MX2008000137A - Tigeycline crystalline forms and processes for preparation thereof - Google Patents

Abstract

The present invention relates to solid crystalline Tigecycline, and crystalline forms thereof.

Description

TIGECICLINE CRYSTALLINE FORMS AND PROCESSES FOR PREPARATION CROSS REFERENCE TO RELATED REQUESTS [0001] The present application claims the benefit of the filing date of the provisional patent application of the United States No. 60 / 794,763 filed on April 24, 2006, and of the provisional patent application of the United States No. 60 / 796,800 2006, filed May 1, 2006, the descriptions of which are incorporated herein by reference.

FIELD OF THE INVENTION [0002] The present invention relates to crystalline tigecycline forms and to the processes for their preparation.

BACKGROUND OF THE INVENTION [0003] Tigecycline (CAS 220620-09-7), (4S, 4aS, 5aR, 12aS) -9- (2- (tert-butylamino) acetamido) -4,7-bis (dimethylamino) -1 , 4, a, 5, 5a, 6, 11, 12a-octahydro-3, 10, 12, 12a-tetrahydroxy-l, 11-dioxo-2-naphthacenecarboxamide, is the first drug of a new generation of tetracycline antibiotics called glycylcyclines. Tigecycline has a broader range of activity than the original drug tetracycline and its analogues discovered so far. In addition, it can be administered less frequently and / or at lower doses.

[0004] Tigecycline has been introduced and marketed by yet under the trade name TIGACIL® and is especially indicated against acute lethal infections caused by gram-negative bacteria. TIGACIL® is marketed as a lyophilized powder or cake for intravenous injection. The drug substance does not contain excipients or preservatives. [0005] Tigecycline has the following structure: Tigecycline: C29H39N5O8 PM: 585.65 g / mol and was disclosed in U.S. Patent Nos. 5,494,903 and 5,284,963. [0006] U.S. Patent No. 5,675,030 describes a specific method for obtaining solid tigecycline by evaporation of a dichloromethane solution. The request of P.C.T. No. WO 2006128150 describes crystalline forms and their processes. [0007] The present invention relates to the physical properties of the solid state of tigecycline. These properties they can be influenced by the control of the conditions in which tigecycline is obtained in solid form. The physical properties of the solid state include, for example, the flowability of the ground solid. The ability to flow affects the ease of handling the material during processing in a pharmaceutical product. When the particles of the powdered compound do not flow with respect to each other easily, a formulator should require the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate. [0008] Another important property of the solid state of a pharmaceutical compound is its dissolution rates in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an active ingredient administered orally can reach the patient's bloodstream. The dissolution rate should also be considered in the formulation of syrups, elixirs and other liquid medications. The solid state form of a compound can also affect its behavior on compaction and its deposit stability. [0009] These practical physical characteristics are influenced by the conformation and orientation of the molecules in the unit cell, which defines a form particular polymorphic of a substance. The polymorphic form can give rise to a thermal behavior different from the amorphous material or another polymorphic form. The thermal behavior is measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to differentiated spectroscopic properties that can be detected by X-ray crystallography of dust, 13C NMR solid state spectrometry, and infrared spectrometry. [0010] Generally, the crystalline solid has greater chemical and physical stability than the amorphous form, and the forms with low crystallinity. They can also exhibit higher hygroscopicicad, mass properties, and ability to flow. [0011] The discovery of new polymorphic forms of a pharmaceutical utility compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. This increases the repertoire of materials available to a formula scientist to design, for example, a pharmaceutical dosage form of a drug with a release profile of interest or other desired characteristics. There is a need in the art for crystalline tigecycline and its polymorphic forms.

EXTRACT OF THE INVENTION [0021] In a first embodiment of the present invention, a tigecycline solvate is provided. Preferably, the solvate is a methyl ethyl ketone solvate ("MEK") or an ethyl acetate solvate. [0013] In another embodiment of the present invention, a crystalline form of tigecycline characterized by X-ray powder diffraction reflections is provided at about 4.2, 9.1, 11.4, 14.0 and 15, 7 + 0.2 degrees two ^ theta. This crystalline form can be an ethyl acetate solvate or a MEK solvate. [0014] In another embodiment, the present invention provides a crystalline form of tigecycline, characterized by X-ray powder diffraction reflections at approximately 9.5, 9.8, 18.1, 20.2 and 21.6 ± 0.2 degrees two-theta. [0015] In another aspect, the present invention provides methods for preparing the above crystalline forms. [0016] In another aspect, the present invention provides a pharmaceutical composition comprising at least one of the crystalline forms of tigecycline described above, prepared by the processes of the present invention, and one or more pharmaceutically acceptable excipients. [0017] The present invention also provides a process for the preparation of a pharmaceutical formulation comprising combining one or more of the crystalline forms of tigecycline described above with at least one pharmaceutically acceptable excipient. [0018] The present invention also provides the use of at least one of the crystalline forms of tigecycline described above for the manufacture of a pharmaceutical composition for the treatment of infections.

