Solid forms of clofazodone and its salts

Abstract

The present disclosure relates to solid forms of clofazodone and its salts, processes for preparing the same, and pharmaceutical compositions thereof.

Description

Technical Field

[0001] The present disclosure relates to solid forms of Tafamidis and its salts, processes for preparing the same, and pharmaceutical compositions thereof.

[0002] background

[0003] Lofenac has the chemical name 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. Lofenac has the following chemical structure:

[0004]

[0005] Tafamidis meglumine has the chemical name 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid mono(1-deoxy-1-methylamino-D-glucitol). Tafamidis meglumine has the following chemical structure:

[0006]

[0007] VYNDAQEL (tofragulaf meglumine) and VYNDAMAX (tofragulaf) are both capsules for oral administration and contain tofragulaf as the active moiety. The U.S. Food and Drug Administration ("FDA") has approved VYNDAQEL and VYNDAMAX for the treatment of wild-type or inherited transthyretin-mediated amyloid cardiomyopathy in adults to reduce cardiovascular mortality and cardiovascular-related hospitalizations. The EMA has approved VYNDAQEL for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral nerve damage.

[0008] Tamiflu is known from US Pat. No. 7,214,695.

[0009] Solid forms of clofazoline meglumine are known from U.S. Pat. No. 9,249,112, International Publication No. WO2017190682 and International Publication No. WO2019175263. Solid forms of clofazoline are known from U.S. Pat. No. 9,770,441 and International Publication No. WO2019175263.

[0010] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single compound, such as clofazodone, can occur with different crystal structures and physical properties such as melting point, thermal behavior (e.g. as measured by thermogravimetric analysis – "TGA" or differential scanning calorimetry – "DSC"), powder X-ray diffraction (PXRD) patterns, infrared absorption fingerprints, Raman absorption fingerprints and solid state ( 13 C-) NMR spectroscopy of various polymorphs. One or more of these techniques can be used to distinguish between different polymorphic forms of a compound.

[0011] Different salts and solid forms (including solvated forms) of active pharmaceutical ingredients can have different properties. Such changes in the properties of different salts and solid forms and solvates can provide a basis for improving preparations, for example, by promoting better processing or handling characteristics, improving dissolution profiles, or improving stability (polymorphs and chemical stability) and shelf life. These changes in the properties of different salts and solid forms can also provide improvements for final dosage forms, for example, if they are used to improve bioavailability. Different salts and solid forms and solvates of active pharmaceutical ingredients can also produce multiple polymorphs or crystalline forms, which can then provide additional opportunities to use the properties of solid active pharmaceutical ingredients and the changes in characteristics for providing improved products.

[0012] Discovery of new salts, solid forms, and solvates of drug products can provide materials with desirable processing properties such as ease of handling, ease of processing, storage stability, and ease of purification, or as desirable intermediate crystalline forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms, and solvates of pharmaceutically useful compounds can also provide opportunities to improve the performance characteristics (dissolution profile, bioavailability, etc.) of drug products. It expands the set of materials available to formulation scientists for formulation optimization, for example, by providing products with different properties, such as different crystal habits, higher crystallinity or polymorphic stability or solubility, which can provide better processing or handling characteristics, improved dissolution profiles, or improved shelf life.

[0013] For at least these reasons, crystalline forms of tamifluanil and its salts, including solvated forms, having desirable properties remain desirable.

[0014] Overview

[0015] The present disclosure relates to solid forms of clofazodone and its salts, to processes for preparing the same, and to pharmaceutical compositions comprising the solid forms.

[0016] The present disclosure also provides the use of solid forms of tamiprofen and its salts for preparing other solid forms of tamiprofen, tamiprolate salts and solid forms thereof.

[0017] In another embodiment, the present disclosure encompasses the above-described solid-state forms of tamiflu acid and salts thereof for use as a medicament, in embodiments for the treatment of transthyretin-mediated amyloidosis.

[0018] In another embodiment, the present disclosure encompasses methods for treating transthyretin-mediated amyloidosis using the above-described solid-state forms of tamiflu and salts thereof.

[0019] In another embodiment, the present disclosure also provides the use of any of the solid forms of clofaconazole and its salts described according to any embodiment herein for preparing a pharmaceutical composition or pharmaceutical preparation of clofaconazole, wherein the clofaconazole in the pharmaceutical composition or preparation is in solid form, wherein the solid form can be any crystalline form or amorphous form.

[0020] The present disclosure also provides a pharmaceutical composition comprising a solid state form of clofazodone and a salt thereof according to the present disclosure.

[0021] In yet another embodiment, the present disclosure encompasses pharmaceutical formulations comprising the above-described solid state forms of tamifluanil and its salts and at least one pharmaceutically acceptable excipient, in embodiments for oral administration in dosage forms such as tablets, capsules, and the like.

[0022] The present disclosure encompasses processes for preparing the pharmaceutical formulations of tamiflu by combining at least one of the above solid-state forms and at least one pharmaceutically acceptable excipient.

[0023] Solid state forms, and pharmaceutical compositions or formulations of tamiflu acid and its salts in solid state forms as defined herein, may be used as medicaments, in embodiments for the treatment of transthyretin-mediated amyloidosis.

[0024] The present disclosure also provides a method of treating thyroxine transporter-mediated amyloidosis by administering a therapeutically effective amount of a solid form of tamiflu and / or its salt of the present disclosure or at least one of the above pharmaceutical compositions or formulations to a subject suffering from thyroxine transporter-mediated amyloidosis or otherwise in need of treatment.

[0025] The present disclosure also provides use of at least one of the solid forms of clofazodone and its salts of the present disclosure or the above pharmaceutical compositions or preparations for the manufacture of a medicament for treating thyroxine transporter-mediated amyloidosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1Shown is a powder X-ray diffraction pattern ("powder XRD" or "PXRD") of an amorphous form of tamifluan.

[0028] Figure 2 The PXRD of tamifluanil Form I is shown.

[0029] Figure 3 The PXRD of clofazodone Form II is shown.

[0030] Figure 4 The PXRD of tamiflu acid Form III is shown.

[0031] Figure 5 The PXRD of tamifluacil Form IV is shown.

[0032] Figure 6 The PXRD of tamifluacil Form V is shown.

[0033] Fig. 6A The PXRD of tamifluacil Form V is shown.

[0034] Figure 7 The PXRD of tamiprofen Form 4 is shown.

[0035] Figure 8 The anhydrous form V of clofazodone is shown 13 C NMR.

[0036] Details

[0037] The present disclosure relates to solid-state forms of tamiflu acid and its salts, and in embodiments to crystalline forms of tamiflu acid free acid, processes for their preparation, and pharmaceutical compositions comprising the solid-state forms.

[0038] The solid state form of clofazodone according to the present disclosure may have advantageous properties selected from at least one of chemical purity or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability and thermal and mechanical stability with respect to polymorphic conversion, stability to dehydration and / or storage stability, a lower degree of hygroscopicity, a low content of residual solvents, and advantageous processing and handling characteristics such as compressibility or bulk density.

