CN1688310A - Novel crystalline forms of gatifloxacin - Google Patents

Abstract

Provided are novel crystalline forms of gatifloxacin, designated as Forms L, M, P, Q, S, and T1, and methods for preparing the same. Also provided are methods for converting the novel crystalline forms of gatifloxacin of the present invention into other crystalline forms of gatifloxacin.

Description

New crystal form of gatifloxacin

Cross References to Related Applications

Pursuant to 35 U.S.C. 119(e), this application claims priority to provisional application serial numbers 60/401,672, filed August 6, 2002, and provisional application serial numbers 60/402,749, filed August 12, 2002, Both are incorporated herein by reference.

field of invention

The present invention relates to (±)1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazine commonly known as gatifloxacin Novel polymorphs and pseudopolymorphs of -4-oxo-3-quinolinecarboxylic acid.

related application

This application claims priority from the filing dates of the following US provisional patent applications: 60/401,672; 60/402,749; and 60/409,860.

Background of the invention

Gatifloxacin, known as (±)1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4 -Oxo-3-quinolinecarboxylic acid, having the following structure:

Gatifloxacin, a fungicide, is sold under the tradename Tequin ^(R) by Bristol-Myers Squibb. Tequin(R ⁾ is available in 200 and 400 mg doses in vial or tablet form, which can be injected or taken orally.

Many pharmaceutically active organic compounds can crystallize in more than one type of molecule, containing more than one type of internal lattice. That is, the compound crystallizes out in different crystal forms. The resulting corresponding crystal structures (crystal forms) may have, for example, different unit cells. This phenomenon of the same chemical structure but different internal structures is called polymorphism, and species with different molecular structures are called polymorphs.

Many pharmacologically active organic compounds can also be crystallized in the form of crystals, so that second foreign molecules, especially solvent molecules, are regularly introduced into the crystal structure of the main pharmacologically active compound. This phenomenon is sometimes called pseudopolymorphism, and the resulting structures are called pseudopolymorphs. When the second molecule is a solvent molecule, the pseudopolymorph can be called a solvate.

However, it is often impossible to predict whether a particular organic compound will form different crystalline forms, let alone predict the structure and properties of the crystalline forms themselves.

The discovery of new crystalline forms of pharmaceutically useful compounds provides an opportunity to improve the performance characteristics of pharmaceutical products. It adds to the catalog of substances available to formulation scientists for designing, for example, pharmaceutical dosage forms of drugs with targeted release profiles or other desirable properties. It is clearly beneficial when this catalog is augmented by the discovery of new polymorphs or pseudopolymorphs of useful compounds. For a comprehensive review of polymorphs and their pharmaceutical applications, 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.

By controlling the conditions under which a solid compound is obtained, it is possible to influence the crystal form. Solid state physical properties that can differentiate one polymorph from another include, for example, flowability of the ground solid. Different crystal forms can be more or less hygroscopic. Absorption of atmospheric humidity by compounds in powder form may impede their fluidity. Flowability affects how easily the substance can be handled during processing into a drug. Formulation professionals developing tablet or capsule formulations must consider the possible need to use glidants such as colloidal silicon dioxide, talc, starch, or tricalcium phosphate when powdered compound particles do not readily flow with each other.

Another important solid-state property of a pharmaceutical compound that can differentiate one polymorph or pseudopolymorph from another is its rate of dissolution in aqueous media such as gastric juice . The rate of dissolution of an active ingredient in a patient's gastric fluid may have therapeutic consequences as it affects the upper limit of the rate at which an orally administered active ingredient can reach the patient's bloodstream. Dissolution rate is also a consideration when formulating slurries, elixirs, and other liquid medications. The solid state form of the compound may also affect its performance in terms of compaction and its storage stability.

These actual physical properties are influenced by the morphology, orientation, and packing of molecules in the unit cell that characterizes a particular polymorph or pseudopolymorph. A polymorph may have different thermodynamic properties than the amorphous material or another polymorph. Thermodynamic properties can be used to distinguish between different polymorphs or pseudopolymorphs. Thermodynamic properties that can be used to distinguish polymorphs from pseudopolymorphs can be determined in the laboratory by methods such as capillary melting point, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and differential thermal analysis ( DTA) method determination.

Certain crystalline forms can also have distinct spectroscopic properties, which can be detected, for example, by solid-state 13C NMR spectroscopy and infrared (IR) spectroscopy. This method is particularly useful in cases where the crystalline form is a solvate, due to the presence of a second foreign molecule that produces absorption or resonance.

(±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolin Phenylcarboxylic acid, commonly known as gatifloxacin, is a synthetic broad-spectrum antibacterial agent for oral or intravenous administration.

