CN101282955A - Crystalline forms of docetaxel and processes for their preparation - Google Patents

Abstract

This invention provides novel crystal forms of docetaxel, as well as pharmaceutical compositions and treatment methods. A novel method for preparing crystalline docetaxel is also provided.

Description

Crystal form of docetaxel and preparation method thereof

Cross References to Related Applications

This application claims U.S. Provisional Application No. 60/725,321, filed October 12, 2005; U.S. Provisional Application No. 60/726,647, filed October 17, 2005; and U.S. Provisional Application No. 60/736,870 entitlement. These applications are incorporated herein by reference.

field of invention

The present invention includes the solid state chemistry of docetaxel. In certain embodiments, new crystalline forms of docetaxel and methods for their preparation are provided.

Background of the invention

Docetaxel is an antineoplastic agent belonging to the taxoid family. Docetaxel is a semisynthetic anticancer agent obtained by chemically modifying a taxane core (called 10-deacetylbaccatin III or 10-DAB) extracted from the leaves and bark of the European or Indian yew tree. The chemical name of docetaxel is: (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester, 5(β), 20-epoxy-1,2 (α), 4, 7(β), 10(β), 13(α)-hexahydroxytaxane-11-en-9-one 4-acetate 2-benzoate trihydrate. The structural formula of docetaxel is:

Docetaxel is a white to off-white powder with an empirical formula of C ₄₃ H ₅₃ NO ₁₄ ·3H ₂ O and a molecular weight of 861.9.

。TAXOTERE

注射剂是澄清的黄色至褐黄色的粘性溶液。销售的TAXOTERE

注射剂为单剂量的小瓶，包含20毫克(0.5毫升)或者80毫克(0.2毫升)的多西他赛(无水)。Docetaxel is available as a concentrated injection under the trade name TAXOTERE

. TAXOTERE

The injection is a clear yellow to brown-yellow viscous solution. TAXOTERE for sale

Injection is provided as a single-dose vial containing 20 mg (0.5 mL) or 80 mg (0.2 mL) of docetaxel (anhydrous).

It is a property of certain molecules and molecular complexes that different crystal forms (polymorphs) exist. A molecular or salt complex that produces a variety of solids with unique physical properties such as melting points, X-ray diffraction patterns, infrared absorption fingerprints, and NMR spectra. Said crystalline form produces a different thermal behavior than amorphous material or other crystalline forms. Thermal behavior, measured in the laboratory using techniques such as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), can be used to distinguish certain polymorphic forms from others type. The difference in physical properties of different crystal forms is due to the orientation and intermolecular interaction of adjacent molecules (complexes) in a large number of solids. Thus, a polymorph is a distinct solid having the same molecular formula, but with uniquely advantageous and/or unfavorable physical properties compared to other crystalline forms in the polymorph family. These properties can be influenced by controlling the conditions under which the salt is obtained in solid form.

Exemplary solid state physical properties include flowability of comminuted solids. Flowability affects how easily a material can be handled when it is made into a drug. If the particles of a powdered compound do not flow easily through each other, the formulation specialist must take this into account when developing a tablet or capsule, which may require the use of glidants (e.g., colloidal silicon dioxide, talc, starch or calcium phosphate).

One of the most important physical properties of drug polymorphs is their solubility in aqueous solutions, especially in the gastric fluid of patients. For example, while absorption through the gastrointestinal tract is slow, it is often desirable for drugs that are not stable to the patient's stomach or intestinal conditions to dissolve slowly so that the drug does not accumulate under deleterious circumstances.

The solid-state characteristics of docetaxel are reported in J. Phys. IV France 11 (2001). This article discloses stoichiometric hydrates (trihydrates) containing three molecules of water per molecule of drug. The article also reports that "in nitrogen vapor, in dynamic dry air (0% relative humidity), or under heat, docetaxel dehydrates and forms an anhydrous crystalline phase".

U.S. Patent No. 6,022,985, according to its abstract, discloses "a preparation of 4-acetoxy-2.α-benzoyloxy-5.β,20-epoxy-1,7.β,10β-tri Method for Hydroxy-9-Oxo-Tax-11-ene-13.α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate Trihydrate , characterized in that: 4-acetoxy-2.α-benzoyloxy-5.β,20-epoxy-1,7.β,10β-trihydroxy-9-oxo-taxane-11 -en-13.α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is a mixture of water and fatty alcohols containing 1 to 3 carbon atoms crystallization in a medium, and then the resulting product is dried under specified conditions of temperature, pressure and humidity”.

U.S. Patent No. 6,838,569, according to its abstract, discloses "a process for the conversion of paclitaxel or docetaxel to the respective trihydrates, ... the process comprising dissolving paclitaxel or docetaxel in an alkane and In a mixture of chlorinated alkanes, a crude product with a content of 65 to 75% is obtained. The crude product is dissolved in an alkyl ketone, and then an alkane is added to obtain a product. ... The product whose chromatographic purity has been increased is dissolved in an aliphatic nitrile, and water is added to make Precipitation of taxane trihydrate".