[0039] Crystal forms may be referred to herein as being characterized by graphical data "as depicted in the figure". Such data include, for example, powder X-ray diffraction patterns and solid-state NMR spectra. As is well known in the art, graphical data potentially provide additional technical information to further define the corresponding solid-state form (a so-called "fingerprint"), which may not necessarily be described solely by reference to numerical values ​​or peak positions. In any case, the skilled person will understand that such graphical representations of data may be subject to small changes, such as small changes in peak relative intensity and peak position, due to factors such as changes in instrument response and changes in sample concentration and purity, which are well known to the skilled person. Nevertheless, the skilled person will readily be able to compare the graphical data in the figures herein with the graphical data generated for an unknown crystal form, and confirm whether the two sets of graphical data characterize the same crystal form or two different crystal forms. Therefore, the crystal forms of tamiflu acid and its salts referred to herein as being characterized by graphical data "as depicted in the figure" will be understood to include any crystal forms of tamiflu acid and its salts characterized by graphical data having such small changes compared to the figure as is well known to the skilled person.

[0040] Solid forms (or polymorphs) may be referred to herein as polymorphically pure or substantially free of any other solid (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other form" will be understood to mean that the solid form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of any other form of the subject compound as measured, for example, by PXRD. Therefore, the solid forms of tlobazam and tlobazam salts described herein as being substantially free of any other solid forms will be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% (w / w) of the subject solid forms of tlobazam and / or tlobazam salts. Thus, in some embodiments of the present disclosure, the described solid state forms of tamiflu and / or tamiflu salts may contain from about 1% (w / w) to about 20% (w / w), from about 5% (w / w) to about 20% (w / w), or from about 5% (w / w) to about 10% (w / w) of one or more other solid state forms of the same tamiflu and / or tamiflu salts.

[0041] As used herein, unless otherwise stated, PXRD peaks reported herein use CuK α radiation, Measurement.

[0042] As used herein, the term "isolated" with respect to the solid state forms of tamiflu and tamiflu salts of the present disclosure corresponds to solid state forms of tamiflu and tamiflu salts that are physically separated from the reaction mixture from which they are formed.

[0043] Object, such as reaction mixture, can be characterized as being at "room temperature" or allowed to reach "room temperature", usually abbreviated as "RT" in this article. This means that the temperature of the object is close to the temperature of the space such as the room or fume hood where the object is located or is the same as the temperature of the space such as the room or fume hood where the object is located. Typically, room temperature is from about 20 ° C to about 30 ° C or about 22 ° C to about 27 ° C or about 25 ° C. Process or step can be referred to as "overnight" in this article. This refers to a time interval, such as a time interval for a process or step, which spans the time during the night, when the process or step may not be actively observed. The time interval is from about 8 hours to about 20 hours or about 10 hours to about 18 hours, and in an embodiment is about 16 hours.

[0044] As used herein and unless otherwise indicated, the term "solvate" refers to a crystalline form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in the solvate can be present in stoichiometric amounts or in non-stoichiometric amounts.

[0045] Crystalline hydrates indicated by water analysis by Karl Fischer (KF) titration or by TGA analysis of the product are believed to have arisen due to water introduced from the atmosphere in which the material was handled, or by trace amounts of water present in the solvent in contact with the material, or a combination of these factors.

[0046] The amount of solvent used in a chemical process (such as a reaction or crystallization) may be referred to herein as "volume" or "vol" or "V" number. For example, a material may be referred to as being suspended (or dissolved) in 10 volumes (or 10vol or 10V) of solvent. In this context, the expression will be understood to mean the material suspended (or dissolved) in milliliters of solvent per gram, so that 5 grams of material suspended (or dissolved) in 10 volumes of solvent means that the solvent is used in the amount of 10 milliliters of solvent per gram of material suspended (or dissolved), or in this example, 50mL of solvent. In another context, the term "v / v" may be used to indicate the volume of the solvent added to the mixture based on the volume of the liquid mixture. For example, adding methyl tert-butyl ether (MTBE) (1.5v / v) to a 100ml reaction mixture will indicate the addition of 150mL of MTBE.

[0047] As used herein, the term "reduced pressure" refers to a pressure of about 10 mbar to about 50 mbar.

[0048] As used herein, clofazodone Form 4 is described in U.S. Pat. No. 9,770,441. U.S. Pat. No. 9,770,441 describes Form 4 having a powder X-ray diffraction pattern including peaks at diffraction angles (2-θ) of 15.9 ± 0.2, 16.9 ± 0.2, 18.0 ± 0.2, and 27.3 ± 0.2. Alternatively, the crystalline form has a peak having a crystalline form ... Figure 7 The powder X-ray diffraction patterns of the peaks at substantially the same diffraction angle (2-θ) are shown in FIG.

[0049] As used herein, unless otherwise stated, the 13 C CP / MAS NMR spectra are measured at 125 MHz, preferably at a temperature of 293 K ± 3 °C.

[0050] The present disclosure encompasses amorphous forms of clofazolin. The amorphous form of clofazolin can be prepared by, for example, Figure 1 The PXRD patterns depicted in .

[0051] The present disclosure includes a crystalline form of tamiprofen designated as Form I. Crystalline Form I of tamiprofen can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 5.1 degrees, 8.4 degrees, 18.5 degrees, 21.0 degrees, and 25.8 degrees 2-θ ± 0.2 degrees 2-θ; Figure 2 PXRD patterns depicted in; and combinations of these data.

[0052] The crystalline Form I of clofazodone may also be characterized by a PXRD pattern having peaks at 5.1 degrees, 8.4 degrees, 18.5 degrees, 21.0 degrees, and 25.8 degrees 2-θ ± 0.2 degrees 2-θ, and also having one, two, three, four, or five additional peaks at 10.2 degrees, 10.5 degrees, 15.3 degrees, 24.4 degrees, and 27.1 degrees 2-θ ± 0.2 degrees 2-θ.

[0053] Crystalline Form I of clofazodone can be characterized by each of the above characteristics alone or by all possible combinations, for example, by a PXRD pattern having peaks at 5.1 degrees, 8.4 degrees, 18.5 degrees, 21.0 degrees and 25.8 degrees 2-θ ± 0.2 degrees 2-θ and a peak at 1.5°, 2.0°, 3.0° and 5.5° 2-θ ± 0.2 degrees 2-θ. Figure 2 The PXRD patterns depicted in .

[0054] Crystalline Form I of tamiflu can alternatively be characterized by a PXRD pattern having peaks at 5.1 degrees, 8.4 degrees, 10.2 degrees, 10.5 degrees, 15.3 degrees, 18.5 degrees, 21.0 degrees, 24.4 degrees, 25.8 degrees, and 27.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0055] The crystalline form I of tamiflu according to any of the above embodiments may be a hydrate.

