U.S. patent application number 09/932045 was filed with the patent office on 2002-05-02 for gatifloxacin pentahydrate.
Invention is credited to Davidovich, Martha, DiMarco, John D., Gougoutas, Jack Z., Newman, Ann, Parker, William L., Raghavan, Krishnaswamy S., Ranadive, Sunanda A..
Application Number | 20020052379 09/932045 |
Document ID | / |
Family ID | 22872564 |
Filed Date | 2002-05-02 |
United States Patent
Application |
20020052379 |
Kind Code |
A1 |
Raghavan, Krishnaswamy S. ;
et al. |
May 2, 2002 |
Gatifloxacin pentahydrate
Abstract
There are provided in accordance with the present invention
crystalline gatifloxacin pentahydrate represented by the formula 1
in a highly homogeneous form with respect to other crystalline
forms thereof.
Inventors: |
Raghavan, Krishnaswamy S.;
(Cranbury, NJ) ; Ranadive, Sunanda A.; (East
Brunswick, NJ) ; Gougoutas, Jack Z.; (Princeton,
NJ) ; DiMarco, John D.; (East Brunswick, NJ) ;
Parker, William L.; (Pennington, NJ) ; Davidovich,
Martha; (East Brunswick, NJ) ; Newman, Ann;
(Lafayette, IN) |
Correspondence
Address: |
MARLA J MATHIAS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
22872564 |
Appl. No.: |
09/932045 |
Filed: |
August 17, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60232293 |
Sep 13, 2000 |
|
|
|
Current U.S.
Class: |
514/253.08 ;
544/363 |
Current CPC
Class: |
A61P 31/04 20180101;
A61P 11/00 20180101; A61P 31/00 20180101; C07D 215/56 20130101 |
Class at
Publication: |
514/253.08 ;
544/363 |
International
Class: |
A61K 031/496; C07D
43/02 |
Claims
We claim:
1. Crystalline gatifloxacin pentahydrate represented by the formula
4and characterized by single crystal parameters approximately equal
to the following: Cell dimensions a=9.339(1) angstrom
alpha=106.55(2) degrees b=13.556(3) angstrom beta=91.93(1) degrees
c=9.269(1) angstrom gamma=100.44(1) degrees V=1101.7(7) cubic
angstrom Spacegroup: P1 bar Triclinic Molecules/unit cell=2 Density
(calculated) (g/cubic cm)=1.403
2. Crystalline gatifloxacin pentahydrate in accordance with claim
1, highly homogeneous with respect to other crystalline forms of
gatifloxacin.
3. Crystalline gatifloxacin in accordance with claim 2, containing
no detectable amounts of said other gatifloxacin crystalline forms
as determined by the powder x-ray diffraction technique.
4. A process for the preparation of highly homogenous crystalline
gatifloxacin pentahydrate which comprises equilibrating
gatifloxacin in any crystalline form in water at room temperature
until highly homogenous gatifloxacin pentahydrate is formed.
5. A process according to claim 4 wherein there is added to the
water suspension of the gatifloxacin seed crystals of crystalline
gatifloxacin pentahydrate.
6. A pharmaceutical composition which comprises as an active
ingredient an amount of crystalline gatifloxacin pentahydrate as
claimed in claim 2 and one or more pharmaceutically acceptable
carriers, excipients or diluents.
7. A pharmaceutical composition in accordance with claim 6, wherein
said composition is a solid dosage form for oral
administration.
8. A pharmaceutical composition in accordance with claim 6, wherein
said composition is a powder intended for suspension in water for
oral administration.
9. A pharmaceutical composition in accordance with claim 6, wherein
said composition is a ready to use suspension in water for oral
administration.
10. A method for treating infections which comprises administering
to a mammal in need thereof an effective amount of gatifloxacin
pentahydrate as claimed in claim 2.
11. A method in accordance with claim 10 wherein crystalline
gatifloxacin pentahydrate is administered parenterally.
12. A method in accordance with claim 10 wherein the crystalline
gatifloxacin pentahydrate is administered orally.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application Serial No. 60/232,293 filed on Sep. 13, 2000.
FIELD OF THE INVENTION
[0002] The present invention relates to crystalline gatifloxacin
pentahydrate and a process for producing it.
BACKGROUND OF THE INVENTION
[0003] Gatifloxacin, chemically
1-cyclopropyl-6-fluoro-1,4-dihydro-8-metho- xy-7-(3-methyl
1-piperizinyl)-4-oxo-3-quinolinecarboxylic acid, is represented by
the following structure: 2
[0004] Gatifloxacin is a broad-spectrum quinolone antibiotic which
is disclosed and claimed in U.S. Pat. No. 5,043,450 as being
isolated as the hemihydrate. U.S. Pat. No. 5,880,283 discloses a
sesquihydrate crystalline form of gatifoxacin that is disclosed as
having advantages over the hemihydrate in pharmaceutical
manufacturing. Such advantageous properties for the sesquihydrate
in comparison to the hemihydrate include enhanced stability under
varying conditions of humidity and superior disintegration and
dissolution rates of tablets made therefrom.