The discovery of new forms of pharmaceutical compounds offers the opportunity to improve the performance characteristics of pharmaceuticals. This expands the range of substances available to the formulation scientist with which to design, for example, pharmaceutical dosage forms with targeted release properties or other desired properties. Additional polymorphic forms can also assist in determining the polymorphic content of a batch of active pharmaceutical ingredients, for example by providing reference standards for use in XRD instruments.

Summary of the invention

In one embodiment, the invention includes a crystalline form of docetaxel characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 7.3, 8.8, 13.7, 17.2, and 20.2 ± 0.2° 2Θ, an FTIR spectrum at There are peaks at about 1098, 1165, 1248, 1701 and 1720 cm ^-1 .

Another embodiment of the invention includes a method of preparing crystalline docetaxel, wherein the crystalline docetaxel is characterized by data selected from the group consisting of: powder XRD patterns at about 7.3, 8.8, 13.7, 17.2, and 20.2±0.2° 2θ with peaks at 1098, 1165, 1248, 1701 and 1720 ^cm in the FTIR spectrum, the method comprising crystallizing crystalline docetaxel from a mixture of methyl isobutyl ketone (MIBK) and an organic anti-solvent .

Another embodiment of the invention includes a method of preparing crystalline docetaxel characterized by major X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5, and 16.9 ± 0.2° 2Θ, said The method comprises precipitating a crystalline form of docetaxel from a mixture of a solvent and an organic anti-solvent, wherein the solvent is selected from the group consisting of: acetone and ethyl acetate, acetone and tert-butanol, tetrahydrofuran (THF), ethyl acetate, tert-butyl Alcohol, ethanol and mixtures thereof.

In one embodiment, the present invention includes a pharmaceutical composition comprising a pharmaceutically effective amount of crystalline docetaxel and at least one pharmaceutically acceptable excipient, wherein the crystalline docetaxel is characterized by being selected from Data: Powder XRD pattern has peaks at about 7.3, 8.8, 13.7, 17.2 and 20.2±0.2° 2Θ, FTIR spectrum has peaks at about 1098, 1165, 1248, 1701 and 1720 cm ⁻¹ .

Another embodiment of the present invention includes a method of preparing a pharmaceutical composition comprising the step of combining crystalline docetaxel or a solution prepared from crystalline docetaxel with a pharmaceutically acceptable carrier, wherein the crystalline docetaxel Docetaxel is characterized by data selected from: powder XRD pattern with peaks at about 7.3, 8.8, 13.7, 17.2 and 20.2 ± 0.2° 2Θ, FTIR spectrum at about 1098, 1165, 1248, 1701 and 1720 cm ⁻¹ There are peaks.

Yet another embodiment of the present invention includes a pharmaceutical composition comprising a pharmaceutically effective amount of crystalline docetaxel prepared according to the method of the present invention and at least one pharmaceutically acceptable excipient.

Another embodiment of the invention includes the use of crystalline docetaxel for the manufacture of a medicament, wherein the crystalline docetaxel is characterized by data selected from the group consisting of powder XRD patterns at about 7.3, 8.8, 13.7, 17.2 and 20.2±0.2° There are peaks at 2θ, and the FTIR spectrum has peaks at about 1098, 1165, 1248, 1701 and 1720 cm ^-1 .

Yet another embodiment of the invention includes a method of treating a hyperplastic disorder (such as cancer) in a mammal (such as a human), said method comprising administering to the mammal a pharmaceutically acceptable amount of a drug containing or derived from crystalline docetaxel. A pharmaceutical composition prepared with docetaxel, wherein crystalline docetaxel is characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 7.3, 8.8, 13.7, 17.2 and 20.2 ± 0.2° 2Θ, an FTIR spectrum at about 1098 , 1165, 1248, 1701 and 1720cm ^-1 have peaks.

Brief description of the drawings

Figure 1 is a characteristic PXRD pattern of crystalline docetaxel of the present invention.

Fig. 2 is a characteristic FTIR diagram of crystalline docetaxel of the present invention.

Fig. 3 is a characteristic DSC thermogram of crystalline docetaxel of the present invention.

Figure 4 is a characteristic PXRD pattern of crystalline docetaxel characterized by major X-ray powder diffraction peaks at approximately 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2Θ.

Figure 5 is a characteristic DSC thermogram of crystalline docetaxel characterized by major X-ray powder diffraction peaks at approximately 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2Θ.

Detailed description of the invention

The invention provides a polymorphic form of docetaxel and a preparation method thereof. The solubility of the docetaxel polymorph of the present invention is greater than that of docetaxel trihydrate.