[0056] The present disclosure includes a crystalline form of tamiprofen designated as Form II. The crystalline Form II of tamiprofen can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 3.9 degrees, 11.3 degrees, 13.3 degrees, 16.0 degrees, and 27.2 degrees 2-θ ± 0.2 degrees 2-θ; Figure 3 PXRD patterns depicted in; and combinations of these data.

[0057] Crystalline Form II of clofazodone may also be characterized by a PXRD pattern having peaks at 3.9, 11.3, 13.3, 16.0, and 27.2 degrees 2-θ ± 0.2 degrees 2-θ, and also having one, two, three, four, or five additional peaks at 5.3, 6.4, 17.8, 19.2, and 22.0 degrees 2-θ ± 0.2 degrees 2-θ.

[0058] Crystalline Form II of clofazodone can be characterized by each of the above characteristics alone or by all possible combinations, for example, by a PXRD pattern having peaks at 3.9 degrees, 11.3 degrees, 13.3 degrees, 16.0 degrees and 27.2 degrees 2-θ ± 0.2 degrees 2-θ and a peak at 14.8 degrees 2-θ ± 0.2 degrees 2-θ. Figure 3 The PXRD patterns depicted in .

[0059] Crystalline Form II of clofazodone may alternatively be characterized by a PXRD pattern having peaks at 3.9, 5.3, 6.4, 11.3, 13.3, 16.0, 17.8, 19.2, 22.0, and 27.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0060] The present disclosure includes a crystalline form of tamiprofen designated as Form III. The crystalline Form III of tamiprofen can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 5.5, 10.9, 14.7, 19.6, and 21.7 degrees 2-θ ± 0.2 degrees 2-θ; Figure 4 PXRD patterns depicted in; and combinations of these data.

[0061] Crystalline Form III of clofazodone may also be characterized by a PXRD pattern having peaks at 5.5, 10.9, 14.7, 19.6 and 21.7 degrees 2-θ ± 0.2 degrees 2-θ, and also having one, two, three, four or five additional peaks at 10.3, 11.3, 16.3, 18.6 and 25.7 degrees 2-θ ± 0.2 degrees 2-θ.

[0062] Crystalline Form III of clofazodone can be characterized by each of the above characteristics alone or by all possible combinations, for example, by a PXRD pattern having peaks at 5.5, 10.9, 14.7, 19.6 and 21.7 degrees 2-θ ± 0.2 degrees 2-θ and a peak at 14.7, 19.6 and 21.7 degrees 2-θ ± 0.2 degrees 2-θ. Figure 4 The PXRD patterns depicted in .

[0063] Crystalline Form III of tamiflu acid may alternatively be characterized by a PXRD pattern having peaks at 5.5, 10.3, 10.9, 11.3, 14.7, 16.3, 18.6, 19.6, 21.7, and 25.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0064] The crystalline Form III of tamifluamide according to any of the above embodiments may be an acetic acid solvate.

[0065] The present disclosure includes a crystalline form of tamiprofen designated as Form IV. Crystalline Form IV of tamiprofen can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 7.5, 12.9, 15.1, 17.7, and 25.4 degrees 2-θ ± 0.2 degrees 2-θ; Figure 5 PXRD patterns depicted in; and combinations of these data.

[0066] Crystalline Form IV of clofazodone may also be characterized by a PXRD pattern having peaks at 7.5, 12.9, 15.1, 17.7, and 25.4 degrees 2-θ ± 0.2 degrees 2-θ, and also having one, two, three, four, or five additional peaks at 20.2, 21.3, 22.7, 23.7, and 27.0 degrees 2-θ ± 0.2 degrees 2-θ.

[0067] Crystalline Form IV of clofazodone can be characterized by each of the above characteristics alone or by all possible combinations, for example, by a PXRD pattern having peaks at 7.5, 12.9, 15.1, 17.7 and 25.4 degrees 2-θ ± 0.2 degrees 2-θ and a peak at 14.7, 16.9, 18.1, 19.9 and 20.8 degrees 2-θ. Figure 5 The PXRD patterns depicted in .

[0068] Crystalline Form IV of clofazodone may alternatively be characterized by a PXRD pattern having peaks at 7.5, 12.9, 15.1, 17.7, 20.2, 21.3, 22.7, 23.7, 25.4 and 27.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0069] The crystalline Form IV of tamifluamide according to any of the above embodiments may be an acetic acid solvate.

[0070] The present disclosure includes a crystalline form of tamifluamide designated as Form V. Crystalline Form V of tamifluamide can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.0 degrees, 19.9 degrees, 20.6 degrees, 23.9 degrees, and 29.2 degrees 2-θ ± 0.2 degrees 2-θ; Figure 6 PXRD patterns depicted in; and combinations of these data.

[0071] Alternatively, the crystalline Form V of clofazodone may be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.0 degrees, 19.9 degrees, 20.6 degrees, 23.9 degrees, and 29.2 degrees 2-θ ± 0.2 degrees 2-θ; Fig. 6A PXRD patterns depicted in; and combinations of these data.

[0072] Crystalline Form V of clofazodone may also be characterized by a PXRD pattern having peaks at 6.0, 19.9, 20.6, 23.9, and 29.2 degrees 2-θ ± 0.2 degrees 2-θ, and also having one, two, three, or four additional peaks at 17.8, 25.8, 27.3, and 31.1 degrees 2-θ ± 0.2 degrees 2-θ.

[0073] Crystalline Form V of clofazodone can be characterized by each of the above characteristics alone or by all possible combinations, for example, by a PXRD pattern having peaks at 6.0 degrees, 19.9 degrees, 20.6 degrees, 23.9 degrees and 29.2 degrees 2-θ ± 0.2 degrees 2-θ and a peak at 14.8 degrees 2-θ. Figure 6 or Fig. 6A The PXRD patterns depicted in .

[0074] The crystalline Form V of clofazodone may be in an anhydrous form or a solvated form. In a specific embodiment, the crystalline Form V may be in an anhydrous form or a methanol solvate.

[0075] Crystalline Form V of tamiflu can alternatively be characterized by a PXRD pattern having peaks at 6.0, 17.8, 19.9, 20.6, 23.9, 25.8, 27.3, 29.2, and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0076] In any embodiment of the present invention, the crystalline Form V may be an anhydrous form or a methanol solvate.

[0077] In any embodiment of the present invention, the anhydrous Form V of clofazodone can be alternatively or additionally prepared by solid phase chromatography with peaks at 171.5 ppm, 161.0 ppm, 149.1 ppm, 144.7 ppm, 131.0 ppm ± 0.2 ppm. 13 C NMR spectroscopy. Anhydrous Form V of clofazodone can alternatively or additionally be characterized by solid phase with the following absolute differences in chemical shift from a reference peak at 109.5 ppm ± 0.2 ppm: 13 C NMR spectrum: 62.1 ppm, 51.6 ppm, 39.6 ppm, 35.2 ppm, 21.5 ppm ± 0.1 ppm. In any embodiment of the present invention, the anhydrous Form V of tamifluan can be alternatively or additionally prepared by substantially as follows Figure 8 The solid state depicted in 13 C NMR spectroscopy.