[0005] Both the hemihydrate and the sesquihydrate forms have
demonstrated a definite tendency to form higher hydrates in the
presence of water.
[0006] In accordance with the present invention, it has been found
that gatifloxacin pentahydrate in highly homogeneous form is
advantageous to previously known forms and can be utilized to
prepare stable pharmaceutical dosage forms, including an aqueous
suspension, because it is the most physically stable form and does
not have a tendency over time to convert to another crystalline
form.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is an illustration of the interrelationship among the
crystalline forms of gatifloxacin.
[0008] FIG. 2 shows the powder x-ray diffraction patterns of the
pentahydrate and other crystalline forms of gatifloxacin.
[0009] FIG. 3 is a powder x-ray diffraction pattern of gatifloxacin
pentahydrate.
[0010] FIG. 4 is a differential scanning calorimetry analysis of
gatifloxacin pentahydrate.
[0011] FIG. 5 is a thermogravimetric analysis of gatifloxacin
pentahydrate.
SUMMARY OF THE INVENTION
[0012] In accordance with the present invention, there is provided
a crystalline gatifloxacin pentahydrate which is highly homogeneous
in regard to other crystalline forms thereof and has superior
properties in comparison to such other crystalline forms. The
present invention further pertains to a process for the preparation
of homogeneous gatifloxacin pentahydrate, pharmaceutical
formulations containing it and the use thereof in the treatment of
a wide variety of infections.
DETAILED DESCRIPTION OF THE INVENTION
[0013] In accordance with the present invention, there is provided
a novel highly homogenous crystalline pentahydrate form of the
broad spectrum antibiotic gatifloxacin,
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(-
3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid,
represented by the following structure: 3
[0014] Gatifloxacin is approved for use as a broad spectrum
antibacterial therapeutic agent. Gatifloxacin has been shown to be
both safe and efficacious in the treatment of infections in
individuals with impaired liver function. It has also been shown to
be effective against a broad spectrum of microorganisms including
antibiotic-resistant strains of Streptococcus Pneumoniae and to
possess excellent overall tolerability.
[0015] The initial formulation process for the preparation of
tablet dosage forms containing gatifloxacin sesquihydrate was a
conventional wet granulation procedure. However, when a clinical
batch of such tablets failed to conform to specifications, it was
discovered by Differential Scanning Calorimetry that the pattern of
the bulk material used in this batch was qualitatively different
from that of the earlier small scale batches, and that this
difference correlated with the failure of the tablets to meet
performance specifications. Further investigation revealed a
complex array of transformations involving a number of hydrated and
anhydrous forms of the drug, principal among which were the
sesquihydrate, the pentahydrate and the hexahydrate. In all, at
least twelve different crystalline forms of gatifloxacin were
identified and their interrelationships mapped as illustrated in
FIG. 1.
[0016] The crystal structures and ideal water content of seven of
these forms were established through single crystal x-ray analyses.
Each form gives rise to unique and characteristic single crystal
and powder x-ray diffraction. The kinetic and thermodynamic
relationships among the three major hydrates were investigated
leading to the understanding of their stability order in water as a
function of temperature and their interconversion relationship.
Further, the aqueous solubility relationship among them was found
to parallel their thermodynamic stability order with the
pentahydrate and sesquihydrate having the lowest and highest
solubility at 25.degree. C., respectively. The implications of
these findings were very significant in the discovery and
development of highly homogeneous gatifloxacin pentahydrate in
accordance with the present invention. Further, these findings made
it evident that very strict process controls were necessary in the
production of crystalline gatifloxacin and dosage forms containing
it and that it was necessary to obtain crystalline gatifloxacin
pentahydrate in high homogeneity vs. the other crystalline forms in
order to realize the advantageous properties thereof. By high
homogeneity is meant that crystalline gatifloxacin pentahydrate
must contain no detectable levels of the other crystalline forms
thereof as determined by powder x-ray diffraction technique.
[0017] Gatifloxacin pentahydrate is further characterized by
crystal parameters obtained from single crystal x-ray
crystallographic analysis as set forth below.