In one embodiment, the invention includes a crystalline form of docetaxel characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 7.3, 8.8, 13.7, 17.2, and 20.2 ± 0.2° 2Θ, an FTIR spectrum at There are peaks at about 1098, 1165, 1248, 1701 and 1720 cm ^-1 . The crystalline form is further characterized by a powder XRD pattern having peaks at approximately 4.9, 12.5, 13.1, 18.8 and 19.8 ± 0.2° 2Θ. The XRD pattern of the crystalline form of docetaxel of the present invention is basically shown in FIG. 1 . The crystalline form is further characterized in that the FTIR spectrum has peaks at about 719, 848, 957, 3429 and 3461 cm ⁻¹ . The FTIR spectrum of the crystalline form of docetaxel of the present invention is basically shown in FIG. 2 . The crystal form is further characterized in that: the DSC thermogram has endothermic peaks at about 30°C to about 70°C and 173°C. The DSC thermogram of the crystalline form of docetaxel of the present invention is basically shown in FIG. 3 .

The crystalline form of the present invention is anhydrous. "Anhydrous" means that the crystalline form contains no more than about 1.0% water, or contains other solvents in the crystalline structure. The crystals are anhydrous if the TGA weight loss does not exceed about 1.0%.

Another embodiment of the present invention includes a method of preparing crystalline docetaxel of the present invention comprising crystallizing crystalline docetaxel from a mixture of methyl isobutyl ketone (MIBK) and an organic anti-solvent.

Preferably, the method for crystallizing crystalline docetaxel comprises the following steps: combining docetaxel in MIBK with an organic anti-solvent to obtain a crystalline form. In one embodiment of the invention, docetaxel and MIBK are combined to form a solution. Preferably, MIBK is present in an amount of about 7 to about 10 volumes (ml/gram of docetaxel). Preferably, the mixture of MIBK and docetaxel is heated to about 80°C to about 120°C, more preferably to about 100°C, to facilitate dissolution of the docetaxel.

An organic anti-solvent is then preferably added to this solution to obtain a suspension. Preferably, the anti-solvent is selected from _C5 to _C8 linear and branched alkanes. More preferably, the anti-solvent is n-heptane. Preferably, the anti-solvent is added slowly to the solution, for example dropwise, over a period of about 30 minutes to about 4 hours. The anti-solvent is preferably present in an amount of about 3.5 to about 5 volumes (ml of anti-solvent/gram of starting solid).

The suspension can be cooled to increase precipitation and obtain higher yields of crystalline docetaxel according to the invention. Preferably, the suspension is cooled to about 25°C to about 30°C, more preferably to about 25°C. A mixture of MIBK and n-heptane is optionally added to the suspension to facilitate recovery of crystalline docetaxel. Preferably, crystalline docetaxel is recovered by filtering the suspension and washing with n-heptane.

Another embodiment of the present invention includes a crystalline form of docetaxel of the present invention having a maximum particle size of less than about 300 μm. "Maximum particle size" means that at least 99% of the particles contained in the sample have a size equal to or smaller than the largest particle size. The particle size of the crystalline form of docetaxel can be measured by methods such as sieving, sedimentation, coulter counter, microscopy, and/or low-angle laser light scattering (LALLS).

Another embodiment of the present invention includes the crystalline form of docetaxel of the present invention, wherein the content of any other form of docetaxel (especially docetaxel trihydrate) is less than about 5%, preferably less than about 2%. %, more preferably less than about 1%.

Another embodiment of the invention includes a method of making crystalline docetaxel, wherein the crystalline docetaxel is characterized by major X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2Θ. The crystalline docetaxel is further characterized by X-ray powder diffraction peaks at about 4.7, 9.2, 13.9, 20.4 and 23.5±0.2° 2Θ.

The method of the present invention for the preparation of crystalline docetaxel characterized by major X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2Θ comprising making docetaxel from a mixture of a solvent and an organic anti-solvent wherein the solvent is selected from the group consisting of: acetone and ethyl acetate, acetone and tert-butanol, tetrahydrofuran (THF), ethyl acetate, tert-butanol, ethanol and mixtures thereof. Preferably, the anti-solvent is selected from _C5 to _C8 linear and branched alkanes, more preferably n-heptane or n-hexane. In one embodiment, the anti-solvent is n-heptane, and the solvent is selected from acetone/tert-butanol, ethyl acetate, ethyl acetate/acetone, tetrahydrofuran and ethanol. In one embodiment, docetaxel and solvent are combined to form a solution or suspension, which is then combined with n-heptane or n-hexane to obtain a reaction mixture.

The solvent is preferably present in an amount of about 3.5 to about 5 volumes (ml/gram of docetaxel). Optionally, the reaction mixture of the solvent and docetaxel is heated, preferably to about 45°C to about 65°C, more preferably to about 50°C. In one embodiment, when the solvent is a mixture of acetone and tert-butanol, the suspension is not heated.

The anti-solvent is preferably added to the solution or suspension of docetaxel in the solvent. Preferably, the anti-solvent is n-heptane. Preferably, the anti-solvent is added slowly, eg dropwise, in an amount of about 3 to about 7 volumes (ml anti-solvent/gram docetaxel).