BRIEF DESCRIPTION OF THE FIGURES [0019] Figure 1 illustrates a diffraction pattern by lightning X powder for amorphous tigecycline. [0020] Figure 2 illustrates a diffraction pattern by lightning X powder for a crystalline form of tigecycline characterized by X-ray powder diffraction reflections at 4.2, 9.1, 14.0 and 15.7 ± 0.2 degrees two-theta (as prepared by the Example 1 ) . [0021] Figure 3 illustrates a powder X-ray diffraction pattern for a crystalline form of tigecycline characterized by X-ray powder diffraction reflections at approximately 9.5, 9.8, 18.1, 20.2 and 21.6 ± 0.2 degrees two-theta (as prepared by example 2).

DETAILED DESCRIPTION OF THE INVENTION [0022] As used herein, the term "room temperature" refers to a temperature between about 15 ° C to about 30 ° C. In addition, the term "spontaneous evaporation" refers to the evaporation of a solvent from a mixture, solution or suspension without manipulating the temperature and / or pressure of the environment of said mixture, solution or suspension. In general, said spontaneous evaporation takes place at approximately room temperature and approximately at atmospheric pressure. [0023] As used herein, "solvate" refers to any crystalline form that incorporates solvent at a level of more than about 1% by weight. [0024] U.S. Patent No. 5,675,030 mentions the isolation of solid tigecycline by evaporation of a dichloromethane solution. According to FIG. 1, the repetition of evaporation from the dichloromethane stage results in amorphous tigecycline. [0025] The present invention provides tigecycline solvate. Preferably, the solvate is a MEK solvate or an ethyl acetate solvate. [0026] The present invention provides a crystalline form of tigecycline, characterized by powder X-ray diffraction reflections at approximately 4.2, 9.1, 11.4, 14.0 and 15.7 ± 0.2. two-theta degrees. This crystalline form can also be characterized by powder X-ray diffraction reflections at about 8.3, 16.6, 18.1, 21.0 and 21.7 ± 0.2 degrees two-theta, or substantially as it is shown in FIG. 2. Preferably, this crystalline form of tigecycline is substantially in pure form, with less than about 20% of any other form of tigecycline present, more preferably with less than about 10% of any other form of tigecycline present, with even greater preference with less than about 5% of any other form of tigecycline present, and most preferably with less than about 5% of any other form of tigecycline present. This crystalline form can be a solvate of MEK or ethyl acetate, depending on the solvent from which it is prepared. [0027] When this form is prepared from MEK, it shows a weight loss of about 11.7% as measured by thermal gravimetric analysis ("TGA") in the range of about 25 ° C to about 180 ° C. Kart Fisher measured a water content of approximately 1.4% for this solvate. This form of preference is in monosolvate of MEK, 12% solvento and accordingly contains about 10% to about. [0028] When this form was prepared from ethyl acetate, it showed a weight loss of about 16.5% as measured by TGA in the range of about 25 ° C to about 180 ° C. Karl Fisher measured a water content of approximately 0.7% by this solvate. [0029] The present invention provides processes for the preparation of the tigecycline form comprising preparing and maintaining a mixture of tigecycline, preferably amorphous tigecycline, in a solvent selected from a saturated or aromatic C5-C8 hydrocarbon, a low-point ketone. of boiling and a low-boiling ester. Preferably, the mixture is maintained for at least about one hour. More preferably, the solvent evaporates spontaneously. [0030] A ketone or low-boiling ester is preferably a ketone or ester having a boiling point of less than about 120 ° C. [0031] Preferably, the solvent is selected from benzene, toluene, xylene, MEK or ethyl acetate. More preferably, the solvent is toluene. [0032] Preferably, the mixture or solution is maintained at a temperature between about 0 ° C to about 40 ° C, more preferably, at room temperature or below. With even greater preference, the mixture is stirred. [0033] Generally, the mixture is maintained for at least about 0.5 hours, preferably for more than about 6 hours, more preferably for between about 12 hours to about 16 hours, although this period will vary according to the amount of material that crystallizes, among other factors. The periodic X-ray diffraction patterns can be recorded until the desired shape is obtained. [0034] Preferably, the solvent is in a tigecycline weight-weight ratio of about 10 to about 30, preferably in a weight-to-weight ratio of about 20. Preferably, when MEK is used as a solvent, the precipitate obtained it is dried, with even greater preference, the precipitate is dried for about 16 hours at about 40 ° C. [0035] The present invention provides another crystalline form of tigecycline, characterized by X-ray powder diffraction reflections at approximately 9.5, 9.8, 18.1, 20.2 and 21.6 ± 0.2 degrees two -theta. This crystalline form can also be characterized by X-ray powder diffraction reflections at about 6.8, 12.1, 12.6, 23.3 and 26.8 ± 0.2 degrees two-theta, or substantially as described in FIG. 3. Preferably, this crystalline form of tigecycline is substantially in pure form, and has less than about 20% of, any other form of tigecycline, more preferably less than 10% of any other form of tigecycline, with even greater preference Tigecycline has less than about 5% of any other form of tigecycline, and with maximum Preference has approximately 2% of any other form of tigecycline. [0036] A weight loss of up to about 1.1% was measured by TGA in the range of about 25 ° C to about 180 ° C. The water content was measured in up to about 1% by Karl Fisher. [0037] The present invention provides processes for the preparation of the crystalline form of tigecycline, characterized by X-ray powder diffraction reflections at approximately 9.5, 9.8, 18.1, 20.2 and 21.6 ± 0.2 degrees two-theta, comprising preparing and maintaining a mixture of tigecycline, preferably amorphous tigecycline, in a solvent selected from C 1-5 nitrile, for a period to allow evaporation of the solvent and formation of precipitate. Preferably, the evaporation is carried out at a rate at which a crystalline form is obtained. More preferably, the solvent evaporates spontaneously. Alternatively, 1 suspension can be filtered. [0038] Preferably, the solvent is acetonitrile. More preferably, the solvent is in a tigecycline weight-to-weight ratio of about 10 to about 30, with even more preferably the solvent being in a weight-to-weight ratio of about 20.

