TW201029981A - Tianeptine sulfate salt forms and methods of making and using the same - Google Patents

Abstract

Disclosed herein is a novel sulfate salt of tianeptine with improved properties. Also described herein are novel pharmaceutical compositions comprising tianeptine sulfate salt, methods of making, and related methods of treatment.

Description

201029981 VI. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention relates to tianeptine sulphate, which is an anthracene performance of tianeptine, and a phthalic acid salt. This publication also provides a method for making day/7 morning water-salt-salt m έΗ senaprofen sulphate in oral medicine and a phase treated with sennapeptine sulphate [prior art]

J Pu'er is a tricyclic 1 conjugate whose chemical name is η (3- 虱, - hydrogen ... methyl one and M [U] thiazepine _η_ group) amino] heptanoic acid, s, S-dioxide. Scale technique anti-depressant drugs. The free state of 嗟napron >τ is amphoteric, and there is a known amorphous sodium salt in the technical field. Wu Guo Patent No. 3758528 discloses a method for synthesizing 嗟nupeptine and its sodium salt, "Senaprofen, Ding Na (Print STABL (10) 8, .

Tatinol is currently approved for use in the treatment of one or more depressions in countries such as Europe, Latin America, Asia and parts of the Middle East. Thiopeptide, /butna (ie STABL0N®, Cc>axi and TatinQl8) will be rapidly and completely absorbed 'and have a very short terminal half-life, so effective treatment often requires multiple doses in one day. . > Before f, the pharmaceutical composition of 嗟 naproxen and butyl salt is generally administered orally three times a day. Such frequent oral administration may result in reduced compliance with the recommended medication 1. A controlled release tianeptine pharmaceutical composition should have a better control of the ride curve and therefore a lower recommended dose of 201029981. An advantage of such tianeptine sulphate is that it can be used to prepare a pharmaceutical composition for the controlled release of guanidinium. SUMMARY OF THE INVENTION The present invention is directed to a novel tianeptine sulfate, particularly an improved performance of tianeptine monohydrate hemisulfate. Such improved performance may include, but is not limited to, hygroscopicity, physical stability, and solubility. The present invention also provides novel pharmaceutical compositions containing tianeptine sulfate, methods of preparing tianeptine sulfate, and related methods of treatment. For example, tianeptine monohydrate hemisulfate provides an alternative to the commercially available pharmaceutical composition dosage form (tianapeptin sodium). The free state of tianeptine has the following structure (I):

(I). The tianeptine sulphate can be used in pharmaceutical compositions to treat conditions well known in the art, such as one or more of depression, intestinal tract (IBS), attention deficit hyperactivity disorder (ADHD), one or more Neurodegenerative diseases and asthma. 201029981 In some embodiments of the invention, 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][l,2]thiazepine-11 is provided -yl)amino]heptanoic acid, S,S-dioxide monohydrate hemisulfate, which exhibits the following formula (II):