Preferably, the reaction mixture is cooled, especially after heating, to about 0°C to about 25°C, more preferably to about 10°C. Low temperature can increase the yield of the obtained crystalline form.

Preferably, the crystalline form is recovered by filtration and drying. Preferably, drying is performed under vacuum at about 55°C to about 80°C. Preferably, the resulting crystalline form is anhydrous. Optionally, docetaxel used as a starting material in a process for the preparation of crystalline docetaxel characterized by major X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2Θ , is crude docetaxel prepared by any method known in the art (eg, US Pat. No. 5,808,113).

Docetaxel of defined particle size can be prepared by known particle size reduction methods starting from crystals, powder aggregates and coarse powder of the new crystalline form of docetaxel. The main operation for conventional particle size reduction is to grind the feed material and classify the ground material by size.

A fluid energy mill or micronizer is a particularly preferred type of mill due to its ability to produce small size particles with a narrow diameter distribution. As is known to those skilled in the art, micronizers use the kinetic energy of collisions of particles suspended in a fast moving liquid stream to break up particles. An air jet mill is the preferred fluid energy mill. Suspended particles are injected under pressure into a circulating particle stream. Smaller particles are carried in the upper part of the pulverizer and swept into an outlet connected to a sizer (eg cyclone). The feedstock should first be ground to about 150 to 850 μm, which can be done using conventional ball mills, drum mills or hammer mills. It will be understood by those skilled in the art that certain crystalline forms can be transformed into other crystalline forms during the particle size reduction process.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline docetaxel and at least one pharmaceutically acceptable excipient, wherein the crystalline docetaxel is characterized by data selected from the group consisting of: powder XRD pattern Has peaks at about 7.3, 8.8, 13.7, 17.2, and 20.2±0.2° 2Θ, and the FTIR spectrum has peaks at about 1098, 1165, 1248, 1701, and 1720 cm ^-1 .

Another embodiment of the present invention includes a method of preparing a pharmaceutical composition comprising the step of combining crystalline docetaxel or a solution prepared from crystalline docetaxel with a pharmaceutically acceptable carrier, wherein the crystalline Docetaxel is characterized by data selected from: powder XRD pattern with peaks at about 73, 8.8, 13.7, 17.2 and 20.2 ± 0.2° 2Θ, FTIR spectrum at about 1098, 1165, 1248, 1701 and 1720 cm ⁻¹ There are peaks.

Another embodiment of the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of crystalline docetaxel prepared according to the method of the present invention and at least one pharmaceutically acceptable excipient.

Another embodiment of the invention includes the use of crystalline docetaxel for the manufacture of a medicament, wherein the crystalline docetaxel is characterized by data selected from the group consisting of powder XRD patterns at about 7.3, 8.8, 13.7, 17.2 and 20.2±0.2° There are peaks at 2θ, and the FTIR spectrum has peaks at about 1098, 1165, 1248, 1701 and 1720 cm ^-1 .

Another embodiment of the present invention includes a method of treating a hyperplastic disorder (such as cancer) in a mammal (such as a human), said method comprising administering to the mammal a pharmaceutically acceptable amount of A pharmaceutical composition prepared wherein crystalline docetaxel is characterized by data selected from the group consisting of a powder XRD pattern with peaks at about 7.3, 8.8, 13.7, 17.2 and 20.2 ± 0.2° 2Θ, an FTIR spectrum at about 1098 , 1165, 1248, 1701 and 1720cm ^-1 have peaks.

The pharmaceutical composition can be formulated for oral, parenteral, rectal, transdermal, bucally or nasal administration. Suitable dosage forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sublingual tablets, syrups and suspensions. Suitable formulations for parenteral administration include aqueous or non-aqueous solutions or emulsions, while suitable formulations for rectal administration include suppositories with hydrophilic or hydrophobic carriers. For topical administration, the present invention provides suitable transdermal formulations known in the art. Delivery systems, for nasal administration, suitable aerosol delivery systems known in the art are provided.

The pharmaceutical composition may comprise a single form of docetaxel, or a mixture of forms of docetaxel (with or without the amorphous form). In addition to the active ingredients, the pharmaceutical compositions of the present invention can contain one or more excipients or adjuvants. The choice of excipients and their amounts can be readily determined by a formulation scientist based on experience and consideration of standard protocols and reference books in the art.

)、微粉纤维素、乳糖、淀粉、预胶化淀粉、碳酸钙、硫酸钙、糖、葡萄糖结合剂(dextrates)、糊精、葡萄糖、二水合磷酸氢钙、磷酸钙、高岭土、碳酸镁、氧化镁、麦芽糊精、甘露醇、聚甲基丙烯酸酯(如Eudragit

)、氯化钾、粉末纤维素、氯化钠、山梨醇和滑石粉。Diluents increase the bulk of the solid pharmaceutical composition, making the pharmaceutical dosage form comprising the composition more convenient for the patient and caregiver to use. Diluents for solid compositions include, for example: microcrystalline cellulose (e.g., Avicel

), micronized cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, glucose, calcium hydrogen phosphate dihydrate, calcium phosphate, kaolin, magnesium carbonate, oxidized Magnesium, Maltodextrin, Mannitol, Polymethacrylate (such as Eudragit

), Potassium Chloride, Powdered Cellulose, Sodium Chloride, Sorbitol and Talc.

