacuum. The sample was analyzed by XRD analysis with
no further drying.
Example 12
Form I
[0246] 5 g of gatifloxacin were put in suspension in 40 mL of
1-butanol. The mixture was heated to reflux temperature until
complete dissolution of the material. The solution was then stirred
at this temperature for 5 minutes, cooled to ambient temperature,
and then to 5.degree. C. The stirring was maintained at this
temperature for one hour and then the mixture was filtered under
vacuum. The sample was analyzed by XRD analysis with no further
drying.
Example 13
Form J
[0247] 3 g of gatifloxacin were slurried in 20 mL of technical IPA.
The mixture was stirred at ambient temperature for a slurry time of
24 hours with a magnetic stirrer. Then the mixture was filtered
under vacuum and the isolated solid rinsed with technical IPA (10
mL). The sample was divided in two portions. The first portion was
dried in a vacuum oven at 50.degree. C. for 24 hours and the second
portion was dried in an atmospheric oven at 60.degree. C. for 24
hours. These two dried samples were analyzed by XRD analysis and
shown to be form J.
Example 14
Form J
[0248] 2 g of gatifloxacin were put in a beaker. This beaker was
put open in a bottle-containing isopropanol. Then this bottle was
hermetically closed for 15 days in order to create an atmosphere
saturated with isopropanol vapors. The sample was then analyzed by
XRD analysis.
Example 15
Form J
[0249] 2 g of gatifloxacin were put in a beaker. This beaker was
put open in a bottle-containing methylethyl ketone. Then this
bottle was hermetically closed for 15 days in order to create an
atmosphere saturated with methylethyl ketone vapors. The sample was
then analyzed by XRD analysis.
Example 16
Form J
[0250] 3 g of gatifloxacin were slurried in 20 mL of acetone. The
mixture was stirred at ambient temperature for a slurry time of 24
hours with a magnetic stirrer. Then the mixture was filtered under
vacuum, and the isolated solid rinsed with acetone (10 mL). The
sample was divided in two portions. The first portion was not dried
and the second portion was dried in a vacuum oven at 50.degree. C.
for 24 hours. These two samples were analyzed by XRD analysis and
found to be form J.
Example 17
Form J
[0251] 3 g of gatifloxacin were slurried in 20 mL of THF. The
mixture was stirred at ambient temperature for a slurry time of 24
hours with a magnetic stirrer. Then the mixture was filtered under
vacuum, rinsed with THF (10 mL). The sample was divided in two
portions. The first portion was not dried and the second portion
was dried in a vacuum oven at 50.degree. C. for 24 hours. These two
samples were analyzed by XRD analysis and found to be form J.
Example 18
Form J
[0252] 5 g of gatifloxacin were put in suspension in 30 mL of
technical IPA. The mixture was heated to reflux temperature and IPA
(39 mL) was added to get the complete dissolution of the material.
The solution was then stirred at this temperature for 5 minutes,
cooled to ambient temperature, and then to 5.degree. C. The
stirring was maintained at this temperature for one hour and then
the mixture was filtered under vacuum. The solid was divided in
three portions. The first portion was not dried, the second portion
was dried in a vacuum oven at 50.degree. C. for 24 hours and the
third portion was dried in an atmospheric oven at 60.degree. C. for
24 hours. These three samples were analyzed by XRD analysis and
found to be form J.
Example 19
Form J
[0253] 5 g of gatifloxacin were put in suspension in 40 mL of
1-butanol. The mixture was heated to reflux temperature until
complete dissolution of the material. The solution was then stirred
at this temperature for 5 minutes, cooled to ambient temperature,
and then to 5.degree. C. The stirring was maintained at this
temperature for one hour and then the mixture was filtered under
vacuum. The sample was dried in a vacuum oven at 50.degree. C. for
24 hours and analyzed by XRD analysis and found to be form J.
Example 20
Form E1-ACN
[0254] Gatifloxacin (20 g) was charged to a 150 mL reactor equipped
with a mechanical stirrer and thermometer. Acetonitrile (140 mL)
was added and the mixture was heated to 85.degree. C. until a clear
solution formed. Hyflow.RTM. (5%) was added to the solution and the
solution was stirred at 85.degree. C. for 1 hour. A hot filtration
was then performed through a jacketed Buchner funnel at 80.degree.
C. and the solution was transferred in a clean reactor at
85.degree. C. The solution was then maintained at 85.degree. C. for
5 minutes, then cooled to 60.degree. C. over 30 minutes. At this
temperature (seeding temperature) the solution was seeded with
gatifloxacin solid, maintained for 1 hour at 60.degree. C. (i.e.,
seeding time=1 hour), and then cooled to 5.degree. C. over 5 hours.
The resulting suspension was then maintained at 5.degree. C. for 1
hour. The mixture was filtered under vacuum. The isolated solid was
washed with acetonitrile (15 mL) and dried in a vacuum oven at
50.degree. C. overnight.