Single Crystal Parameters of Gatifloxacin Pentahydrate
[0018] Cell dimensions
[0019] a=9.339(1) angstrom
[0020] alpha=106.55(2) degrees
[0021] b=13.556(3) angstrom
[0022] beta=91.93(1) degrees
[0023] c=9.269(1) angstrom
[0024] gamma=100.44(1) degrees
[0025] V=1101.7(7) cubic angstrom
[0026] Space group:
[0027] P1 bar
[0028] Triclinic
[0029] Molecules/unit cell=2
[0030] Density (calculated) (g/cubic cm)=1.403
[0031] Crystalline gatifloxacin pentahydrate may be prepared in
high homogeneity by transforming the crude sesquihydrate product as
formed by the process taught in U.S. Pat. No. 5,880,283.
Gatifloxacin is initially crystallized from 90% ethanol as a highly
solvated ethanolate (E in FIG. 1). The ethanolate desolvated to a
crystalline product which approximates a hemihydrate (TE in FIG.
1). This product is rapidly transformed in water to the
sesquihydrate (RP in FIG. 1) by heating to about 80.degree. C. and
slowly transformed to the hexahydrate (H6 in FIG. 1) at room
temperature over a longer period. Continued equilibration of the
hexahydrate product in water at room temperature will produce the
pentahydrate (H5 in FIG. 1). Alternatively, once the pentahydrate
has been formed and isolated, it may be utilized as seed crystals
for a more rapid process of forming it from the sesquihydrate (or
any other form). In this process, a small quantity of the
pentahydrate, i.e. from about 0.1% to 2% by weight based on the
weight of the sesquihydrate, is combined with the sesquihydrate (or
any other crystalline form) and suspended in water with stirring at
ambient temperature until conversion to the pentahydrate is
completed, usually 24 hours or longer.
[0032] In addition to the crystalline forms of gatifloxacin
described in the previous paragraph, other forms exist as
illustrated in FIG. 1, which is a chart of the various forms and
their process interrelations and FIG. 2, which shows the powder
x-ray diffraction patterns of the various forms. In FIG. 1, the
forms for which single crystal x-ray structures have been
determined are indicated. Further, various equilibrium and kinetic
transformations among the crystalline forms are indicated. The
designations beginning with "T" indicate crystal forms produced by
solid-solid transformations. Of the various crystalline forms of
gatifloxacin, the primary ones that crystallize directly from
aqueous solvents, as opposed to forms that crystallize from a
molten phase or by solid-solid transformations, are the
sesquihydrate, the hexahydrate and the pentahydrate.
[0033] Formation of the thermodynamically most stable form is a
reasonable expectation for a solution mediated process, and using
the most stable form rather than a metastable form is advantageous
regarding physical stability of the crystalline form. The increased
physical stability will afford additional advantages in
formulation.
[0034] It has been found in accordance with the present invention
that the advantageous stability and solubility properties of the
pentahydrate of gatifloxacin can be applied to the formulation of
pharmaceutical dosage forms. While the pentahydrate of gatifloxacin
can be utilized to prepare tablets by wet granulation, it can also
be formulated in accordance with the present invention into stable
pharmaceutical solid dosage forms by conventional dry granulation.
Stability studies on the pentahydrate form have demonstrated no
evidence of form change or other degradation under stressed
conditions of temperature and humidity, indicating that tablets
made by dry granulation using the pentahydrate form are expected to
be stable. Such formulations will include conventional inert
ingredients such as binders, excipients, disintegrants, and the
like. Examples of such agents include various starch derivatives
such as pregelatinized starch, hydroxypropyl cellulose
microcrystalline cellulose, sodium starch glycolate, magnesium
stearate, lactose, mannitol and the like.
[0035] The pentahydrate of gatifloxacin is also more appropriate
for the preparation of aqueous dosage forms than the metastable
sesquihydrate in spite of being less soluble. This is commercially
significant since gatifloxacin has demonstrated excellent efficacy
both parenterally and via oral administration. Such oral
formulations are formulated as ready to use suspensions or packaged
as a dry powder suitable to be suspended in an appropriate amount
of water just prior to use. The powder could be prepared by any
conventional technique recognized in the art, but would preferably
be formulated by mixing the highly homogeneous crystalline
gatifloxacin pentahydrate with the other ingredients in powder form
and the mixture packaged in an appropriate container. The other
ingredients utilized to formulate such preparations would include
conventional inert ingredients such as microcrystalline cellulose,
methyl cellulose and the like, suitable sweetening and/or flavoring
agents, and preservatives therefor if required. Such solid oral
dosage forms or dry formulations suitable for the preparation of
suspensions would be formulated such that they would contain an
effective dose of gatifloxacin. In general, solid dosage forms
containing 200 mg or 400 mg of gatifloxacin are contemplated.
Preparations suitable for oral suspension would contain a similar
dosage.