[0078] The present disclosure also provides the use of solid forms of tamiprofen and tamiprofen salts for preparing other solid forms of tamiprofen, tamiprofen salts and solid forms thereof.

[0079] The present disclosure also encompasses processes for preparing other solid forms of tamiprofen or its solid forms, and other tamiprofen salts or their solid forms. The process comprises preparing a solid form of the present disclosure and converting it to other solid forms of tamiprofen. Alternatively, the process comprises preparing a solid form of the present disclosure and converting it to a tamiprofen salt. The conversion can be, for example, by comprising reacting the obtained tamiprofen with a suitable base such as meglumine, an alkali metal / alkaline earth metal base such as potassium, sodium, calcium, magnesium, ammonia or an alkylamine (in embodiments C 1-6 Monoalkylamine, C 1-6 Dialkylamine or C 1-6 In an embodiment, the alkali metal / alkaline earth metal base is selected from the group consisting of potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, calcium hydroxide or magnesium hydroxide.

[0080] In another embodiment, the present disclosure encompasses the solid-state forms described above of tamiflu and its salts for use in the preparation of a pharmaceutical composition and / or formulation, in embodiments for use in the treatment of thyroxine transporter-mediated amyloidosis. In embodiments, the present disclosure encompasses the use of the solid-state forms described above of tamiflu and its salts for the preparation of a pharmaceutical composition comprising tamiflu or its salt.

[0081] In another embodiment, the present disclosure encompasses the use of the solid forms described above of tamiprofen and its salts, or a combination thereof, for preparing a pharmaceutical composition and / or formulation, in embodiments an oral formulation, such as a tablet or capsule. In an embodiment, the present disclosure encompasses the solid forms described above of tamiprofen and / or its salts, for preparing a pharmaceutical composition or formulation, in embodiments an oral formulation in the form of a dispersion comprising tamiprofen or its salt.

[0082] The present disclosure also provides a pharmaceutical composition comprising a solid state form of clofazodone and a salt thereof according to the present disclosure or a combination thereof.

[0083] In yet another embodiment, the present disclosure encompasses a pharmaceutical formulation comprising at least one of the above-described solid-state forms of tamifluanil and / or its salts, and at least one pharmaceutically acceptable excipient.

[0084] The pharmaceutical formulations of the present disclosure contain any one or combination of the solid forms of clofazodone of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0085] Diluents add bulk to solid pharmaceutical compositions and can make pharmaceutical dosage forms containing the compositions easier for patients and caregivers to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel ), microcellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, dextrates, dextrin, dextrose, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit ), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0086] Solid pharmaceutical compositions 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 (e.g., carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ), hydroxypropyl methylcellulose (such as Methocel ), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (e.g. Kollidon 、Plasdone ), pregelatinized starch, sodium alginate and starch.

[0087] The dissolution rate of a compressed solid pharmaceutical composition in a patient's stomach can be increased by adding a disintegrant to the composition. Disintegrants include alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (e.g., Ac-Di-Sol 、Primellose ), colloidal silicon dioxide, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone (e.g., Kollidon 、Polyplasdone ), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab ) and starch.

[0088] Glidants may be added to improve the flowability of uncompressed solid compositions and to improve the accuracy of dosing. Excipients that may be used as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0089] When dosage form such as tablet is made by compressing powdered composition, composition is subjected to pressure from punch (punch) and dye.Some excipients and active ingredients have the tendency of adhering to the surface of punch and dye, and this can cause product to have depression and other surface irregularities.Lubricant can be added to composition, to reduce adhesion and make product easy to release from dye.Lubricant comprises magnesium stearate, calcium stearate, glyceryl monostearate, palmitic acid stearic acid glyceride (glyceryl palmitostearate), hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talcum powder and zinc stearate.

[0090] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the compositions of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0091] Solid and liquid compositions may also be dyed using any pharmaceutically acceptable coloring agent to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0092] In the liquid pharmaceutical compositions of the present disclosure, 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.

[0093] Liquid pharmaceutical compositions may include emulsifiers to evenly disperse active ingredients or other excipients that are insoluble in the liquid carrier throughout the composition. Emulsifiers that may be used in the liquid compositions of the present disclosure include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, tragacanth, carrageenan, pectin, methylcellulose, carbomer, cetearyl alcohol, and cetyl alcohol.

[0094] The liquid pharmaceutical compositions of the present disclosure may also contain viscosity enhancers to improve the mouthfeel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid, bentonite, carbomer, calcium or sodium carboxymethylcellulose, cetearyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, tragacanth gum, and xanthan gum.

[0095] Sweeteners such as sorbitol, saccharin, saccharin sodium, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.

[0096] Preservatives and chelating agents such as ethanol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improve storage stability.

[0097] According to the present disclosure, the liquid composition may also include a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. The choice of excipient and the amount used can be readily determined by a formulation scientist based on experience and consideration of standard procedures and reference work in the field.

[0098] Solid compositions of the present disclosure include powders, particles, aggregates and compressed compositions. Dosage includes dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular and intravenous), suction and ocular administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments, the route of administration is oral. Dosage can be conveniently presented in unit dosage form and can be prepared by any of the methods known in the pharmaceutical field.

[0099] Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches and lozenges, and liquid syrups, suspensions and elixirs.

[0100] The dosage form of the present disclosure can be a capsule containing a composition, in an embodiment a powdered or granular solid composition of the present disclosure, within a hard or soft shell. The shell can be made of gelatin and optionally contain a plasticizer such as glycerol and sorbitol, and an opacifier or colorant.

[0101] The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0102] Compositions for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid (water in an embodiment), which causes the powder to agglomerate into particles. The particles are screened and / or milled, dried, and then screened and / or milled to a desired particle size. The particles can then be tableted, or other excipients, such as glidants and / or lubricants, can be added before tableting.

[0103] Tablet compositions can be prepared conventionally by dry blending. For example, a blended composition of an active substance and an excipient can be compressed into a slug or sheet and then crushed into compressed granules. The compressed granules can then be compressed into tablets.

[0104] As an alternative to dry granulation, the blended composition can be directly compressed into a compressed dosage form using direct compression techniques. Direct compression produces a more uniform tablet without particles. Excipients particularly suitable for direct compression tableting include microcrystalline cellulose, spray-dried lactose, calcium hydrogen phosphate dihydrate, and colloidal silicon dioxide. The proper use of these and other excipients in direct compression tableting is known to those skilled in the art who have experience and skills in the specific formulation challenges of direct compression tableting.

[0105] The capsule filling of the present disclosure may include any of the above-mentioned blends and granules described with respect to tableting, but they are not subjected to a final tableting step.