US Patent 5,880,283 (the '283 patent) discloses a hygroscopic hemihydrate form of gatifloxacin. It is mentioned that the hemihydrate (pseudopolymorph) can be readily formed when gatifloxacin is crystallized from an aqueous organic solvent. The hemihydrate has been reported to be deficient when used in the manufacture of solid oral dosage forms such as tablets. The patent also discloses a new pseudopolymorph of gatifloxacin, sesquihydrate, and provides thermal analysis and X-ray diffraction data of this substance. Sesquihydrate has been reported to be less hygroscopic and more stable during manufacturing.

US Patent 6,413,969 discloses at least 12 different polymorphs or pseudopolymorphs of gatifloxacin, and discloses X-ray powder diffraction patterns of at least 10 of them. Hexahydrate, pentahydrate and sesquihydrate are crystallized directly from water solvent. Other crystalline forms are obtained by crystallization from the melt phase or by solid-solid phase transformation. According to the disclosure of US Patent 6,413,969, the pentahydrate form is the most thermodynamically stable form and has the least water solubility at room temperature. The correlation between the twelve crystalline forms identified is given in this application.

Summary of the invention

In one aspect, the present invention relates to a crystalline form of gatifloxacin, designated as crystalline form L, characterized by its X-ray reflection at about 17.2 ± 0.2 degrees 2Θ.

In another aspect, the present invention relates to a process for the preparation of crystalline Form L of gatifloxacin, comprising the step of providing Gatifloxacin in a solvent consisting essentially of a mixture of methanol and water at a temperature of at least about 70°C. Gatifloxacin solution, wherein the volume percentage of water is about 5% by volume to about 15% by volume, especially about 10% by volume; the solution is cooled to ambient temperature, then cooled to about 0°C to about 10°C, especially about At a temperature of 5°C, a suspension is obtained; the solid is separated from the suspension; the separated solid is dried at a temperature of about 40°C to about 70°C, especially about 55°C, to obtain L of gatifloxacin crystal form.

In another aspect, the present invention relates to a crystalline form of gatifloxacin, designated as crystalline form M, characterized in that its X-ray reflection is about 8.8, 14.1, 17.6, 18.2, 22.0, and 22.6±0.2 degrees at 2θ angles place.

In another aspect, the present invention relates to a method for preparing crystalline form M of gatifloxacin, which comprises the following steps: slurring gatifloxacin in ethanol, wherein the slurried gatifloxacin is selected from crystalline form T1RP , T1, and mixtures thereof; isolating the solid from the slurry; and drying the isolated solid at ambient temperature and pressure to obtain this crystalline form of gatifloxacin.

In yet another aspect, the present invention relates to a crystalline form of gatifloxacin, designated Form P, characterized by X-ray reflections at approximately 11.1, 11.7, 12.5 and 23.0 ± 0.2 degrees 2Θ.

In another aspect, the present invention relates to a process for the preparation of Form P of gatifloxacin, comprising the step of providing Gatifloxacin in a solvent consisting essentially of a mixture of ethanol and water at a temperature of at least about 75°C. Gatifloxacin solution, wherein the volume percent of ethanol in the mixture is at least about 95% by volume, especially about 99% by volume; the solution is cooled to ambient temperature and thereafter cooled to about 0°C to about 10°C, especially to about 5°C temperature, thereby obtaining a suspension; this crystalline form of gatifloxacin is isolated from the suspension.

In another embodiment, the present invention relates to a crystalline form of gatifloxacin, designated Form Q, characterized by an X-ray reflection of about 6.8, 7.1, 11.1, 15.5, and 17.4±0.2 at 2θ angles degrees.

In another aspect, the present invention relates to a method for preparing crystalline form Q of gatifloxacin, comprising the steps of: providing a solution of gatifloxacin in a solvent substantially consisting of a mixture of acetonitrile and water under reflux , wherein the volume percentage of water in the mixture is about 2% by volume; the solution is cooled to ambient temperature and then cooled to a temperature of about 0°C to about 10°C, especially about 5°C, to obtain a suspension; the solid This crystalline form of gatifloxacin is obtained by isolation from the suspension; drying the isolated solid at about 50°C and a pressure of about 10 to about 400 mm Hg.

In yet another aspect, the present invention relates to a new crystal form of gatifloxacin, named as crystal form T1, characterized in that its X-ray reflection is about 7.4, 8.9, 9.6, 11.4, 12.2, 12.9, 14.1 at 2θ angles, 16.7, 21.2, 21.8, 24.1, and 26.0±0.2 degrees.

In another aspect, the present invention relates to a method for preparing T1 of gatifloxacin crystal form, which comprises the steps of: crystallizing gatifloxacin from acetonitrile; separating the gatifloxacin crystallized from acetonitrile; The isolated gatifloxacin is slurried in ethanol for about 2 hours or less; and the T1 crystalline form of gatifloxacin is isolated.