[0255] The dry sample was analyzed by XRD and found have the
characteristic XRD reflections of form E1.
Example 21
Hydrated E1
[0256] A 1 liter reactor equipped with mechanical stirrer,
condenser and thermometer, was charged with gatifloxacin (crude
dry; 100 g) and acetonitrile (ACN 1000 mL). The slurry was then
heated to reflux (80.degree. C.) and stirred at a rate of 400 rpm.
The heating was continued for 0.5 hours until clear solution was
obtained.
[0257] The clear solution was cooled to 56-58.degree. C. and seeded
with 0.1 g of GTF. At the end of the addition the seeded solution
was maintained for a seeding time of 2 hours at the seeding
temperature of 56-58.degree. C., then cooled over 8 hours to a
temperature of 5.degree. C. The temperature was maintained at
5.degree. C., with stirring for 12 hours.
[0258] The resulting slurry was filtered (suction) and the
collected solid washed with ACN (150 mL) to obtain 91.7 g of wet
material.
[0259] The wet sample was analyzed by XRD and found to be E1 (Water
content by KF=2.48 wt %).
[0260] The material obtained was loaded into a Fluidized bed drier
and treated at 50.degree. C. for 4 hours with to obtain 84 g of
gatifloxacin crystals, form E1 dihydrate.
[0261] The sample was analyzed by XRD and found to be E1 (Water
content by KF=8.25 wt %).
Example 22
E1-ACN
[0262] 2 g of gatifloxacin were put in a beaker. This beaker was
put open in a bottle-containing acetonitrile. Then this bottle was
hermetically closed for 15 days in order to create an atmosphere
saturated with acetonitrile vapors. The sample was then analyzed by
XRD analysis.
Example 23
Form .OMEGA.
[0263] Gatifloxacin (crude, 15 g) was charged to a 250 mL reactor
equipped with a mechanical stirrer and thermometer. Acetonitrile
(110 mL) was added and the mixture was heated to 85.degree. C.
until a clear solution formed. Hyflow.RTM. (5%) was added to the
solution was stirred at 85.degree. C. for 30 minutes. A hot
filtration was then performed through a jacketed Buchner funnel at
80.degree. C. and the solution was charged to a reactor at
85.degree. C. The solution was maintained at 85.degree. C. for 1
h30, then cooled to 55.degree. C. over 1 hour. At 55.degree. C. the
solution was seeded with gatifloxacin solid and maintained for 30
minutes at 55.degree. C. The resulting suspension was then cooled
to 50.degree. C. over 30 minutes, maintained at this temperature
for 30 minutes, cooled to 5.degree. C. over 2 hours, and maintained
at 5.degree. C. for 1 hour. The mixture was filtered under vacuum
and dried in a vacuum oven at 50.degree. C. overnight.
[0264] The dry sample was analyzed by XRD and found to be form
.OMEGA..
Example 24
T2RP
[0265] Form E1 (1 g) was slurried in 6.6 mL of ethanol and stirred
at ambient temperature for 2 hours. The slurry was then filtered
under vacuum and the collected solid washed with ethanol (3 ml).
The washed collected solid was then dried at 50.degree. C.
overnight and was analyzed by XRD analysis and shown to be form
T2RP.
Example 25
T2RP
[0266] 3 g of dry form .OMEGA. were put in a flask equipped with a
condenser and a magnetic stirrer. Ethanol (19.8 mL) was added and
the slurry was stirred at ambient temperature for 4 hours. A
portion of the solid isolated from the slurry was dried at
50.degree. C. under vacuum until constant weight and then was
analyzed by XRD. This sample was form T2RP.
Example 26
Form T2RP Hemihydrate
[0267] A 10 liter reactor equipped with mechanical stirrer,
condenser and thermometer, was charged with GTF-Crude dry (1 Kg)
and acetonitrile (10 liter). The slurry was then heated to reflux
(80.degree. C.) and stirred at a rate of 400 rpm for 2 hours at
this temperature to obtain a solution. The solution was filtered.
The clear solution was cooled to 56-58.degree. C. and gatifloxacin
T2RP hemihydrate (0.1 g) was added.
[0268] After seeding, the seeded solution was stirred for a seeding
time of 2 hours at the seeding temperature of 56-58.degree. C.,
cooled to 5.degree. C. over about 8 hours, and maintained with
stirring for 2 hours at this temperature. The resulting slurry was
filtered under vacuum and the collected solid washed with
acetonitrile (1.5 L) to obtain 865.3 g of wet material.
[0269] The wet material was charged to a 10 L reactor and EtOH (6
L) was then charged to the reactor. The slurry was stirred at
25.degree. C. for 24 hours. The slurry was filtered under vacuum
and washed with EtOH (1 L).