)、羟丙基甲基纤维素(如Methocel)、液体葡萄糖、硅酸镁铝、麦芽糊精、甲基纤维素、聚甲基丙烯酸酯、聚维酮(如Kollidon

、Plasdone

)、预胶化淀粉、藻酸钠和淀粉。Solid pharmaceutical compositions that are compressed into dosage forms such as tablets may contain excipients whose functions include helping to bind the active ingredient and other excipients together 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, Hydroxyethylcellulose, hydroxypropylcellulose (such as Klucel

), hydroxypropyl methylcellulose (such as Methocel ), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (such as Kollidon

、Plasdone

), pregelatinized starch, sodium alginate and starch.

、Primellose

)、胶态二氧化硅、交联羧甲基纤维素钠、交联聚维酮(如Kollidon、Polyplasdone

)、瓜尔胶、硅酸镁铝、甲基纤维素、微晶纤维素、波拉克林钾、粉末纤维素、预胶化淀粉、藻酸钠、羟基乙酸淀粉钠(如Explotab

)和淀粉。The rate of dissolution of compressed solid pharmaceutical compositions in the stomach of a patient can be increased by adding a disintegrant to the composition. Disintegrants include alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (such as Ac-Di-Sol

, Primellose

), colloidal silicon dioxide, croscarmellose sodium, crospovidone (such as Kollidon 、Polyplasdone

), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (such as Explotab

) and starch.

Glidants can be added to improve the flow of the uncompressed solid composition and to increase the accuracy of dosage. Excipients that can be used as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and calcium phosphate.

When dosage forms such as tablets are made by compressing a powdered composition, the composition is subjected to pressure from punches and dies. Some excipients and active ingredients tend to stick to the surface of punches and dies, which can lead to products with dents and other surface defects. Lubricants may be added to the composition to reduce sticking and 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, lauryl Sodium sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

Flavoring and flavoring agents can make dosage forms more palatable to patients. Common flavoring and flavoring agents used in pharmaceutical products that may be included in the compositions of the present invention include: maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl malt alcohol and tartaric acid.

Solid and liquid compositions may also be colored with pharmaceutically acceptable colorants to improve their appearance and/or to facilitate patient identification of product and unit dosage levels.

In liquid pharmaceutical compositions of the invention, the active ingredient and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

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 useful in the liquid compositions of the present invention include, for example: gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methylcellulose, carbomer, cetyl Octadecanol and Cetyl Alcohol.

Liquid pharmaceutical compositions may also contain viscosity-increasing agents to improve product mouthfeel and/or to coat the lining of the gastrointestinal tract. Such viscosity builders include: gum arabic, bentonite, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar, hydroxy Ethyl Cellulose, Hydroxypropyl Cellulose, Hydroxypropyl Methyl Cellulose, Maltodextrin, Polyvinyl Alcohol, Povidone, Propylene Carbonate, Propylene Glycol Alginate, Sodium Alginate, Sodium Starch Glycolate, Starch tragacanth and xanthan gum.

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, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improve storage stability.

According to the invention, the liquid composition may also comprise a buffering agent such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.

The choice of excipients and amounts can readily be determined by a formulation scientist empirically and by consideration of standard procedures and reference works in the art.

The solid compositions of the present invention include powders, granules, aggregates and compressed compositions. Dosage forms include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular and intravenous), inhalation and ophthalmic administration. Although the optimum route of administration in any given situation will depend upon the nature and severity of the condition being treated, the most preferred route of administration in the present invention is oral. 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, troches and lozenges, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention may be a capsule (in a hard or soft capsule shell) comprising the composition of the present invention (preferably a powdery or granular solid composition). The capsule shell can be made of gelatin, and optionally contain plasticizers, such as glycerol and sorbitol, and opacifiers or coloring agents.

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

Compositions for tablet compression or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients in powder form are mixed with excipients and then further mixed in the presence of a liquid, usually water, to agglomerate the powders into granules. The granules are sieved and/or ground, dried and then sieved and/or ground to the desired particle size. The granules may then be compressed, or other excipients, such as glidants and/or lubricants may be added prior to compression.

Compression compositions can generally be prepared by dry blending. For example, a mixed composition of the active ingredient and excipients can be compressed into a slug or tablet and then pulverized into compressed granules. The compressed granules are then compressed into tablets.

As an alternative to dry granulation, the blended composition can be compressed directly into a compressed dosage form using direct compression technology. Tablets obtained by direct compression are more uniform and free of grains. Excipients that are particularly suitable for direct compression include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate, and colloidal silicon dioxide. The appropriate use of these and other excipients in direct compression is well known to those skilled in the art having experience and skill, particularly in direct compression formulations.