[0106] Pharmaceutical formulations of tamiflu can be formulated for administration to mammals, in embodiments humans. Tamiflu can be formulated, for example, as a viscous liquid solution or suspension for injection, in embodiments a clear solution. The formulation can include one or more solvents. Suitable solvents can be selected by considering the physical and chemical stability of the solvent at various pH levels, viscosity (which will allow injectability), fluidity, boiling point, miscibility, and purity. Suitable solvents include ethanol USP, benzyl alcohol NF, benzyl benzoate USP, and castor oil USP. Additional substances can be added to the formulation, such as buffers, solubilizers, and antioxidants, and others, including those disclosed in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition. The present disclosure encompasses a process for preparing the formulation of tamiflu by combining at least one of the above solid forms with at least one pharmaceutically acceptable excipient.

[0107] The solid state form, and pharmaceutical composition or formulation of tamiflu as defined herein may be used as a medicament, in embodiments for the treatment of transthyretin mediated amyloidosis.

[0108] The present disclosure also provides a method of treating thyroxine transporter-mediated amyloidosis by administering a therapeutically effective amount of a solid form of tamiflu of the present disclosure or at least one of the above pharmaceutical compositions or formulations to a subject with thyroxine transporter-mediated amyloidosis (in embodiments, wild-type or hereditary thyroxine transporter-mediated amyloid cardiomyopathy, or thyroxine transporter amyloidosis in an adult patient with stage 1 symptomatic polyneuropathy) to delay peripheral nerve damage or to a subject otherwise in need of treatment.

[0109] The present disclosure also provides the use of a solid form of clofazodone of the present disclosure or at least one of the above pharmaceutical compositions or formulations for the manufacture of a medicament for treating thyroxine transporter-mediated amyloidosis (in an embodiment, wild-type or hereditary thyroxine transporter-mediated amyloid cardiomyopathy, or thyroxine transporter amyloidosis in adult patients with stage 1 symptomatic polyneuropathy) to delay peripheral nerve damage.

[0110] The present invention has been described with respect to certain preferred embodiments, and other embodiments will become apparent to those skilled in the art by consideration of this specification. The present invention is further illustrated by reference to the following examples which describe in detail the preparation of the composition and the methods of using the composition. It will be apparent to those skilled in the art that many modifications to both materials and methods may be implemented without departing from the scope of the present disclosure.

[0111] Analytical methods

[0112] Powder X-ray Diffraction ("PXRD") Method:

[0113] The sample after pulverization with a mortar and pestle was applied directly to a silicon plate holder. The X-ray powder diffraction pattern was obtained with a Cu irradiation source = , Philips X'Pert PRO X-ray powder diffractometer with X'Celerator (2.022° 2θ) detector. Scanning parameters: angle range: 3°-40°, step length 0.0167, time per step 37 s, continuous scanning.

[0114] 13 C solid-state nuclear magnetic resonance ("ss-NMR" or 13 C solid state NMR) method

[0115] Solid-state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500 US / WB NMR spectrometer (Karlsruhe, Germany, 2013). 13 C CP / MAS NMR spectra were acquired at a rotation frequency of 11 kHz using a standard pulse scheme. The recycle delay was 8 s and the cross-polarization contact time was 2 ms. The rotation locking field B1 ( 13 C) has an intensity of 64kHz.

[0116] 13 The C NMR scale was referenced to α-glycine (176.03 ppm). Frictional heating of the rotating sample was counteracted by active cooling, and temperature calibration was performed with Pb(NO3)2. The NMR spectrometer was fully calibrated, and all experimental parameters were carefully optimized prior to the study. The magic angle was set using KBr during a standard optimization procedure, and the homogeneity of the magnetic field was optimized using adamantane samples (at an acquisition time of 250 ms, the resulting line width at half-height Δν1 / 2 was less than 3.5 Hz). Example

[0117] Tamiflu can be prepared according to the procedure described in US Pat. No. 7,214,695.

[0118] Example 1: Preparation of amorphous clofazodone

[0119] Trafenac (2.730 g) was subjected to grinding in a ball mill (agate jar, 3 agate balls φ=7 mm, frequency: 25 Hz, time: 6 h). The solid obtained was analyzed. The amorphous form of trafenac was confirmed by PXRD.

[0120] Example 2: Preparation of clofazodone Form I

[0121] The tamiprofen amorphous form (100 mg) obtained according to Example 1 was exposed to the vapor of a water / acetone solvent mixture (water / acetone volume ratio = 97 / 3) at 25°C for 33 days. The obtained solid was analyzed. Tamiprofen Form I was confirmed by PXRD.

[0122] Example 3: Preparation of clofazodone Form I

[0123] The tamiprofen amorphous form (100 mg) obtained according to Example 1 was exposed to the vapor of a water / methanol solvent mixture (water / methanol volume ratio = 99 / 1) at 25°C for 33 days. The obtained solid was analyzed. Tamiprofen Form I was confirmed by PXRD.

[0124] Example 4: Preparation of clofazodone Form I

[0125] The amorphous form of clofaconazole (100 mg) obtained according to Example 1 was exposed to water vapor at 25° C. for 33 days. The solid obtained was analyzed. Clofaconazole Form I was confirmed by PXRD.

[0126] Example 5: Preparation of clofazodone Form I

[0127] The amorphous form of clofaconazole (100 mg) obtained according to Example 1 was exposed to 100% relative humidity at 25°C for 30 days. The solid obtained was analyzed. Clofaconazole Form I was confirmed by PXRD.

[0128] Example 6: Preparation of clofazodone Form I

[0129] At room temperature, tautomer (1000 mg) was dissolved in 50 ml of tetrahydrofuran (THF). The obtained solution was added dropwise to 200 ml of water cooled to a temperature of 10° C. Crystallization was instantaneously obtained and the suspension was further mixed for one hour. The obtained solid was separated by vacuum filtration (973 mg) and analyzed by PXRD. Tautomer Form I was obtained.

[0130] Example 7: Preparation of clofazodone Form II

[0131] At 61° C., tamiprofen (122 mg) was dissolved in 7 mL of 2-methyltetrahydrofuran. The obtained solution was rapidly cooled in a cold bath and crystals were obtained at 7° C. The obtained solid was isolated by vacuum filtration (33 mg) and analyzed by PXRD. Tamiprofen Form II was obtained.

[0132] Example 8: Preparation of clofazodone Form II

[0133] At 25° C., tamiprofen (20 mg) was dissolved in 4 mL of 2-methyltetrahydrofuran. The obtained solution was allowed to evaporate slowly at room temperature for 7 days with the lid loosely attached. The obtained solid was analyzed by PXRD. Tamiprofen Form II was obtained.