In yet another aspect, the present invention relates to a new crystalline form of gatifloxacin, named Form S, characterized by X-ray reflections at approximately 9.3, 11.0, and 21.2 ± 0.2 degrees 2Θ. Form S is further characterized by its X-ray reflection at approximately 12.0, 14.5, and 18.6 ± 0.2 degrees 2Θ.

In another aspect, the present invention relates to a method for preparing the crystal form S of gatifloxacin, which comprises the steps of: crystallizing gatifloxacin from acetonitrile; separating the gatifloxacin crystallized from acetonitrile; making such The isolated gatifloxacin is slurried in a lower alkanol having 1 to 4 carbon atoms for a period of at least about 2 hours; form S of gatifloxacin is isolated from the slurry.

In another embodiment, the present invention relates to a method for the preparation of gatifloxacin hemihydrate, sesquihydrate, and crystalline form Ω, which method comprises, for example, treating one or more new crystals of the present invention by heating or aging type steps.

Brief description of the drawings

Figure 1 is a typical X-ray diffraction pattern of Gatifloxacin Form L.

Figure 2 is a typical X-ray diffraction pattern of gatifloxacin Form M.

Figure 3 is a typical X-ray diffraction pattern of gatifloxacin Form P.

Figure 4 is a typical X-ray diffraction pattern of gatifloxacin Form Q.

Figure 5 is a typical X-ray diffraction pattern of gatifloxacin Form S.

Fig. 6 is a typical X-ray diffraction pattern of gatifloxacin crystal form T1.

Detailed description of the invention

The term "about" as used herein with respect to a measurand refers to an amount of variation of the measurand that would be expected by one of ordinary skill in making the measurement and at a level closely commensurate with the purpose of the measurement and the precision of the measuring equipment used.

The symbols used herein for the composition of solvent mixtures: volume percent (vol-%), %v:v, and N%v/v (where N is a number from 1 up to and including 100) have the same meaning, and is calculated as follows (species A is used as an example):

Vol-% _A ＝Wt _A ×ρ _A /(Wt _A ×ρ _A +Wt _B x×ρ _B )

in:

Wt _A and Wt _B are the weights of substances A and B, respectively, in grams, and ρ _A and ρ _B are the densities of substances A and B, respectively, in grams per milliliter.

As used herein, the term "ambient temperature" refers to a temperature of about 20°C to about 30°C.

As used herein, the term "ambient pressure" refers to a pressure of about 750 mm Hg to about 765 mm Hg.

The term "reduced pressure" as used herein in connection with the drying of gatifloxacin samples means a pressure of from about 1 to about 600 mm Hg.

The term "crystalline form Ω" (Ω) as used herein refers to the crystalline form of gatifloxacin disclosed in Raghavan et al., US Patent 6,413,969 (the '969 patent) according to the nomenclature.

The term "sesquihydrate" of gatifloxacin as used herein refers to the crystalline form of gatifloxacin disclosed in the '969 and '283 patents according to the nomenclature.

The term "form T2RP" as used herein refers to the crystalline form of gatifloxacin hemihydrate disclosed in the '969 patent according to the nomenclature.

As used herein, the term "Form J" refers to the crystalline form of gatifloxacin characterized by its X-ray reflections at about 67, 11.3, 13.8, and 16.4 ± 0.2 degrees 2Θ.

Form J can be obtained by the method described in the working examples below.

The X-ray reflectance reported in this invention is determined by X-ray diffraction. X-ray diffraction refers to X-ray diffraction measured by powder diffractometry. X-ray powder diffraction analysis was performed using a Scintag powder diffractometer with variable crystal goniometer, CuK ^alpha source, and solid state detector. Use standard round aluminum sample holders with zero-background quartz slices. The sample is scanned from 2 to 40 degrees in a continuous scan at a rate of 3 degrees per minute. The peak maximum in the resulting intensity vs. 2Θ plot was recorded as the reflection point, subject to standard experimental error (uncertainty), estimated at ±0.2 degrees. When a sample is described as "wet", it means that the sample was analyzed "as is".

In a particular embodiment, the novel crystalline form of the present invention is prepared by crystallization, which may include a treatment step (such as a drying step), whereby the crystalline form or its penultimate precursor is removed from the solution provided. Precipitates out, thereby obtaining a suspension (slurry). In certain embodiments using crystallization methods, precipitation occurs by lowering the temperature of a provided solution of the compound in a solvent of fixed composition.

Depending on the desired crystalline form, it may be necessary to adjust the rate at which the temperature of the solution is lowered (ie, the cooling rate).

In other embodiments using the crystallization method, by changing the solvent composition of the provided solution at a given temperature, such as by adding an anti-solvent to the provided solution, so that the solubility of the compound in the solvent whose composition is changed is low Depending on its solubility in the original solvent of the provided solution, the precipitation proceeds. Altering the solvent composition of a provided solution (eg, by adding an antisolvent) can be performed simultaneously with or subsequent to lowering the temperature of the resulting solution.