In still other embodiments of the invention, crystalline 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][l,2]thiazepine is provided. -11-yl)amino]heptanoic acid, S,S-dioxide monohydrate hemisulfate, characterized by a powder X-ray diffraction pattern comprising about 8.97, about 11.49, about 14.73, in 2-inch. 20.59, about 22.83 and a peak of about 23.27 degrees. In other specific embodiments of the invention, there is provided a 7-[(3- gas-6,11-dihydro-6-methyldibenzo[c,f][l,2) formula (II) A method for the preparation of a sulfazepine-11-yl)amino]heptanoic acid, S,S-dioxide monohydrate hemisulfate, comprising the steps of: (a) dissolving 7-[(3-chloro-6,11-di) a mixture of hydrogen-6-methyldibenzo[c,f][l,2]thiazepine-11-yl)amino]heptanoic acid, S,S-dioxide or its sodium salt in water and acetic acid Adding a solvent to the reaction mixture of step (a) in water alone or in combination with acetic acid in sulfuric acid, and (c) crystallizing the compound of formula (II). 201029981 In a further embodiment of the invention, there is provided a controlled release matrix lozenge comprising a pharmaceutically effective amount of 7-[(3-chloro-6,11-dihydro-6-fluorenyl) Dibenzo[c,f][l,2]thiazepine-11-yl)amino]heptanoic acid, S,S-dioxide monohydrate hemisulfate, and one or more controlled release polymers, The tablet can provide an average southern plasma concentration (Cmax) of 7-[(3-chloro-6,11-dihydro-6-mercaptodibenzo[c,f][ when administered orally to a patient. l,2]thiazepine-11-yl)amino]heptanoic acid, S,S-dioxide is from about 100 ng/ml to 150 ng/ml. For a better understanding of the present invention, reference should be made to the accompanying drawings. The present invention relates to a novel tianeptine sulphate, more particularly σ sinap, and succinic monosulphate. Compared with one or more known tianeptine types, such as tianeptine free base or tianeptine sodium (currently used tianeptine type), tianeptine sulfate has improved efficacy . The sulfate can be formed in a variety of forms including, but not limited to, hydrates, solvates, and sulfate counterions of the various ionic ratios of ionic tianeptine. The invention also includes other forms of tianeptine sulfate, including but not limited to polymorphs, co-crystals and amorphous bodies. The invention also provides novel pharmaceutical compositions comprising these forms, methods of making the same, and related methods of treatment. All of the "tianapeptine sulfates" mentioned herein specifically mean tianeptine monohydrate hemisulfate. The salt of the present invention is a tianeptine sulfate. The tianeptine free base has the following structure (I): 201029981

〇 (1). In a first embodiment, the invention includes tianeptine sulfate. In a further embodiment, the tianeptine sulfate can be incorporated into a pharmaceutical composition. In other embodiments, the tianeptine sulfate can be incorporated into a controlled release pharmaceutical composition. In another embodiment, the tianeptine sulfate can be incorporated into a pharmaceutical composition comprising one or more layers of tianeptine sulfate, such that in the body, one layer can be released prior to bulk release in another layer. In another embodiment, the tianeptine sulfate can be incorporated into a pharmaceutical composition comprising granules, wherein the granules can have coatings of different ranges or chemical compositions, such that the release time of tianeptine can be substantially increased. Longer than the currently available tianeptine (eg STABLON®, Coaxil® or Tatinol®). In another embodiment, the tianeptine sulfate can be incorporated into a pharmaceutically active pharmaceutical composition suitable for oral administration. Permeable active pharmaceutical compositions suitable for oral administration, osmotic pumps, osmotic administration, and other infiltration techniques can include, but are not limited to, OROS® Push-Pull and OROS® 7 201029981 compositions. In another embodiment, "plug (iv) butyl sulphide is incorporated into the OROS8 drug delivery system. This controlled release composition constitutes (iv) naproxen (tetra) acid salt, such as a pharmaceutically acceptable pharmaceutical composition suitable for oral administration, which may have a longer lasting effect than the currently available form of the material 9 > In another embodiment of the invention, the sputum monohydrate + sulfate is included. Qian Pu, the structure of the single water and Wei Wei, the town (ιι):