[0134] Example 9: Preparation of clofazodone Form III

[0135] At reflux temperature (118°C), tautomer (20 mg) was dissolved in acetic acid (6 ml). The obtained solution was evaporated slowly. Crystallization was obtained after 24 hours. The obtained solid was separated by vacuum filtration and analyzed by PXRD. Tautomer Form III was obtained.

[0136] Example 10: Preparation of clofazodone Form III

[0137] Tamiflu (100 mg) was subjected to grinding in a ball mill (agate jar, 5 agate balls φ=7 mm, frequency: 25 Hz, time: 30 minutes). Acetic acid was added dropwise (three drops) in the ball mill. The solid obtained was analyzed by PXRD. Tamiflu Form III was obtained.

[0138] Example 11: Preparation of clofazodone Form III

[0139] At 92° C., tamiprofen (113 mg) was dissolved in 20.5 mL of acetic acid. The obtained solution was rapidly cooled in a cold bath and crystals were obtained at 65° C. The obtained solid was isolated by vacuum filtration (75 mg) and analyzed by PXRD. Tamiprofen Form III was obtained.

[0140] Example 12: Preparation of clofazodone Form III

[0141] Tamiflu (100 mg) was stirred in 1 mL of acetic acid at room temperature (25° C.). The solid obtained was analyzed by PXRD after 4 hours. Tamiflu Form III was obtained.

[0142] Example 13: Preparation of clofazodone Form III

[0143] Tamiflu (100 mg) was stirred in 1 mL of acetic acid at 50° C. The solid obtained was analyzed by PXRD after 2 hours. Tamiflu Form III was obtained.

[0144] Example 14: Preparation of clofazodone Form IV

[0145] At a temperature of 105°C, tautomer (511 mg) was dissolved in acetic acid (35 ml). The obtained solution was slowly (spontaneously) cooled. Crystallization was obtained at 89°C. The suspension was stirred for one hour and then separated by vacuum filtration (495 mg). The obtained solid was analyzed by PXRD. Tautomer Form IV (acetic acid solvate) was obtained.

[0146] Example 15: Preparation of clofazodone Form V

[0147] At room temperature, tautomer (172 mg) was dissolved in THF (12 ml). Antisolvent (methanol) was cooled to 0 ° C (ice bath) and added dropwise to the solution (48 ml). Crystallization was instantaneous. The suspension was stirred for one hour and then separated by vacuum filtration (108 mg). The obtained solid was washed with a solvent mixture of THF: methanol (1: 4). The obtained solid was analyzed by PXRD. Tautomer Form V was obtained.

[0148] Example 16: Preparation of clofazodone Form 4

[0149] Form II (2-methyl THF solvate) (Example 7) obtained from the snap cooling crystallization was dried in a vacuum desiccator at 150°C for 20 minutes. The obtained solid was analyzed by PXRD. Pure Form 4 was obtained (HPLC purity: 99.99%).

[0150] Example 17: Preparation of clofazodone Form 4

[0151] Form III (acetic acid solvate) obtained from the snap cooling crystallization (Example 11) was dried in a vacuum desiccator at 100°C for 1 hour. The solid obtained was analyzed by PXRD. Pure Form 4 was obtained.

[0152] Example 18: Preparation of clofazodone Form 4

[0153] Form IV (acetic acid solvate) was dried in a vacuum desiccator at 80°C. After 5 hours, Form IV began to convert into a mixture of Form IV and Form 4. The sample was dried for 22 hours. The solid obtained was analyzed by PXRD. The result was pure Form 4.

[0154] Example 19: Preparation of clofazodone Form 4

[0155] Form I (hydrate form) obtained from solvent-antisolvent reverse crystallization (Example 6) was dried in a vacuum desiccator at 150° C. for 20 minutes. The solid obtained was analyzed by PXRD. Pure Form 4 was obtained.

[0156] Example 20: Preparation of clofazodone Form 4

[0157] Form V (Example 15) obtained from solvent-antisolvent crystallization was heated in DSC up to 160°C for 10 minutes. The solid obtained was analyzed by PXRD. Pure Form 4 was obtained.

[0158] Example 21: Preparation of clofazodone Form V

[0159] By heating until 70 ℃-75 ℃, clofazoline (1.0 gram, 3.25 mmol, form 1) is dissolved in a mixture of solvent toluene / NMP (15V; 15% NMP). The solution is cooled spontaneously to 30 ℃, and slowly added to cold methanol (30V) at 0 ℃-5 ℃. Crystallization is instantaneous. The obtained suspension is stirred at 0 ℃-5 ℃ for 2 hours. The obtained crystals are separated by vacuum filtration. The obtained solid is washed with methanol (10V) and dried in a vacuum dryer at 80 ℃, 20 mbar for 6 hours (obtaining 0.9 gram of crystals, chromatographic purity 99%). The obtained solid is analyzed by PXRD. Clofazoline Form V is obtained.

[0160] Example 22: Preparation of clofazodone Form V

[0161] At room temperature, clofazoline (498 mg, Form 1) was dissolved in THF (28 ml). Antisolvent (methanol) was cooled to 0 ° C (ice bath) and added dropwise to the solution (92 ml). Crystallization was instantaneous. The suspension was stirred for one hour and then separated by vacuum filtration (427 mg). The obtained solid was washed with solvent mixture THF: methanol (1: 4). The obtained solid was analyzed by XRD. Clofazoline Form V (methanol solvate) was obtained. The obtained solid was heated at 80 ° C in a vacuum desiccator for 2 hours. The obtained solid was analyzed by PXRD. Clofazoline Form V (anhydrous) was obtained.

[0162] Example 23: Preparation of clofazoline anhydrous form V

[0163] 4-(3,5-Dichlorobenzamido)-3-hydroxybenzoic acid (25.00 grams; 76.7 mmol), toluene (281.3 ml), N-methyl-pyrrolidone (93.8 ml) and methanesulfonic acid (14.9 ml; 230.0 mmol; 3.0 equiv) were charged into a reactor at 20°C-25°C. The reaction mixture was heated to reflux temperature (117°C-119°C) and stirred until the reaction was complete (approximately 15 hours). The reaction mixture was then cooled to 100°C-110°C and the pH was adjusted to 1.4-1.8 with the addition of triethylamine (32 ml; 230.0 mmol; 3.0 equiv). The reaction mixture was added dropwise to cold methanol (750 ml; previously cooled to 0°C-5°C) over a period of 1 hour. Crystallization occurred. The suspension was stirred at 0°C-5°C for an additional 3 hours. The crystals of clofazoline methanol solvate were filtered off through a Buchner funnel and washed with methanol (2×100 ml). The wet crystals were suspended in fresh methanol (375 ml) at 20° C.-25° C. for 3 h-6 h. The crystals of clofazoline methanol solvate were filtered off through a Buchner funnel, washed with methanol (2×50 ml) and dried at 80° C., 20 mbar for 10 hours. White crystals of clofazoline anhydrous Form V were obtained.