An antisolvent is an organic compound, usually liquid at ambient temperature, that is a poor solvent for the compound to be crystallized (in this case gatifloxacin). The compound to be crystallized has a lower solubility in the solvent mixture of the provided solution's solvent and the antisolvent than in the solvent of the originally provided solution.

Either embodiment of the crystallization method may include a well-known seeding step whereby crystals of the compound to be crystallized or impurities are added to the solution at a selected seed temperature at which the seed remains substantially insoluble.

In other embodiments, the new crystal form of the present invention can be prepared by a slurry (suspension) method, which includes mixing gatifloxacin with a slurry solvent in which gatifloxacin is slightly dissolved for a certain amount of slurry under stirring. time. The desired crystalline form is either isolated from the slurry or obtained by treating (eg drying) the solid separated from the slurry at the end of slurrying.

Unless otherwise stated, the relative proportions of solids and slurrying solvent are not critical. Mixing may be performed in any suitable vessel equipped with an agitator capable of dispersing the solids in the slurrying solvent and providing uniform mixing of the solids with the slurrying solvent. Slurry is performed for a time ("slurry time") sufficient to substantially complete formation of the desired crystalline form. The skilled person will know to adjust the slurrying time by routine optimization by monitoring the crystal form of the solids in the slurry, eg by any method that can characterize the desired crystal form (X-ray diffraction). The pulping times disclosed in the present invention are approximate and are empirically taken. Depending on, for example, the temperature, the relative proportions of solids and slurrying solvent, and the equipment used, longer slurrying times may be required. It is also possible that a shorter period of time is sufficient.

In either crystallization or slurrying, a suspension (slurry) of solids and liquids is obtained. The solids may be separated from the suspension by any means known in the art, such as filtration (gravity or suction) or centrifugation, to name only two methods mentioned here.

In another embodiment, the present invention provides a new crystalline form of gatifloxacin, designated as Form L, which can be characterized by reflections at about 17.2±0.2 degrees 2θ in X-ray diffraction. A typical X-ray diffraction pattern of Form L is shown in Fig. 1 .

The new crystalline form described in the immediately preceding paragraph may be prepared by a crystallization method comprising the steps of providing a solution of gatifloxacin in a mixture of methanol and water at a temperature of at least about 70° C., preferably under reflux, wherein the methanol The mixture with water contains about 5% to about 15% water by volume (i.e. 95:5 to 85:15, v:v, methanol/water), preferably about 10% water by volume; the solution is cooled to ambient temperature , followed by cooling to a temperature of about 0°C to about 10°C to obtain a suspension; the solid is isolated from the suspension; the separated solid is dried at about 40°C to about 70°C to obtain gatifloxacin of this new crystal form.

Upon prolonged (eg, 2 months) storage at ambient temperature and pressure, Form L converts to Form Ω.

In another embodiment, the present invention provides a new crystalline form of gatifloxacin, designated as Form M, characterized in that its X-rays are approximately 8.8, 14.1, 17.6, 18.2, 22.0, and 22.6 at 2θ angles. Reflections occur at ±0.2 degrees. A typical X-ray diffraction pattern of Form M is shown in FIG. 2 .

The new crystal form of gatifloxacin described in the immediately preceding paragraph can be prepared by a slurry method, which includes the following steps: Gatifloxacin selected from crystal form T1, T1RP and a mixture thereof in absolute ethanol ( EtOH) for a period of time, the solid was separated from the slurry, and the separated solid was dried at about 50° C. under reduced pressure to obtain this new crystalline form of gatifloxacin.

Upon prolonged (eg, 2 months) storage at ambient temperature and pressure, Form M converts to Form T2RP (hemihydrate).

In another embodiment, the present invention provides a new crystalline form of gatifloxacin, named Form P, characterized by its X-ray reflection at about 11.1, 11.7, 12.5, and 23.0±0.2 degrees at 2θ angles place. A typical X-ray diffraction pattern of Form P is shown in FIG. 3 .

The new crystalline form of gatifloxacin described in the immediately preceding paragraph may be prepared by a crystallization process comprising the steps of providing gatifloxacin in a mixture of ethanol and water at a temperature of at least about 75°C, preferably under reflux Star solution, wherein said mixture includes at least about 95% by volume of ethanol; cooling the solution to ambient temperature and then to about 0°C to about 10°C to obtain a suspension; gatiza is isolated from the suspension This new crystal form of the star.

Upon prolonged (eg, 1 month) storage at ambient temperature and pressure, Form P was converted to gatifloxacin sesquihydrate. As described below, when Form P is heated at about 50°C, Form T1, infra of gatifloxacin is formed.