The capsule fill of the present invention may comprise any of the above blends and granules as described for tabletting, but they are not subjected to the final tabletting step.

When preparing injectable (parenteral) pharmaceutical compositions, solutions and suspensions are sterile and are preferably rendered isotonic with the blood. For injections, well-known carriers in the art can be used. For example, carriers for injection include, but are not limited to, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan. The amount of sodium chloride, dextrose or glycerol to make an injection isotonic can readily be determined by one of ordinary skill in the art with little or no experimentation. Other ingredients such as solvents, buffers and analgesics may be added.

The dosage used is preferably from about 0.5 mg to about 500 mg of docetaxel, more preferably from about 20 to about 100 mg.

Example

overview

XRD

的铜射线。X-ray powder diffraction (XRD) data were obtained using a Scintag X-ray powder diffractometer (model X'TRA) equipped with a copper tube solid state detector. A circular standard aluminum sample holder with an approximately background-free quartz disc, lumen: 25 (diameter) x 0.5 mm (depth) was used. Scanning parameters: range: 2 to 40°2θ; scanning mode: continuous scanning; step size: 0.05°; rate: 3°/min. use

copper rays.

thermal analysis

DSC thermograms were recorded on a DSC 821e, Mettler Toledo, sample weight about 3 to 6 mg, heating rate about 10°C/min, range: 25 to 250°C. The oven was constantly purged with nitrogen at a flow rate of 40 ml/min. Use a standard 40 μl aluminum crucible with a lid and 3 holes.

FTIR

FTIR spectra were measured on a Perkin-Elmer spectrum One spectrometer. Samples were analyzed using mineral oil (Nujol). Samples were ground and mixed with a few drops of mineral oil, and spectra were recorded using a blank sample chamber as background. The scanning parameters are: range: 4000 to 400cm ^-1 , 16 scans (16scans), resolution: 4.0cm ^-1 .

Example 1: Preparation of crystalline docetaxel by crystallization from MIBK/n-heptane

A 100 mL reactor was charged with crude docetaxel (2.8 g, 3.47 mmol), 21 mL of methyl isobutyl ketone (MIBK) was added, and the mixture was heated to 80 °C to obtain a clear solution. To this solution was added n-heptane (11.7 mL) dropwise, forming a white solid. The mixture was then cooled to 25°C over 3 hours and stirred at 25°C for 13 hours.

A premade mixture of MIBK (4.0ml) and n-heptane (2.2ml) was added to give a readily stirrable suspension. The suspension was filtered on gooch P3 and washed with n-heptane (14 ml) to give docetaxel (2.13 g, yield 76%) as a white solid, the PXRD of which is shown in Figure 1.

Example 2: Preparation of crystallized clips from acetone/tert-butanol and n-heptane characterized by major X Crystals with X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 155 and 16.9±0.2°2θ Docetaxel

A 100 mL round bottom flask was charged with crude docetaxel (3.0 g, 3.7 mmol) and dissolved in acetone (24 mL) and tert-butanol (3 mL) at 25°C. Then n-heptane (30 ml) was added slowly over 15 minutes, and after stirring for 1 hour at 25 °C, the suspension was filtered on gooch P3, washed twice with n-heptane (10 ml), and dried under vacuum at 55 °C for 16 hours, docetaxel (2.80 g) was obtained as a white solid with a yield of 93.0% and a purity of 99.6%.

Example 3: Crystallization from Ethyl Acetate and n-Heptane to Produce Characterized Primary X-ray Crystal Dorsey with powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2θ other games

5 grams of crude docetaxel (99.7% purity) were charged into a round bottom glass flask. Ethyl acetate (5 vol, 25 mL) was added to the solid and the suspension was heated to 50°C to give a solution. Maintaining this temperature, n-heptane (5 vol, 25 mL) was added dropwise. Precipitation occurred when the addition was complete. With stirring, the suspension was kept at this temperature for a further hour and then allowed to cool to 25°C. After 1 hour at 25°C, the suspension was filtered on gooch P3 and the solid was dried under vacuum at 55°C overnight.

A second crop of crystals was obtained from the mother liquor. The suspension was filtered on Gooch P3, and the solid was dried under vacuum at 55 °C overnight to obtain a solid with a purity of 99.7%.

Example 4: Crystallization from Ethyl Acetate/Acetone and n-Heptane to Prepare Characterized by Major X Crystals with X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9±0.2°2θ Docetaxel

Crude docetaxel (4.8 g, 99.6% purity) was suspended in 10 volumes of a 1:1 ethyl acetate/acetone mixture. The suspension was heated to 50°C. A suspension was still observed at this temperature. Keeping this temperature, 27 volumes of n-heptane were added dropwise to the suspension, and the suspension was stirred for a further 1 hour. The mixture was then cooled to 0 °C and filtered on gooch P3, and the solid was dried under vacuum at 55 °C overnight to obtain docetaxel with a purity of 99.8% (90% yield).