[0164] Example 24: Preparation of clofazodone Form III

[0165] Tamiflu (100 mg) was stirred in 1 mL of acetic acid at room temperature (25° C.) for 4 hours. The mixture was filtered and the solid obtained was analyzed by PXRD. Tamiflu Form III was obtained.

[0166] Example 25: Preparation of clofazodone Form III

[0167] Tamiflu (100 mg) was stirred in 1 mL of acetic acid at 50°C for 2 hours. The mixture was filtered and the solid obtained was analyzed by PXRD. Tamiflu Form III was obtained.

[0168] This article also provides the following items:

[0169] 1. A crystalline form of tamiflu, designated Form V, characterized by data selected from one or more of the following:

[0170] (a) a PXRD pattern having peaks at 6.0 degrees, 19.9 degrees, 20.6 degrees, 23.9 degrees, and 29.2 degrees 2-θ ± 0.2 degrees 2-θ;

[0171] (b) Generally based on Figure 6 or Fig. 6A PXRD pattern depicted in;

[0172] (c) a solid state 13C NMR spectrum having peaks at 171.5 ppm, 161.0 ppm, 149.1 ppm, 144.7 ppm, 131.0 ppm ± 0.2 ppm;

[0173] (d) a solid-state 13C NMR spectrum having the following absolute differences in chemical shifts from a reference peak at 109.5 ppm ± 0.2 ppm: 62.1 ppm, 51.6 ppm, 39.6 ppm, 35.2 ppm, 21.5 ppm ± 0.1 ppm;

[0174] (e) Generally based on Figure 8 The solid-state 13C NMR spectrum depicted in; or

[0175] (f) Combination of these data.

[0176] 2. The crystalline form of clofazodone according to claim 1, characterized by being selected from the following data:

[0177] (a) a PXRD pattern having peaks at 6.0 degrees, 19.9 degrees, 20.6 degrees, 23.9 degrees, and 29.2 degrees 2-θ ± 0.2 degrees 2-θ;

[0178] (b) Generally based on Figure 6 PXRD pattern depicted in;

[0179] (c) Generally based on Fig. 6A PXRD pattern depicted in .

[0180] 3. A crystalline form of clofazod according to claim 1 or claim 2, characterized by having a PXRD pattern with peaks at 6.0, 19.9, 20.6, 23.9 and 29.2 degrees 2-θ ± 0.2 degrees 2-θ, and also having one, two, three or four additional peaks at 17.8, 25.8, 27.3 and 31.1 degrees 2-θ ± 0.2 degrees 2-θ.

[0181] 4. A crystalline form of clofazodone according to any one of items 1, 2 or 3, characterized by a PXRD pattern having peaks at 6.0, 17.8, 19.9, 20.6, 23.9, 25.8, 27.3, 29.2 and 31.1 degrees 2-θ ± 0.2 degrees 2-θ.

[0182] 5. Crystalline clofazodone methanol solvate.

[0183] 6. The crystalline clofazoline methanol solvate according to item 5, characterized by a PXRD pattern as defined in any one of items 2, 3 and 4.

[0184] 7. The crystalline form of tamifluanid according to any one of items 1, 2, 3 or 4, which is an anhydrous form or a solvated form.

[0185] 8. The crystalline form of tamifluanid according to any one of items 1, 2, 3 or 4, which is in an anhydrous form.

[0186] 9. Use of the crystalline form of tamiprofen according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8 for the preparation of other solid forms of tamiprofen, tamiprolate salts and solid forms of tamiprolate salts.

[0187] 10. A process for preparing other solid forms of tamiflu, other tamiflu acid salts or solid forms thereof, comprising preparing a crystalline form of tamiflu according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8 and converting it into other solid forms or salts of tamiflu.

[0188] 11. A process according to item 10, comprising reacting a crystalline form of clofazodone as defined in any one of items 1, 2, 3, 4, 5, 6, 7 or 8 with a base to form a salt, preferably wherein the base is selected from meglumine or an alkali metal / alkaline earth metal base, preferably wherein the alkali metal / alkaline earth metal base is selected from the group consisting of potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, calcium hydroxide or magnesium hydroxide, ammonia or an alkylamine, preferably a C1-6 mono(C1-6 alkyl)amine, a C1-6 di(C1-6 alkyl)amine or a C1-6 tri(C1-6 alkyl)amine.

[0189] 12. The crystalline form of tamiflu acid according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8, preferably wherein the crystalline form of tamiflu acid is according to any one of items 1, 2, 3 or 4, for use in the preparation of a pharmaceutical preparation or pharmaceutical composition, or a pharmaceutical preparation or pharmaceutical composition comprising another solid state form of tamiflu acid or a salt of tamiflu acid.

[0190] 13. The use according to item 12, wherein the pharmaceutical preparation is an oral preparation, preferably wherein the oral preparation is a tablet or a capsule.

[0191] 14. The use according to item 13, wherein the pharmaceutical preparation is a capsule, preferably a soft capsule.

[0192] 15. A pharmaceutical composition comprising the crystalline form of tamifluamide according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8, preferably wherein the pharmaceutical composition comprises the crystalline form of tamifluamide according to any one of items 1, 2, 3 or 4.

[0193] 16. The pharmaceutical composition according to item 15, which is in the form of a dispersion.

[0194] 17. A pharmaceutical formulation comprising a crystalline form of clofazolin according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8, and at least one pharmaceutically acceptable excipient; preferably wherein the pharmaceutical formulation comprises a crystalline form of clofazolin according to any one of items 1, 2, 3 or 4, and at least one pharmaceutically acceptable excipient.

[0195] 18. The pharmaceutical preparation according to item 17, wherein the pharmaceutical preparation is an oral preparation, preferably wherein the oral preparation is a tablet or a capsule, and preferably wherein the oral preparation is a soft capsule.

[0196] 19. A process for preparing a pharmaceutical formulation according to item 18, comprising combining the crystalline form of tamiflu according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8, preferably the crystalline form of tamiflu according to any one of items 1, 2, 3 or 4, with at least one pharmaceutically acceptable excipient.

[0197] 20. The crystalline form of tamiflu according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8, preferably the crystalline form of tamiflu according to any one of items 1, 2, 3 or 4, the pharmaceutical composition according to item 15 or item 16, or the pharmaceutical formulation according to item 17 or item 18, for use as a medicament.

[0198] 21. A crystalline form of tamiflu according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8, preferably a crystalline form of tamiflu according to any one of items 1, 2, 3 or 4, a pharmaceutical composition according to item 15 or item 16, or a pharmaceutical formulation according to item 17 or item 18, for use in the treatment of transthyretin-mediated amyloidosis, preferably for use in the treatment of familial amyloid polyneuropathy, wild-type or hereditary transthyretin-mediated amyloid cardiomyopathy, or transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy.