[0036] It is understood that various other embodiments and
modifications in the practice of the invention will be apparent to,
and can be readily made by, those of ordinary skill in the art
without departing form the scope and spirit of the invention as
described above. Accordingly, it is not intended that the scope of
the claims appended hereto be limited to the exact description set
forth above, but rather that the claims be construed as
encompassing all of the features of patentable novelty that reside
in the present invention, including all the features and
embodiments that would be treated as equivalents thereof by those
skilled in the relevant art. The invention is further described
with reference to the following experimental work.
EXAMPLE 1
Preparation of Gatifloxacin Pentahydrate
[0037] The pentahydrate crystalline form is formed spontaneously
from any other crystal form of gatifloxacin in equilibration in
water at room temperature. A 1-g sample of gatifloxacin
hemihydrate, prepared as described in U.S. Pat. No. 5,880,283, is
suspended in 5 mL of water and stirred 24 hours at room
temperature. The suspension is filtered with gentle suction and
partially dried under suction for 2 hours. The resultant cake is
further dried in a current of air at ambient pressure, temperature
and humidity for 16 hours. The final product was analyzed by powder
x-ray diffraction (FIG. 3), differential scanning calorimety (FIG.
4), thermogravimetric analysis (FIG. 5), and KF titration to
confirm that it was the pentahydrate crystalline form of
gatifloxacin.
[0038] FIG. 3 shows the powder x-ray diffraction pattern of
gatifloxacin pentahydrate.
[0039] FIG. 4 shows the differential scanning calorimetry analysis
of gatifloxacin pentahydrate.
[0040] FIG. 5 shows the thermogravimetric analysis of gatifloxacin
pentahydrate.
EXAMPLE 2
Large Scale Production of Gatifloxacin Pentahydrate
[0041] A 9.5-mg sample of gatifloxacin pentahydrate prepared as in
Example 1 was ground with 0.01 mL of water in a mortar and pestle
and transferred in 0.1 mL of water to a flask containing 1.10 g of
gatifloxacin sesquihydrate. Gatifloxacin sesquihydrate was prepared
as described in U.S. Pat. No. 5,880,283. One mL of water was added
and the mixture stirred for one hour at room temperature.
Microscopic examination revealed partial conversion of the
rectangular platelets characteristic of the sesquihydrate to the
needles characteristic of the pentahydrate. This seed mixture,
which had become too thick to flow, was diluted with 1 mL of water
and added to a suspension of 599 g of gatifloxacin sesquihydrate in
600 mL of water. An additional 1800 mL of water was added, and the
mixture was stirred gently at room temperature for 64 hours.
Microscopic examination showed only needles, typically 1.times.40
to 3.times.75 micrometers. The mixture, which had the consistency
of heavy cream, was filtered with gentle suction and partially
dried in the funnel with the suction continually running for 23
hours. The resultant cake, which had the consistency of cream
cheese, was sliced and dried at room temperature in a current of
air at RH 50-60% for 28 hours. The solid (679 g) was passed through
a 20 mesh screen to yield 666 g of powder. Further drying under
ambient conditions produced no further weight loss. The final
product had a water content of 19.4% by KF titration as expected
for the pentahydrate (calculated 19.3%). The powder x-ray
diffraction pattern confirmed that the product was gatifloxacin
pentahydrate. Thermogravimetric analysis and differential scanning
calorimetry also confirmed the pentahydrate form of the
product.
EXAMPLE 3
Typical Composition of Gatifloxacin Pentahydate 100 mg Powder For
Suspenion
[0042] Gatifloxacin pentahydrate for oral suspension was prepared
by combining the following ingredients in the amounts
specified:
1 Ingredient Amount per 5 gram preparation Gatifloxacin
Pentahydrate 107 mg* Microcrystalline cellulose and 50.0 mg sodium
carboxymethylcellulose Avicel .RTM. RC-591 Methyl cellulose and
sodium 12.5 mg carboxymethylcellulose Methocel A4M Premium .RTM.
Sucrose 1000 mg Flavoring agent, preservative As needed *Equivalent
to 100 mg of gatifloxacin/5 g suspension.
[0043] Avicel.RTM. RC-591 is available from FMC Corporation
[0044] Methocel A4M Premium.RTM. is available from Dow Chemical
Co.
[0045] The ingredients were added in the order given and gently
mixed. The resulting mixture was sealed in a suitable container. In
use, the contents are combined with 3.8 g of water and shaken well
to effect the suspension.
EXAMPLE 4
[0046]
2 Typical Composition of Gatifloxacin Pentahydrate 400 mg Tablets
Composition Grams Per Tablet Gatifloxacin pentahydrate 0.428*
Microcrystalline cellulose 0.138 Sodium starch glycolate 0.024
Magnesium stearate 0.009 Total Tablet Weight 0.600 *Equivalent to
400 mg of gatifloxacin
* * * * *