In another embodiment, the present invention provides a new crystalline form of gatifloxacin, named as crystalline form Q, characterized by its X-ray diffraction reflections at 2θ angles of approximately 6.8, 7.1, 11.1, 15.5, and 17.4 ±0.2 degrees. A typical X-ray diffraction pattern of Form Q is shown in FIG. 4 .

The new crystalline form of gatifloxacin described in the immediately preceding paragraph may be prepared by a crystallization process comprising the steps of providing gatifloxacin at a temperature of at least about 75° C., preferably at reflux, and containing about 2% by volume A solution of water in acetonitrile (i.e. ACN/H ₂ O=98:2, v:v); the solution was cooled to ambient temperature and then to about 0°C to about 10°C to obtain a suspension; the solid was removed from the suspension isolated from the liquid; drying the isolated solid at about 50°C under reduced pressure yielded this new crystalline form of gatifloxacin.

In another embodiment, the present invention provides a process for the preparation of a new crystalline form of gatifloxacin, designated as Form S, characterized by approximately 9.3, 11.0 in 2θ angles in X-ray diffraction. , and reflections occur at 21.2±0.2 degrees, and additionally there are X-ray reflections at approximately 12.0, 14.5, and 18.6±0.2 degrees in 2Θ. A typical X-ray diffraction pattern of Form S is shown in Fig. 5 .

The new crystal form of gatifloxacin described in the immediately preceding paragraph can be prepared by a slurry method, which comprises the following steps: crystallizing gatifloxacin from acetonitrile, separating crystallized gatifloxacin from acetonitrile; Gatifloxacin thus isolated is slurried in a lower alkanol having 1 to 4, preferably 2, carbon atoms for at least about 2 hours; and this crystalline form of gatifloxacin is isolated.

In another embodiment, the present invention provides a new crystalline form of gatifloxacin, named as crystalline form T1, characterized in that it is approximately 7.4, 8.9, 9.6, 11.4, 12.2 at 2θ angles in X-ray diffraction , Reflections occur at 12.9, 14.1, 21.2, 21.8, 24.1, and 26.0±0.2 degrees. A typical X-ray diffraction diagram of crystal form T1 is shown in FIG. 6 .

The new crystalline form of gatifloxacin described in the immediately preceding paragraph may be prepared by a process comprising: crystallizing gatifloxacin from acetonitrile; isolating gatifloxacin crystallized from acetonitrile; isolating The obtained gatifloxacin is slurried in a lower alkanol with 1-4, preferably 2 carbon atoms, for about 2 hours or less, preferably less than 2 hours; crystal form.

In another further embodiment, any one of the above-described new crystal forms L, M, P, Q, S and T1 of gatifloxacin is formulated into a pharmaceutical composition alone or in any combination , preferably an oral solid dosage form or a dosage form for parental administration.

The pharmaceutical composition may be in the form of a solid oral dosage form, such as a compressed tablet or capsule, or may be in the form of a liquid oral dosage form, such as a solution or an oral suspension. We found that in formulation, El was also stable at 30°C for at least 3 months.

Compressed tablets may be prepared by dry or wet granulation, as known in the art. In addition to the pharmaceutically active agent or drug, compressed tablets contain many pharmacologically inactive components called excipients. Certain excipients enable or facilitate processing of the drug into tablet dosage form. Other excipients contribute to the proper delivery of the drug, for example by facilitating disintegration.

Excipients can be broadly classified according to their intended function. This classification is sometimes arbitrary, and it is well known that a particular excipient can function in more than one way, or serve more than one purpose in a formulation.

Diluents increase the bulk of the solid pharmaceutical composition, making it easier for patients and caregivers to handle pharmaceutical dosage forms comprising the composition. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. ^AVICEL® ), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrose, dextrin, Dextrose, dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g. EUDRAGIT ^® ), potassium chloride, powdered cellulose, chloride Sodium, sorbitol and talc.

Solid pharmaceutical compositions that are compressed into a tablet-like dosage form may contain excipients whose functions include facilitating the binding together of the active ingredient and other excipients after compression. Binders for solid pharmaceutical compositions include gum arabic, alginic acid, carbomers (such as carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethyl Cellulose, hydroxypropylcellulose (eg ^Klucel® ), hydroxypropylmethylcellulose (eg ^Methocel® ), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, Povidone (eg ^KOLLIDON® , ^PLASDONE® ), pregelatinized starch, sodium alginate and starch. The rate of dissolution of a compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition.

Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (such as Ac-Di-Sol ^® , PRIMELLOSE ^® ), colloidal silicon dioxide, croscarmellose sodium, croscarmellose Vinyl polypyrrolidone (eg KOLLIDON® ^{, POLYPLASDONE®} ), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, potassium ion exchange resin, powdered cellulose, pregelatinized starch, sodium alginate, starch Sodium glycolate (eg ^EXPLOTAB® ) and starch.