[0199] 22. Use of the crystalline form of tamiflu according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8, preferably the crystalline form of tamiflu according to any one of items 1, 2, 3 or 4, the pharmaceutical composition according to item 15 or item 16, or the pharmaceutical formulation according to item 17 or item 18 for the manufacture of a medicament for treating thyroxine transporter-mediated amyloidosis, preferably for treating familial amyloid polyneuropathy, wild-type or hereditary thyroxine transporter-mediated amyloid cardiomyopathy, or thyroxine transporter amyloidosis in adult patients with stage 1 symptomatic polyneuropathy.

[0200] 23. A method for treating thyroxine transporter-mediated amyloidosis, comprising administering a therapeutically effective amount of a crystalline form of tamiflu according to any one of items 1, 2, 3, 4, 5, 6, 7 or 8, preferably a crystalline form of tamiflu according to any one of items 1, 2, 3 or 4, a pharmaceutical composition according to item 15 or item 16, or a pharmaceutical formulation according to item 17 or item 18 to a subject having familial amyloid polyneuropathy, wild-type or hereditary thyroxine transporter-mediated amyloid cardiomyopathy, or an adult patient having stage 1 symptomatic polyneuropathy, thyroxine transporter amyloidosis or otherwise in need of treatment.

Claims

1. A crystalline form of tamiprolak, the crystalline form of tamiprolak being designated as Form V, characterized in that Data selected from one or more of the following: (a) a PXRD pattern having peaks at 6.0 degrees, 19.9 degrees, 20.6 degrees, 23.9 degrees, and 29.2 degrees 2-θ ± 0.2 degrees 2-θ; (b) a solid state 13C NMR spectrum having peaks at 171.5 ppm, 161.0 ppm, 149.1 ppm, 144.7 ppm, 131.0 ppm ± 0.2 ppm; or (c) Combinations of these data.

2. A crystalline form of tamiprolak, the crystalline form of tamiprolak being designated as Form V, characterized in that Data selected from one or more of the following: (d) a PXRD pattern substantially according to that depicted in FIG. 6 or FIG. 6A ; (e) a solid-state 13C NMR spectrum substantially in accordance with that depicted in FIG8 ; or (f) Combination of these data.

3. A crystalline form of tamiprofen, designated Form V, characterized in that Selected from the following data: (g) Solid-state 13C NMR spectrum with the following absolute differences in chemical shifts from the reference peak at 109.5 ppm ± 0.2 ppm: 62.1 ppm, 51.6 ppm, 39.6 ppm, 35.2 ppm, 21.5 ppm ± 0.1 ppm.

4. The crystalline form of tamifluanid according to any one of claims 1 to 3, characterized in that A PXRD pattern having peaks at 6.0 degrees, 19.9 degrees, 20.6 degrees, 23.9 degrees, and 29.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks at 17.8 degrees, 25.8 degrees, 27.3 degrees, and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

5. The crystalline form of tamifluanid according to any one of claims 1 to 3, characterized in that A PXRD pattern having peaks at 6.0 degrees, 17.8 degrees, 19.9 degrees, 20.6 degrees, 23.9 degrees, 25.8 degrees, 27.3 degrees, 29.2 degrees, and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

6. The crystalline form of tamifluanid according to any one of claims 1 to 3, which is in an anhydrous form or a solvated form.

7. The crystalline form of clofazodone according to claim 6, which is a methanol solvate.

8. Use of the crystalline form of tamiprofen according to any one of claims 1 to 7 for the preparation of other solid forms of tamiprofen, tamiprolate salts and solid forms of tamiprolate salts.

9. A process for preparing a solid form of tamiprofen, a salt of tamiprofen or a solid form thereof, comprising preparing a crystalline form of tamiprofen according to any one of claims 1 to 7 and converting it into other solid forms or salts of tamiprofen.

10. A process according to claim 9 comprising reacting a crystalline form of tamifluan as defined in any one of claims 1 to 7 with a base to form a salt.

11. The process according to claim 10, wherein the base is selected from meglumine or an alkali metal / alkaline earth metal base.

12. The process according to claim 11, wherein the alkali / alkaline earth metal base is selected from the group consisting of potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, calcium hydroxide or magnesium hydroxide.

13. The process according to claim 10, wherein the base is selected from ammonia or an alkylamine.

14. The process according to claim 13, wherein the alkylamine is selected from C1-6 mono(C1-6 alkyl)amine, C1-6 di(C1-6 alkyl)amine or C1-6 tri(C1-6 alkyl)amine.

15. Use of a crystalline form of tamifluan according to any one of claims 1 to 7 for the preparation of a pharmaceutical preparation or a pharmaceutical composition, wherein the pharmaceutical preparation or the pharmaceutical composition is for the treatment of transthyretin-mediated amyloidosis.

16. The use according to claim 15, wherein the pharmaceutical preparation or pharmaceutical composition comprises another solid form of tamiflu or a salt of tamiflu.

17. The use according to claim 15 or 16, wherein the pharmaceutical preparation is an oral preparation.

18. The use according to claim 17, wherein the oral formulation is a tablet or a capsule.

19. The use according to claim 17, wherein the pharmaceutical preparation is a soft capsule.

20. A pharmaceutical composition comprising chlorobenzene 2OA according to any one of claims 1 to 7 A crystalline form of oxadiazole acid.

21. The pharmaceutical composition according to claim 20, which is in the form of a dispersion.

22. A pharmaceutical formulation comprising the crystalline form of tamifluanid according to any one of claims 1 to 7, and at least one pharmaceutically acceptable excipient.

23. The pharmaceutical preparation according to claim 22, wherein the pharmaceutical preparation is an oral preparation.

24. The pharmaceutical preparation according to claim 23, wherein the oral preparation is a tablet or a capsule.

25. The pharmaceutical preparation according to claim 23, wherein the oral preparation is a soft capsule.

26. A process for preparing a pharmaceutical formulation according to any one of claims 22 to 25, comprising combining the crystalline form of tamifluan according to any one of claims 1 to 7 with at least one pharmaceutically acceptable excipient.

27. Use of a crystalline form of tamiflu acid according to any one of claims 1 to 7, a pharmaceutical composition according to claim 20 or claim 21, or a pharmaceutical formulation according to any one of claims 22 to 25 for the manufacture of a medicament for treating transthyretin-mediated amyloidosis.

28. The use according to claim 27, wherein the use is for the treatment of familial amyloid polyneuropathy, wild-type or hereditary transthyretin-mediated amyloid cardiomyopathy, or transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy.

29. The use according to claim 27, wherein when the medicament is used, a therapeutically effective amount of the crystalline form of tamifluac according to any one of claims 1 to 7, the pharmaceutical composition according to claim 20 or claim 21, or the pharmaceutical formulation according to any one of claims 22 to 25 is administered to a subject suffering from familial amyloid polyneuropathy, wild-type or hereditary transthyretin-mediated amyloid cardiomyopathy, or adult patients with stage 1 symptomatic polyneuropathy, transthyretin amyloidosis or otherwise in need of treatment.

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