Example 5: Crystallization from THF and n-Heptane to Produce Characterized by Primary X-ray Crystal Dorsey with powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2θ other games

Crude docetaxel (5.0 g, 9.5% purity) was suspended in 4 volume equivalents of tetrahydrofuran. The suspension was heated to 50°C. A solution was observed at this temperature. Maintaining this temperature, 6 volumes of n-heptane were added dropwise to the solution to form a suspension, which was stirred for an additional hour. The mixture was then cooled to 25°C and filtered on a gooch P3, and the solid was dried under vacuum at 55°C overnight to give docetaxel with a purity of 99.6% (96% yield).

Example 6: Crystallization from THF and n-Heptane to Produce Characterized Primary X-ray Crystal Dorsey with powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2θ other games

Crude docetaxel (4.5 g, 99.5% purity) was suspended in 7 volume equivalents of tetrahydrofuran. The suspension was heated to 50°C. A solution was observed at this temperature. Maintaining this temperature, 10 volumes of n-heptane were added dropwise to the solution to form a suspension, which was stirred for a further 1 hour. The mixture was then cooled to 0 °C and filtered on gooch P3, and the solid was dried under vacuum at 55 °C overnight to obtain docetaxel with a purity of 99.8% (90% yield).

Example 7: Crystallization from Ethyl Acetate and n-Heptane to Produce Characterized Primary X-ray Crystal Dorsey with powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2θ other games

Crude docetaxel (9.0 g, 99.5% purity) was charged into a round bottom glass flask. Ethyl acetate (9 vol, 81 mL) was added to the solid and the suspension was heated to 50°C to give a solution. Maintaining this temperature, n-heptane (9 vol, 81 mL) was added dropwise to the solution. Precipitation occurred when the addition was complete. With stirring, the suspension was kept at this temperature for a further hour and then cooled to 25°C.

After 1 hour at 25°C, the suspension was filtered on gooch P3 and the solid was dried under vacuum at 55°C overnight to give docetaxel with a purity of 99.8% (90% yield).

Example 8: Crystallization from Ethyl Acetate/Acetone and n-Heptane to Prepare Characterized by Major X Crystals with X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9±0.2°2θ Docetaxel

Crude docetaxel (4.3 g, 99.5% purity) was suspended in 7 volume equivalents of a 1:1 ethyl acetate/acetone mixture. The suspension was heated to 50°C. Keeping this temperature, 7 volume equivalents of n-heptane were added dropwise to the resulting suspension, and the slurry was stirred for another 1 hour. The mixture was then cooled to 0 °C and filtered on gooch P3, and the solid was dried under vacuum at 55 °C overnight to obtain docetaxel with a purity of 99.8% (90% yield).

Example 9: Crystallization from ethanol and n-heptane to produce a predominantly X-ray powder Crystalline docetaxel with diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9 ± 0.2° 2Θ

Crude docetaxel (5.0 g, 99.5% purity) was charged into a round bottom glass flask. Ethanol (2 vol, 10 mL) was added to the solid and the suspension was heated to 50°C. Maintaining this temperature, n-heptane (5 vol, 25 mL) was added dropwise to the resulting solution. Precipitation occurred when the addition was complete. With stirring, the suspension was kept at this temperature for a further 1 hour and then cooled to 0°C. After 1 hour at 0 °C, the suspension was filtered on gooch P3 and the solid was dried under vacuum at 55 °C overnight to give docetaxel with a purity of 99.6% (80% yield).

Claims (42)