Glidants can be added to enhance the flow characteristics of the uncompacted solid composition and to increase the accuracy of dosage. Excipients that can act as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tricalcium phosphate.

When preparing a dosage form such as a tablet by compacting a powder composition, the composition is compressed using a punch and die. Some excipients and active ingredients have a tendency to adhere to the surfaces of punches and dies, which can lead to pitting and other surface irregularities in the product. Lubricants may be added to the composition to reduce sticking and to facilitate 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.

Flavoring and flavor enhancers make the dosage form more palatable to the patient. Common pharmaceutical flavoring agents and flavor enhancers that can be included in the compositions of the present invention include maltitol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltitol, and tartaric acid .

The solid and liquid components may also be dyed with any pharmaceutically acceptable colorant to improve their appearance and/or to facilitate patient identification of the product and unit dosage.

It goes without saying that wet or dry granules can also be used to fill capsules, for example gelatin capsules. When the capsule is the intended dosage form, the excipients used for granulation may or may not be the same as those used when the tablet dosage form is intended.

The choice of excipients and amounts can be readily determined by a formulation expert based on his experience and discussion of standard procedures and texts in the field.

In the liquid pharmaceutical composition of the present invention, one of the crystal forms L, M, P, Q, S, and T1 of gatifloxacin or a mixture thereof are dissolved or suspended in the liquid with any other solid excipients. in carriers such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition active ingredients or other excipients that are insoluble in the liquid carrier. Emulsifiers that may be used in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, carrageenan, pectin, methylcellulose, carbomer, octadecane Cetyl Alcohol and Cetyl Alcohol.

The liquid pharmaceutical compositions of the present invention may also contain viscosity enhancers for improving the mouthfeel of the product and/or coating the walls of the gastrointestinal tract. Such agents include, for example, gum arabic, alginic acid, bentonite, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethyl Hydroxypropyl Cellulose, Hydroxypropyl Cellulose, Hydroxypropyl Methyl Cellulose, Maltodextrin, Polyvinyl Alcohol, Povidone, Propylene Carbonate, Propylene Glycol Alginate, Sodium Alginate, Starch Hydroxy Sodium acetate, starch tragacanth and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve taste.

Preservatives and chelating agents, such as alcohol, sodium benzoate, 2,6-di-tert-butyl-p-cresol, tert-butyl-p-methoxyphenol, and ethylenediaminetetraacetic acid, may be added in ingestion-safe doses to improve storage stability.

The liquid compositions of the invention may also contain buffering agents such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.

Solid compositions of the present invention include powders, granules, agglomerates and compacted compositions. Dosages include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation and ophthalmic administration. In any given case, the most appropriate route will depend on the nature and severity of the condition being treated. The dosages may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, lozenges, and losenge, as well as liquid slurries, suspensions, and elixirs.

Active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

Compositions for tablet or capsule filling can be prepared by wet granulation. During wet granulation, some or all of the active ingredient in powder form and excipients are blended and then further mixed in the presence of a liquid, usually water, causing the powder to agglomerate into granules. The particles are sieved and/or ground, dried, and then sieved and/or ground to the desired particle size. The granules can then be tableted, or other excipients, such as glidants and/or lubricants, can be added prior to tableting.

Tablet compositions can be prepared conventionally by dry blending. For example, a blend of active ingredients and excipients can be compressed into bars or tablets, which can then be divided into compacted granules. The compacted granules can then be compressed into tablets.

As an alternative to dry granulation, the blended composition can be compressed directly into a compact dosage form by direct extrusion. The direct extrusion method results in a more uniform tablet without granules. Excipients which are particularly suitable for direct compression into tablets include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate and colloidal silicon dioxide. The proper use of these and other excipients in direct compression tableting is well known to those skilled in the art and familiar with the specific direct compression tableting formulation tasks.

In the present invention, capsule filling may include any of the blending and granulation steps described above for tableting, except that they are not subjected to the final tabletting step.

Capsules, tablets, and lozenges, as well as other unit dosage forms, can be administered in various dosages as desired.

Certain embodiments of the invention are illustrated by the following non-limiting examples.

Example

Example 1:

To a 500 ml flask was added 10 g of gatifloxacin and 258 ml of a methanol/water mixture (90:10). The composition was heated to reflux until a clear solution was obtained. The solution was cooled to ambient temperature over 1 hour, then to 5°C over 45 minutes. Then, the resulting suspension was filtered and washed with 120 mL of a MeOH: _H2O mixture (90:10).

The samples were dried in a vacuum oven at 55°C for 24 hours. The crystal form of the sample was analyzed by XRD and found to be Form L.

Example 2:

Add 10 g of gatifloxacin and 66 mL of absolute ethanol to a 250 mL flask. The mixture was stirred at ambient temperature for 24 hours, then filtered. The filter cake was washed with 20 mL of absolute absolute ethanol and dried under vacuum for 24 hours. The crystal form of the sample was analyzed by XRD, which proved to be Form M.