[0039] Preferably, the mixture is maintained at a temperature of from about -10 ° C to about 30 ° C, more preferably from about 0 ° C to about 25 ° C. With even greater preference, the mixture is maintained for at least about 1 hour, although it should be noted that according to certain variables, including the amount of material that crystallizes, this time varies. [0040] Periodic powder diffraction patterns can be obtained in order to determine the necessary period. Preferably, the mixture is stirred. Optionally, the precipitate can be dried, for example, overnight at about 30 ° C to about 50 ° C, preferably at about 40 ° C. [0041] In another aspect, the tigecycline form can be prepared by providing a solution of tigecycline, preferably in an amorphous form, in dimethoxyethane ("DME"), and mixing an amount of n-heptane to obtain a suspension. Generally, a suspension is obtained after at least about an hour, although it should be noted that this time may vary according to certain variables, including the amount of material that crystallizes. Periodic X-ray powder diffraction patterns can be obtained in order to determine the necessary period. Preferably, the suspension can then be stirred. From Preferably, the precipitated form is recovered from the suspension and dried in vacuum. [0042] The crystalline forms of tigecycline of the present invention have a maximum particle size of about 300 μt. Preferably, these forms of tigecycline have a particle size of less than about 200. more preferably they have a particle size of less than about 100 im, and most preferably they have a particle size of less than about 50.