[0270] The wet material was loaded into a fluidized bed apparatus
and treated at 50.degree. C. for 4 hours. After treatment in the
fluidized bed drier, the material was found to be form T2RP by XRD
analysis.
Example 27
Hydrated E1
[0271] A 140 liter reactor equipped with mechanical stirrer,
condenser and thermometer, was charged with dimethyl sulfoxide
(DMSO, 120 L). The DMSO was heated to 55.degree. C. and the reactor
was charged with 2-methylpiperazine (8.6 kg). Gatifloxacin acid was
charged, in four portions, every 2 hours (3.times.4=12 Kg). The
reaction mixture was stirred at a rate of 110 rpm under nitrogen
atmosphere. The temperature was maintained for 24 hours until
completion of the reaction. The reaction mixture was cooled to
48.degree. C. and water (24 L) was added at this temperature. The
mixture was cooled to 5.degree. C. during 3.5 hours and maintained
with stirring for 15 hours at this temperature. The mixture was
filtered (suction) and washed with acetonitrile (18 L) to obtain
15.9 Kg of gatifloxacin.
[0272] A 140 liter reactor equipped with mechanical stirrer,
condenser and thermometer, was charged with the wet product from
above (13.3 Kg, 10-20% wetness) and 72 liter of water. The mixture
was stirred at 25.degree. C. for 1 hr. The slurry was filtered
under vacuum and washed with acetonitrile (21 L) to obtain
gatifloxacin wet material (17.5 Kg, about 50% wetness).
[0273] A 140 liter reactor equipped with mechanical stirrer,
condenser and thermometer, was charged with the wet material from
the previous step (8.4 kg) and with acetonitrile (70.9 L). The
mixture was then heated to reflux (80.degree. C.) and stirred at a
rate of 110 rpm. The heating was continued for 0.5 hours until a
clear solution was obtained. The clear solution was cooled to
60.degree. C. and solvent was distilled-off under vacuum (100 mm
Hg). After 3 hr, essentially all the solvent was removed.
Acetonitrile (49 L) was charged and the mixture was heated to
reflux (80.degree. C.). The heating was continued for 0.5 hours
until a clear solution was obtained.
[0274] The clear solution was filter through a-5, 1, 0.2-micron
filter. Then 500 ml of water was added and the clear solution was
cooled to 62.degree. C. and gatifloxacin (0.1 gr) was added. After
addition, the stirring was maintained for 2 hours at 62.degree. C.,
then the mixture was cooled during 3 hours to 5.degree. C. and
maintained with the stirring for 1 hours at this temperature. The
resulting slurry was filtered under vacuum and washed with
acetonitrile (5 L) to obtain 5 kg of wet material.
[0275] The wet sample was form E1 by PXRD.
[0276] A portion of the wet material was loaded into a fluidized
bed drier and dried at 25.degree. C. for 6 hours. Gatifloxacin E1
dihydrate was obtained (water content by Karl-Fisher, 9.4%).
Example 28
E1 Dihydrate
[0277] 1 Kg of gatifloxacin form E1 (6.5% water content by KF) was
packed into a Fluidized bed drier and treated at 25.degree. C. for
6 hours. Gatifloxacin form E1 dihydrate was obtained (9.4% water
content by Karl-Fisher).
Example 29
Interconversion of Forms by Thermal Treatment
[0278] Approximately 200 mg of several of the novel crystalline
forms of the present invention, prepared as described in the
foregoing examples, and several of the prior-art crystalline forms
were subjected to various thermal treatments. The treatments and
the results are described in Table II below
2TABLE II XRD results of Gatifloxacin samples before and after
heating Starting form Heating conditions form Obtained A 50.degree.
C., 24 h, vacuum J or 60 C., 24 h B 50.degree. C., 24 h, vacuum C F
50.degree. C., 24 h, vacuum G G 120.degree. C., 1 h Omega.sup.1. I
60.degree. C., 24 h, C Atmospheric pressure J 120.degree. C., 1 h
omega sesquihydrate 120.degree. C., 1 h T2RP + omega Hemihydrate
120.degree. C., 1 h T2RP T1RP 120.degree. C., 1 h Hemihydrate
.sup.1Contains few additional XRD peaks
Example 30
[0279] 200 mg of gatifloxacin form J were put in 80% relative
humidity for 1 week. The resulting sample was analyzed by XRD, TGA
and KF. The resulting sample was found to have the crystal
structure of the sesquihydrate (LOD=7.8%, KF=6.6%).
Example 31
[0280] 200 mg of gatifloxacin omega form were put in 80% relative
humidity for 1 week, and then analyzed by XRD and by TGA. The
resulting sample was found to have sesquihydrate crystal structure
(LOD=7.7%).
Example 32
[0281] 200 mg of gatifloxacin form E1 were heated to 100.degree. C.
for 1 hour. The XRD of the resulting sample was that of the omega
form.
* * * * *