Example 3:

10 g of gatifloxacin and 120 ml of ethanol-water mixture (EtOH:H ₂ O=99:1) were added to a 250 ml flask. The composition was heated to reflux until a clear solution was obtained. The mixture was cooled to ambient temperature over 1 hour, then to 5°C over 1 hour. Then, the resulting suspension was filtered and washed with 50 mL of EtOH: _H2O mixture (99:1).

The crystal form of the wet filter cake was analyzed by XRD and found to be Form P.

Example 4:

To a 250 ml flask was added 10 g of gatifloxacin and 135 ml of an ACN/water mixture (98:2). The composition was heated to reflux until a clear solution was obtained. The solution was cooled to ambient temperature over 1 hour, then to 5°C over 1 hour. The resulting suspension was then filtered and washed with 100 mL of an aqueous ACN/ _H2O mixture (98:2).

The collected solid was dried in a vacuum oven at 50°C for 12 hours. The crystal form of the sample was analyzed by XRD, which proved to be Form Q.

Example 5:

12.67 g of wet gatifloxacin obtained by crystallization from ACN was slurried in 83.6 ml of ethanol for a total slurry time of about 24 hours. Slurry samples were taken at slurry times of 2, 4, 6, 8 and 24 hours. The solid was separated from the slurry by filtration and analyzed by XRD.

It was found by XRD analysis that the isolated wet solid was Form S.

After drying, the sample was found to be crystalline form T2RP.

Embodiment 6:

14.93 g of dry matter obtained by recrystallization from ACN were slurried in 98.5 ml of ethanol for a total slurry time of 24 hours. Slurry samples were taken at slurry times of 2, 4, 6, 8 and 24 hours. The solid was separated from the slurry by filtration and analyzed by XRD.

It was found by XRD analysis that the isolated wet substance was Form S.

After drying, the sample was found to be crystalline form T2RP.

Embodiment 7 (J crystal form):

Slurry 3 grams of gatifloxacin in 20 milliliters of technical grade IPA. The mixture was stirred at ambient temperature for a slurry time of 24 hours using a magnetic stirrer. The mixture was then filtered (suction) and the separated solid was rinsed with technical grade IPA (10 mL). Divide the sample into two parts. The first part was dried in a vacuum oven at 50°C for 24 hours, and the second part was dried in an atmospheric oven at 60°C for 24 hours. Both dried samples were analyzed by XRD and confirmed to be Form J.

Embodiment 8:

Dry gatifloxacin (7 g), obtained by crystallization of gatifloxacin from acetonitrile, was slurried in absolute ethanol (46.2 ml). The slurry was stirred at ambient temperature for 90 minutes, then filtered (suction). The isolated solid was dried under vacuum overnight. The material was analyzed by XRD and found to be Form T1.

Claims (37)