[0043] The present invention also provides a process for preparing amorphous tigecycline by exposure to the crystalline form of tigecycline characterized by X-ray diffraction reflections at approximately 4.2, 9.1, 11.4, 14.0 and 15, 7 ± 0.2 degrees two-theta at 100% ambient humidity for 7 days at room temperature. [0044] In another aspect of the present invention, the present invention provides a pharmaceutical formulation comprising one or more of the crystalline forms of tigecycline of the present invention. This pharmaceutical composition may further comprise at least one pharmaceutically acceptable excipient. [0045] In another aspect of the present invention, the present invention provides a pharmaceutical composition comprising any one or more of the crystalline forms of tigecycline of the present invention prepared by the processes of the present invention, and one or more pharmaceutically acceptable excipients. [0046] The present invention also comprises a process for preparing a pharmaceutical formulation comprising combining one or more of the crystalline forms of tigecycline of the present invention, with at least one pharmaceutically acceptable excipient. [0047] The present invention also provides the use of a crystalline form of tigecycline, for example one of the crystalline forms of the present invention, for the manufacture of a pharmaceutical composition for the treatment of infections, including bacterial infections, infections by gram-negative bacteria and lethal infections. [0048] The pharmaceutical formulations of the present invention contain at least one of the crystalline forms of tigecycline of the present invention. In addition to crystalline tigecycline, the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients including disintegrants, glidants, binders, diluents, lubricants, flavoring agents and colorants are added to the formulation for various purposes.

[0049] Diluents increase the mass of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier to handle for the patient or caregiver. The diluents for the solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrans, dextrin, dextrose, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (for example, Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and / or talc. [0050] Solid pharmaceutical compositions that are compacted in a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active component and other excipients together after compression. Binders for solid pharmaceutical compositions include, for example, acacia, alginic acid, carbomer (e.g., carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ®), hydroxypropylmethylcellulose (eg, ethocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone for example, Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and / or starch. [0051] The dissolution rate of a solid pharmaceutical composition compacted in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include, for example, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (eg, Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg, Kollidon®, Polyplasdone® ), guar gum, aluminum magnesium silicate, methylcellulose, microcrystalline cellulose, potassium polacrilin, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (for example, Explotab®) and / or starch. [0052] Glidants may be added to improve the flowability of an uncompacted solid composition and to improve the accuracy of the dosage. The excipients that can act as glidants include, for example, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and / or tribasic calcium phosphate. [0053] When a dosage form such as a tablet is prepared by compaction of a powder composition, the composition is subjected to the pressure of a punch and a matrix. Some excipients and active elements have a tendency to adhere to punch and die surfaces, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of product from the matrix. Lubricants include, for example, 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, acid stearic, talc and / or zinc stearate. [0054] Flavoring and / or flavor improving agents make the dosage form more palatable to the patient. Flavoring and / or flavor enhancing agents common for pharmaceutical products that can be included in the composition of the present invention include, for example, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethylmaltol and / or acid tartaric [0055] The solid and liquid compositions are also colored by any dye acceptable for pharmaceutical use to improve its appearance and / or facilitate the identification of the product and unit dose level.