1. A crystalline docetaxel characterized by data selected from the group consisting of powder XRD pattern with peaks at about 7.3, 8.8, 13.7, 17.2 and 20.2±0.2° 2Θ, FTIR spectrum at about 1098, 1165, 1248 , 1701 and 1720 (cm ^-1 ) have peaks. 2. The crystalline docetaxel of claim 1, further characterized in that the powder XRD pattern has peaks at about 4.9, 12.5, 13.1, 18.8 and 19.8 ± 0.2° 2Θ. 3. The crystalline docetaxel of claim 1 or 2, wherein said crystalline docetaxel is further characterized by an FTIR spectrum having peaks at about 719, 848, 957, 3429 and 3461 (cm ^-1 ). 4. The crystalline docetaxel of any one of the preceding claims, wherein said crystalline docetaxel is further characterized by a DSC thermogram having endothermic peaks at about 30°C to about 70°C and 173°C. 5. The crystalline docetaxel of any one of the preceding claims, wherein said crystalline docetaxel has a maximum particle size of less than about 300 [mu]m. 6. The crystalline docetaxel according to any one of the preceding claims, wherein the crystalline docetaxel is further characterized in that: the XRD pattern is as shown in FIG. 1 . 7. The crystalline docetaxel according to any one of the preceding claims, wherein the crystalline docetaxel is further characterized in that the FTIR spectrum is as shown in FIG. 2 . 8. The crystalline docetaxel according to any one of the preceding claims, wherein the crystalline docetaxel is further characterized in that: the DSC thermogram is as shown in FIG. 3 . 9. The crystalline docetaxel of any one of the preceding claims, wherein said crystalline docetaxel is anhydrous. 10. The crystalline docetaxel of any one of the preceding claims, wherein said crystalline docetaxel is present in a composition containing less than about 5% of any other form of docetaxel. 11. The crystalline docetaxel of claim 10, wherein said crystalline docetaxel is present in a composition containing less than about 2% of any other form of docetaxel. 12. The crystalline docetaxel of claim 11, wherein said crystalline docetaxel is present in a composition containing less than about 1% of any other form of docetaxel. 13. The crystalline docetaxel of claim 10, wherein said crystalline docetaxel is present in a composition comprising less than about 5% docetaxel trihydrate. 14. The crystalline docetaxel of claim 13, wherein said crystalline docetaxel is present in a composition comprising less than about 2% docetaxel trihydrate. 15. The crystalline docetaxel of claim 14, wherein said crystalline docetaxel is present in a composition comprising less than about 1% docetaxel trihydrate. 16. A process for the preparation of crystalline docetaxel according to any one of the preceding claims, said process comprising crystallizing docetaxel from a mixture of methyl isobutyl ketone (MIBK) and an organic anti-solvent. 17. The method of claim 16, wherein said crystallization comprises the steps of: a) combining docetaxel and MIBK to obtain a solution; b) adding an organic anti-solvent to the solution to obtain a suspension; and c) recovering crystalline docetaxel from the suspension. 18. The method of claim 17, further comprising heating the solution of docetaxel and MIBK. 19. The method of claim 18, wherein heating is from about 80°C to about 120°C. 20. The method of claim 16 or 17, wherein the organic anti-solvent is selected from: _C5 to _C8 linear or branched alkanes. 21. The method of any one of claims 16 to 20, wherein the anti-solvent is n-heptane. 22. The method of any one of claims 17 to 21, wherein the anti-solvent is added dropwise. 23. The method of any one of claims 17 to 22, wherein the method further comprises cooling the suspension. 24. The method of claim 23, wherein cooling is from about 25°C to about 30°C. 25. The method of claim 23 or 24, further comprising: after cooling, adding a mixture of methyl isobutyl ketone (MIBK) and n-heptane to the suspension. 26. A method of preparing docetaxel crystals characterized by major X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5, and 16.9 ± 0.2° 2Θ, said method comprising making the crystals from a solvent and an organic anti-solvent , wherein the solvent is selected from the group consisting of: acetone and ethyl acetate, acetone and tert-butanol, tetrahydrofuran, ethyl acetate, tert-butanol, ethanol, and mixtures thereof. 27. The method of claim 26, wherein said method comprises: a) combining docetaxel with a solvent to obtain a suspension or solution; and b) adding an organic anti-solvent to precipitate crystalline docetaxel characterized by major X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9±0.2° 2Θ. 28. The method of claim 27, wherein the suspension or solution is heated to about 45 to 65°C. 29. The method of claim 28, wherein the suspension or solution is heated to about 50°C. 30. The method of any one of claims 26 to 29, wherein the organic anti-solvent is selected from _C5 to _C8 linear and branched alkanes. 31. The method of any one of claims 26 to 30, wherein the anti-solvent is n-heptane or n-hexane. 32. The method of any one of claims 27 to 31, wherein the anti-solvent is added dropwise. 33. The method of any one of claims 27 to 32, wherein the method further comprises: cooling the suspension or solution after adding the anti-solvent. 34. The method of claim 33, wherein cooling is from about 0°C to about 25°C. 35. The method of any one of claims 26 to 34, wherein the method further comprises: recovering crystalline docetaxel. 36. The method of claim 35, wherein said crystalline docetaxel is recovered by filtration and drying. 37. The method of claim 36, wherein drying is performed under vacuum at about 55°C. 38. The method of claim 35, wherein the recovered crystalline docetaxel is anhydrous. 39. A pharmaceutical composition comprising a therapeutically effective amount of crystalline docetaxel according to any one of claims 1 to 15 and at least one pharmaceutically acceptable excipient. 40. A pharmaceutical composition comprising a therapeutically effective amount of crystalline docetaxel prepared according to any one of claims 16 to 38 and at least one pharmaceutically acceptable excipient. 41. A method for the preparation of a pharmaceutical composition, said method comprising the steps of: making the crystalline docetaxel according to any one of claims 1 to 15, or the crystalline docetaxel according to any one of claims 1 to 15 A solution prepared from the cetaxel is combined with a pharmaceutically acceptable carrier. 42. Use of crystalline docetaxel according to any one of claims 1 to 15 for the manufacture of a medicament for the treatment of mammals suffering from hyperplasia.

Images