1. A crystal form of gatifloxacin, characterized in that its X-ray reflection is at about 17.2±0.2 degrees at a 2θ angle. 2. The crystalline form of gatifloxacin according to claim 1, which has an X-ray diffraction pattern substantially as shown in FIG. 1 . 3. the method for preparing the crystalline gatifloxacin of claim 1, it may further comprise the steps: a) providing a solution of gatifloxacin in a solvent consisting essentially of a mixture of methanol and water, wherein the volume percent of water is from about 5% by volume to about 15% by volume, at a temperature of at least about 70°C; b) cooling the solution to obtain a suspension; c) separating the solids from the suspension; and d) drying the isolated solid at a temperature of about 40°C to about 70°C to obtain this crystalline form of gatifloxacin. 4. The method of claim 3, wherein the solution is cooled to ambient temperature and then cooled to a temperature of from about 0°C to about 10°C. 5. The method of claim 3, wherein the volume percent of water in the solvent is about 10 volume percent. 6. The method of claim 3, wherein the collected solids are dried at a temperature of about 55°C. 7. A crystalline form of gatifloxacin characterized by X-ray reflections at approximately 8.8, 14.1, 17.6, 18.2, 22.0, and 22.6 ± 0.2 degrees 2Θ. 8. The crystalline form of gatifloxacin according to claim 7, which has an X-ray diffraction pattern substantially as shown in FIG. 2 . 9. the method for preparing the gatifloxacin crystal form of claim 10, it may further comprise the steps: a) Gatifloxacin is slurried in ethanol, wherein the slurried gatifloxacin is selected from crystal forms T1RP, T1, and mixtures thereof; b) separating the solids from the slurry; and c) Drying the isolated solid at ambient temperature and pressure yields this crystalline form of gatifloxacin. 10. A crystalline form of gatifloxacin characterized by X-ray reflections at approximately 11.1, 11.7, 12.5 and 23.0 ± 0.2 degrees 2Θ. 11. The crystalline form of gatifloxacin according to claim 10, which has an X-ray diffraction pattern substantially as shown in FIG. 3 . 12. the method for preparing the gatifloxacin crystal form of claim 10, it comprises the following steps: a) providing a solution of gatifloxacin in a solvent consisting essentially of a mixture of ethanol and water at a temperature of at least about 75° C., wherein the volume percent of ethanol in the mixture is at least about 95 percent by volume; b) cooling the solution to obtain a suspension; and c) Isolation of this crystalline form of gatifloxacin from the suspension. 13. The method of claim 12, wherein the solution is cooled to ambient temperature and thereafter cooled to a temperature of from about 0°C to about 10°C. 14. The method of claim 12, wherein the volume percent of water in the solvent is about 1 volume percent. 15. A crystalline form of gatifloxacin characterized by X-ray reflections at approximately 6.8, 7.1, 11.1, 15.5, and 17.4 ± 0.2 degrees 2Θ. 16. The crystalline form of gatifloxacin according to claim 15, which has an X-ray diffraction pattern substantially as shown in FIG. 4 . 17. prepare the method for the gatifloxacin crystal form of claim 15, it comprises the following steps: a) under reflux, providing a solution of gatifloxacin in a solvent consisting essentially of a mixture of acetonitrile and water, wherein the volume percent of water in the mixture is about 2% by volume; b) cooling the solution to obtain a suspension; c) separating the solids from the suspension; and d) drying the isolated solid at about 50°C and a pressure of about 10 to about 400 mm Hg to obtain this crystalline form of gatifloxacin. 18. The method of claim 21, wherein the solution is cooled to ambient temperature and thereafter cooled to a temperature of from about 0°C to about 10°C. 19. A crystalline form of gatifloxacin characterized by X-ray reflections at approximately 9.3, 11.0, and 21.2 ± 0.2 degrees 2Θ. 20. The crystalline form of gatifloxacin of claim 19, further characterized by its X-ray reflection at approximately 12.0, 14.5, and 18.6 ± 0.2 degrees 2Θ. 21. The crystalline form of gatifloxacin according to claim 20, which has an X-ray diffraction pattern substantially as shown in FIG. 5 . 22. the method for preparing the gatifloxacin crystal form of claim 19, it comprises the following steps: a) crystallizing gatifloxacin from acetonitrile; b) separation of gatifloxacin crystallized out from acetonitrile; c) slurrying the thus isolated gatifloxacin in a lower alkanol having 1-4 carbon atoms for a period of at least about 2 hours; and d) separating the crystalline form of gatifloxacin from the slurry. 23. The method of claim 22, wherein the lower alcohol is ethanol. 24. A crystalline form of gatifloxacin characterized in that its X-ray reflection is about 7.4, 8.9, 9.6, 11.4, 12.2, 12.9, 14.1, 16.7, 21.2, 21.8, 24.1, and 26.0±0.2 at 2θ angles degrees. 25. The crystalline form of gatifloxacin according to claim 24, which has an X-ray diffraction pattern substantially as shown in FIG. 6 . 26. the method for preparing the gatifloxacin crystal form of claim 24, it comprises the following steps: a) crystallizing gatifloxacin from acetonitrile; b) separation of gatifloxacin crystallized out from acetonitrile; c) slurring the gatifloxacin thus isolated in ethanol for about 2 hours or less; and d) Isolating the T1 crystal form of gatifloxacin. 27. A process for the preparation of gatifloxacin sesquihydrate, the process comprising the step of maintaining gatifloxacin Form P at ambient temperature for a period of time sufficient to effect conversion to the sesquihydrate . 28. The method of claim 27, wherein the retention time is about 1 month. 29. A process for preparing crystalline form Ω of gatifloxacin comprising the step of drying crystalline form K of gatifloxacin at about 50°C and a pressure of about 10 mmHg. 30. The method of claim 29, wherein the drying time is about 24 hours. 31. A process for the preparation of crystalline form J of gatifloxacin comprising the step of drying crystalline form K of gatifloxacin at about 50°C and atmospheric pressure. 32. The method of claim 31, wherein the drying time is from about 12 to about 18 hours. 33. A process for the preparation of crystalline form Ω of gatifloxacin comprising the step of maintaining crystalline form L of gatifloxacin at ambient temperature for a period of time sufficient to effect conversion to crystalline form Ω. 34. The method of claim 33, wherein the retention time is about 2 months. 35. A process for the preparation of gatifloxacin hemihydrate comprising the step of maintaining crystalline form M of gatifloxacin at room temperature for a period of time sufficient to effect conversion to the hemihydrate. 36. A method for preparing crystalline form T1 of gatifloxacin, comprising the step of heating gatifloxacin at 50°C. 37. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one crystalline form L, M, P, Q, S and T1 of gatifloxacin.

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