[0056] In the liquid pharmaceutical compositions of the present invention, tigecycline and any other solid such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin. [0057] The liquid pharmaceutical compositions may contain emulsifying agents to disperse an active component or other excipient that is not soluble in the liquid carrier evenly throughout the composition. The emulsifying agents that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, red algae, pectin, methylcellulose, carbomer, cetostearyl alcohol and / or cetyl alcohol . [0058] The liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the palatal taste of the product and / or coat the gastrointestinal tract lining. Such agents include, for example, acacia, alginic acid, bentonite, carbomer, calcium or sodium carboxymethylcellulose, ketostearyl alcohol, methylcellulose, ethylcellulose, guar gelatin gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate. , propylene glycol alginate, sodium alginate, sodium starch glycolate, tragacanth starch and / or xanthan gum. [0059] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar can be added to improve flavor. [0060] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyltoluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid can be added at levels safe for ingestion to improve preservation stability. [0061] According to the present invention, a liquid composition may also contain a buffer solution such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. The selection of excipients and the quantities used can be easily determined by the scientific formulation based on experience and consideration of standard procedures and field reference works. [0062] The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. Doses include adequate doses for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular and intravenous), inhalatory and ophthalmic administration. While the most appropriate administration in each case given will depend on the nature and severity of the disease treated, the most preferred route of the present invention is oral. The dosages may conveniently be presented in unit dosage forms and prepared by any method well known in the pharmaceutical arts. [0063] The dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, lozenges and orally disintegrating tablets, in addition to syrups, suspensions and liquid elixirs. [0064] The dosage form of the present invention can be a capsule containing the composition, preferably a solid composition of the invention powder or granulated, either in a hard or soft shell. The shell may be gelatin and optionally contains a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant. [0065] The active component, tigecycline and excipients can be formulated into compositions and dosage forms according to methods known in the art. [0066] A composition for the preparation of tablets or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active components and excipients in powder form are combined and then further mixed in the presence of a liquid, typically water, which causes the powders to agglomerate into granules. The granulate sieves and / or grinds, dries and then sieves and / or grinds to the desired particle size. The granulate can then form tablets or other excipients can be added prior to tabletting, such as a glidant and / or a lubricant. [0067] A composition for forming tablets can be prepared in a conventional manner by dry combination. For example, the combined composition of the active components and excipients can be compacted into a seal or sheet and then crushed into compacted granules. The compacted granules can be further compressed into a tablet. [0068] As an alternative to dry granulation, a combined composition can be directly compressed into a compacted dosage form by compression techniques. Direct compression produces a more uniform tablet without granules. The excipients that are particularly well suited for tabletting by direct compression include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients by direct compression is known to those having experience and skills in the art in particular formulation challenges of direct compression tablet preparation. [0069] A capsule filling of the present invention may comprise any of the combinations and the granulates previously mentioned that were described with reference to the tablet formation, but do not undergo a final tabletting step. [0070] The present invention also provides methods comprising the administration of a pharmaceutical formulation of tigecicin. Tigecycline is preferably formulated for administration to a mammal, preferably a human, by injection. Tigecycline can be formulated, for example, as a viscous liquid solution or suspension, preferably a clear injectable solution. The formulation may contain one or more solvents. A suitable solvent can be selected considering the chemical and physical stability of the solvent at various novel pH, viscosity (which would allow the ability to apply with syringe), fluidity, boiling point, miscibility and purity. Suitable solvents include USP alcohol, benzyl alcohol NF, benzyl benzoate USP, and USP castor oil. Additional substances can be added to the formulation such as buffer solutions, solubilizers and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. [0071] The present invention also provides methods of treating infections in mammals, preferably humans, by administering an amount therapeutically effective of a crystalline form of tigecycline, described herein. [0072] The invention is already described, this is further illustrated with the following non-limiting examples. Having thus described the invention with reference to particularly preferred embodiments and illustrative examples, those skilled in the art may consider modifications to the described and illustrated invention not departing from the spirit and scope of the invention described in the specification. descriptive The Examples are set forth to aid the understanding of the invention but are not intended and should not be construed in any way as a limit of their scope. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those skilled in the art and are described in numerous publications. Polymorphism in Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences, Volume 95 can be used as a guide. All references mentioned herein are incorporated in their entirety.

EXAMPLES Experimental [0073] X-ray powder diffraction data were obtained by means of methods known in the art, using a SCINTAG model X 'TRA X-ray powder diffractometer equipped with a solid state detector. Copper radiation of 1.5418 Á was used. A round aluminum sample container with zero background was used. The scan parameters included: range: 2 ° to 40 ° 20; Sweep mode: continuous sweep; Step size: 0.05 °. The speed was 3 ° / min using spin. All peak positions are within ± 0.2 degrees two theta.

Example 1: Preparation of a form of a crystalline form of tigecycline characterized by a powder XRD pattern having peaks at approximately 4.2, 9.1, 11.4, 14.0 and 15.7 + 0.2 degrees 2-theta (Form I) [0074] The amorphous tigecycline powder was stirred with toluene at room temperature in an open container until the solvent was evaporated. The remaining solid was collected and identified as Form I.

Example 2: Preparation of a crystalline tigecycline form characterized by powder XRD pattern having peaks at approximately 9.5, 9.8, 18.1, 20.2, and 21.6 ± 0.2 degrees 2-theta (Form II) [0075] The amorphous tigecycline powder was stirred with acetonitrile at room temperature in a open container until the solvent evaporated. The remaining solid was collected and identified as Form II.

Example 3: Preparation of Tigecycline Forms I and II [0076] A tigecycline suspension was prepared by mixing a sample of solid tigecycline and a solvent listed in Table 1 in approximate amounts corresponding to the ratios listed in the table. 1. The mixture was then stirred under the conditions specified in Table 1. Filtering the suspension and air-drying the cake provided the so-called wet material. In certain experiments (indicated in said table), the wet material was further dried overnight at about 40 ° C under vacuum and the solid obtained in this way is referred to as dry material.

Table 1. Results of the experiments according to Example 1 o / n = all night Example 4: Preparation of Tigecycline Form II [0077] A solid tigecycline sample was dissolved in 1,2 * dimethoxyethane, n-heptane was added to the resulting solution to induce precipitation. The formed suspension was stirred for about one hour at room temperature and then filtered. The solid thus obtained was dried overnight at about 40 ° C under vacuum to provide Form II.

Example 5: Preparation of amorphous tigecycline Form I, prepared from ethyl acetate (approximately 80 mg), was exposed to approximately 100% ambient humidity ("HA") for about 7 days at about room temperature. After exposure, the crystalline form was controlled by XRD.

Claims (59)

1. A crystalline form of tigecycline characterized by an XRD pattern of powder having peaks at approximately 4.2, 9.1, 11.4, 14.0 and 15.7 ± 0.2 degrees two-theta.

2. The crystalline tigecycline according to claim 1, characterized by an XRD pattern of powder that also has peaks at approximately 8.3, 16.6, 18.1, 21.0, and 21.7 ± 0.2 degrees 2 -theta.

3. The crystalline tigecycline according to claim 2, further characterized by an XRD pattern of powder as shown in Fig. 2.

4. The crystalline tigecycline according to any of the preceding claims, wherein said crystalline form is a tigecycline methyl ethyl ketone solvate.

5. The crystalline tigecycline according to claim 4, further characterized by a weight loss of approximately 11.7% compared to crystallized tigecycline, determined by thermal gravimetric analysis.

6. The crystalline tigecycline according to any of claims 1-3, wherein said crystalline form is a tigecycline ethyl acetate solvate.

7. The crystalline tigecycline according to claim 6, further characterized by a weight loss of approximately 16.5% compared to crystallized tigecycline, determined by thermal gravimetric analysis.

8. The crystalline tigecycline according to any of the preceding claims, wherein said crystalline tigecycline is present in a composition having less than about 20% of any other form of tigecycline.

9. The crystalline tigecycline according to claim 8, wherein said crystalline tigecycline is present in a composition having less than about 10% of any other form of tigecycline.

10. The crystalline tigecycline according to claim 9, wherein said crystalline tigecycline is present in a composition having less than about 5% of any other form of tigecycline.

11. The crystalline tigecycline according to claim 10, wherein said crystalline tigecycline is present in a composition having less than about 2¾ of any other form of tigecycline.

12. The crystalline tigecycline according to any of the preceding claims, wherein said crystalline tigecycline is present in a substantially pure form.

13. The crystalline tigecycline according to any of the preceding claims, wherein said crystalline tigecycline has a maximum particle size of approximately 300 μp ?.

14. The crystalline tigecycline according to claim 13, wherein said crystalline tigecycline has a maximum particle size of about 200 μp.

15. The crystalline tigecycline according to claim 14 has a maximum particle size of approximately 100 μp ?.

16. The crystalline tigecycline according to claim 15 has a maximum particle size of approximately 50 μp ?.

17. A crystalline form of tigecycline characterized by an XRD pattern of powder having peaks at approximately 9.5, 9.8, 18.1, 20.2, and 21.6 ± 0.2 degrees 2-theta.

18. The crystalline tigecycline according to claim 17, further characterized by an XRD pattern of powder having peaks at about 6.8, 12.1, 23.3, and 26.8, ± 0.2 degrees 2-theta.

19. The crystalline tigecycline according to claim 17, further characterized by an XRD pattern of powder as described in Fig. 3.

20. The crystalline tigecycline according to any of claims 17-19, also characterized by a weight loss of about 1.1% compared to crystallized tigecycline, determined by thermal gravimetric analysis.

21. The crystalline tigecycline according to any of claims 17-20, wherein said crystalline tigecycline is present in a composition having less than about 20% of any other form of tigecycline.

22. The crystalline tigecycline according to claim 21, wherein said crystalline tigecycline is present in a composition having less than about 10% of any other form of tigecycline.

23. The crystalline tigecycline according to claim 22, wherein said crystalline tigecycline is present in a composition having less than about 5% of any other form of tigecycline.

24. The crystalline tigecycline according to claim 23, wherein said crystalline tigecycline is present in substantially pure form.

25. The crystalline tigecycline according to any of claims 17-24, wherein said crystalline tigecycline has a maximum particle size of about 300 μm.

26. The crystalline tigecycline according to claim 25, wherein said crystalline tigecycline has a maximum particle size of about 200 μ ??.

27. The crystalline tigecycline according to claim 26. wherein said crystalline tigecycline has a maximum particle size of about 100 μ ??.

28. The crystalline tigecycline according to claim 27, wherein said crystalline tigecycline has a maximum particle size of approximately 50 μp ?.

29. A process for preparing the crystalline form according to claim 1, comprising the crystallization of tigecycline from the solvent selected from a group consisting of a saturated C5-C8 hydrocarbon, an aromatic C5-Cg hydrocarbon, a lower ketone. boiling point and a low boiling ester.

30. The process according to claim 29, wherein said low boiling point ketone has a boiling point of less than about 120 ° C.

31. The process according to claim 29, wherein said low boiling ester has a boiling point of less than about 120 ° C.

32. The process according to claim 29, wherein said solvent is selected from the group consisting of the group toluene, benzene, xylene, methyl ethyl ketone and ethyl acetate.

33. The process according to claim 32, wherein said solvent is toluene.

34. The process according to claim, wherein said crystallization comprises the steps of: a) preparing a solution of tigecycline in said solvent; and b) evaporating said solvent to obtain said crystalline form.

35. The process according to claim 34, which also comprises the step of stirring said solution.

36. The process according to claims 34 and 35, wherein said solution is maintained at a temperature from about 0 ° C to about 40 ° C.

37. The process according to claim 36, wherein said solution is maintained at a temperature of about 15 ° C to about 30 ° C.

38. The process according to any of claims 34-37, wherein said solution is maintained for at least about 0.5 hours.

39. The process according to any of claims 29-34, wherein said solvent is in a volume to weight ratio of tigecycline from about 10 to about 30.

40. The process according to claim 39, wherein said solvent is in a volume to weight ratio of tigecycline of about 20.

41. A process for preparing the crystalline form of tigecycline according to claim 17, comprising the crystallization of tigecycline from a solvent comprising a saturated Ci_5 nitrile.

42. The process according to claim 41, wherein said solvent is acetonitrile.

43. The process according to claim 41, wherein said crystallization comprises the steps of: a) preparing a solution of tigecycline in said solvent; and b) evaporating said solvent to obtain said crystalline form.

44. The process according to claim 43, wherein said solution is maintained at a temperature of about - * 10 ° C to about 30 ° C.

45. The process according to claim 44, wherein said solution is maintained at a temperature from about 0 ° C to about 25 ° C.

46. The process according to any of claims 43-45, wherein said solution is maintained for about one hour.

47. The process according to claims 43-46, which also comprises the step of agitating said solution.

48. A process for preparing the crystalline form of tigecycline according to claim 17, comprising crystallization of tigecycline in a mixture of dimethoxyethane and n-heptane.

49. The process according to claim 48, wherein said crystallization comprises the steps of: a) preparing a solution of tigecycline in dimethoxyethane; b) mixing n-heptane in said solution to obtain a suspension; and c) recovering said crystalline tigecycline from said suspension.

50. The process according to claim 49, which also comprises the step of agitating said suspension.

51. A pharmaceutical formulation comprising at least one form of crystalline tigecycline according to claims 1 and 17 and a pharmaceutically acceptable excipient.

52. The pharmaceutical formulation according to claim 51, wherein said excipient is selected from the group consisting of diluents, binders, disintegrants, glidants, lubricants, flavoring agents and colorants.

53. A process for preparing pharmaceutical formulations comprising at least one form of crystalline tigecycline according to claims 1 and 17 and a pharmaceutically acceptable excipient.

54. A pharmaceutical formulation comprising at least one form of crystalline tigeclicine according to claims 1 and 17 prepared according to the processes of the present invention, and a pharmaceutically acceptable excipient.

55. The pharmaceutical formulation according to claim 54, wherein said excipient is selected from the group consisting of diluents, binders, disintegrants, glidants, lubricants, flavoring agents and colorants.

56. Use of a compound according to claim 1 or 17 for the preparation of a medicament for treating a mammal suffering from infections.

57. A process for preparing amorphous tigecycline comprising the exposure of said crystalline form in accordance with claim 1 at an ambient humidity of about 100% for about 7 days.

58. Tigecycline solvate.

59. The tigecycline solvate according to claim 58, wherein said solvate is selected from the group consisting of a methyl ethyl ketone solvate and an ethyl acetate solvate.