So42- In one particular embodiment, the invention is directed to a version of tianeptine monohydrate hemisulfate crystals. In another embodiment, the naphthylsulfate monohydrate hemisulfate is present in at least an amount - such as (tetra) a monohydrate hemisulfate crystal. For example, in some embodiments, tianeptine monohydrate hemisulfate may be present in an amount of from about 20% to about 1% by weight of the naphthostatin monohydrate hemisulfate crystals. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the pXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak of about 8.97 degrees. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a 201029981 peak having a temperature of about 8.25 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate wherein the monohydrate hemisulfate exhibits a _pxRD diffraction pattern comprising a peak of about 11.49 degrees. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak of about 8 25 and about 8.97 degrees. In another embodiment, the present invention comprises a ruthenium sulphate, a ruthenium/single sulphur monosulfurate salt, a towel, a monohydrate hemisulfate exhibiting a PXRD diffraction pattern comprising 2-Θ of about 8.97 and about u 49 degrees. The crest. In another embodiment, the invention comprises a scaly monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak of 2_θ of about 3.9! and about 14.73 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises 2-Θ of about 8 25, about 8 97, and about Η49 degrees. crest. In another embodiment, the invention includes a naproxetine monohydrate hemisulfate wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises 2-theta of about 8 97, about 14 is about 18 and about The peak of 19.39 degrees. In another embodiment, the present invention includes thiaprofen > butyl monosulphate, wherein the PXRD diffraction pattern of bismuth monosulfate monohydrate comprises 2 - θ of about 8 25 , about u; 13.9 is about 16.95 and a peak of about 20.59 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises 2_θ of about 16 95, about 18.07, about 19.39, and about 20.59 degrees. crest. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern comprising 2_θ' of about 13.91, about 14.73, about 22.83, and about 23.27 degrees. crest. In another 9 201029981 a specific embodiment 'The present invention includes tianeptine monohydrate hemisulfate, wherein the 'single water hemisulfate exhibits a PXRD diffraction pattern comprising 2-Θ of about 8.25, about 8.97, about 11.49, about 13.91 and a peak of approximately 14.73 degrees. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern comprising 2-Θ of about 16.95, about 18.07, about 19.39, about 20.59, A peak of about 21.99 and about 23.27 degrees. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern comprising 2-Θ of about 8.25, about 8.97, about 11.49, about 13.91, Peaks of about 14.73, about 16.95, about 18.07, about 19.39, about 20.59, about 21.99, about 22.83, and about 23.27 degrees. In another embodiment, the invention comprises a naphthoic acid monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak of about 8.25, about 13.91, and about 14.73 degrees. . In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern comprising 2 - θ of about 8.97, about 18.07, about 19.39, and about 20.59 degrees. The crest. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises 2_θ of about 8.97, about 11.49, about 13 9 about 18.07, about 19.39 and a peak of about 20.59 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern substantially similar to that of Figure i. In another embodiment, the invention includes tianeptine monohydrate hemisulfate wherein the monohydrate hemisulfate exhibits a DSC thermogram comprising an endothermic transition point of about 193 degrees Celsius. In another embodiment, the invention includes 嗟蔡 201029981 ^Ding Zhengshui hemisulfate, wherein the monohydrate hemisulfate exhibits an Ou Wen graph which is substantially similar to FIG. In another embodiment, the invention package (iv) naproxen water hemisulfate, wherein the monohydrate hemisulfate exhibits a TGA temperature map substantially similar to that of FIG. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein 'single water hemisulfate exhibits a dynamic moisture adsorption analysis (D is similar to that of Figure 4. In another embodiment) For example, tianeptine monohydrate hemisulfate can be incorporated into a controlled release pharmaceutical composition. In another embodiment, the invention includes a guanidinium sulfonate; wherein the sulphate is non-hygroscopic. In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is non-hygroscopic at a relative humidity of from about 10% to about 90% relative humidity. In a specific embodiment, the present invention comprises tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate is non-absorbent at a relative humidity of about 10% to about 90% of DVS at 25 degrees Celsius. In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is non-hygroscopic at a relative humidity of from about 20% to about 80% relative humidity. In another specific embodiment, the invention includes a naphthoate sulfate wherein the sulfate is non-hygroscopic at a relative humidity of from about 30% to about 70% relative humidity. In another embodiment, the invention comprises a thionaphthalene Putin sulfate, wherein the sulfate is completely stable. In another embodiment, the present invention comprises a tianeptine sulfate wherein the sulfate is at a relative humidity of about 10% to about 90%. It is completely stable under relative humidity. In another specific embodiment, the present invention comprises a naproxen sulphur 201029981 ^, an acid salt, wherein the sulphate has a relative humidity of about 20% to a relative humidity of about 80%. The following is completely stable. In another embodiment, the invention comprises a tianeptine sulfate wherein the sulfate is fully stable at a relative humidity of from about 30% to about 70% relative humidity. According to the present invention, tianeptine sulfate may have a different stoichiometric ratio of ionized tianeptine (cation) to sulfate relative ion (anion). For example, the ratio of cation: negative ion may be 1:1 or 2: 1. Other equivalent ratios are also included in the present invention. In some embodiments, tianeptine monohydrate hemisulfate comprises an ionic thiophene 10 naproxet than sulfuric acid has a water ratio of about 2:1:2 In another embodiment, the invention includes tianeptine sulfate and methods of making and using same. In another embodiment, the invention includes hydrated statin sulfate hydrate and A method of preparation and use. In another embodiment, the invention comprises a solvate of tianeptine sulfate. In another embodiment, the invention consists of one or more tianeptine sulfate a polymorph of salt, or a polymorph of one or more of the tianeptine sulfate hydrate or solvate. In another embodiment, the invention comprises a co-crystal of tianeptine sulfate. In one embodiment, the invention includes an amorphous form of tianeptine sulfate and methods of making and using same. In another embodiment, the tianeptine sulfate form can be present, for example, but not limited to, in the form of an anhydrous form, a monohydrate form, a dehydrated form or a solvate. Such hydrates and solvate forms may have different tianeptine ion ratios than water or solvent 12 201029981 For example, but not limited to about 1:1, 1:1.5 compound molecular chemical equivalent 2:1 or 1:2 . In another embodiment, the invention provides a method of preparing tianeptine sulfate, comprising: (a) providing tianeptine or a sodium salt thereof; and (b) tianeptine or a sodium salt thereof Sulfuric acid acts to form crystallized tianeptine sulfate. In a particular embodiment, wherein the naproxen is in the form of a sodium salt. In another embodiment, a solvent is added to the sulphate or the sodium salt thereof prior to the incorporation of sulfuric acid. In another embodiment, (1) is completed in the presence of _, so that the solution is formed in the acid salt and the second. In another embodiment, step (b) is carried out in the presence of a solvent such that the suspension is formed in a specific embodiment prior to crystallization of the sulfate. The solvent is selected from the group consisting of: c-, ethanol, fumes, 'methanol' acetonitrile a group consisting of 'dichloromethane, water and a tetrahydrogen (th; ·. In another embodiment, a solvent may be a mixture of any two or more solvents, including For example, acetone, ethanol, nitromethane, methanol, 8.1, acetonitrile, methylene chloride, water, and tetrahydrofuran are provided. In another embodiment, the present invention provides a method for preparing hydrazine pentoxide. A method of semi-sulfate, comprising the steps of: (a) dissolving a guanidine lamp or a sodium salt thereof in a mixture of water and acetic acid; Λ σ (b) adding - a solvent alone or a solution of acetic acid in sulfuric acid a reaction mixture of (a), and (c) crystallized out of the sulphate monohydrate hemisulfate. 201029981 In some embodiments, the method may further comprise the step of: (d) by the above step (c) Separation of the obtained thiaprofen in the reaction mixture (e) washing tianeptine monohydrate hemisulfate with a mixture of water and acetic acid; (f) further cleaning the tianeptine monohydrate hemisulfate with water; and (g) drying Thiapeptin monohydrate hemisulfate. In some embodiments, carrying out the method does not involve isolating the intermediates shown below:

The tianeptine free base and tianeptine sodium can be prepared by one or more methods available in the art including, but not limited to, the method of U.S. Patent No. 3,758,528. In a particular embodiment of the invention, an physiologic and/or therapeutically effective amount of tianeptine sulfate in a mammal that is modulating the mammal is administered to the mammal. In another aspect, an effective amount of tianeptine sulfate which is sufficient to affect the physiology and/or treatment of the mammal is administered. 】4 201029981 Ο

In another embodiment of the present invention, a method of treating a mammal suffering from depression comprising administering an effective amount of tianeptine sulfate to said mammal is provided. In another embodiment, a method of treating a mammal suffering from intestinal fistula is provided, comprising administering to the mammal an effective amount of tianeptine sulfate. In another embodiment, k provides a method of treating a mouth milk animal suffering from attention deficit hyperactivity disorder comprising administering to the mammal an effective amount of tianeptine sulfate. In another embodiment, a method of treating a mammal suffering from filial π is provided, comprising administering to the mammal an effective amount of tianeptine sulfate. In another specific embodiment, the mammal is a human. In another embodiment of the invention, the preparation of a medicament comprising tianeptine sulfate is included. This agent can be used in mammals in need of such treatment to treat depression, intestinal tract, attention deficit hyperactivity disorder, one or more neurodegenerative diseases or asthma. In another specific embodiment, the mammal is a human. The pharmaceutical dosage form of tianeptine sulfate may have a variety of methods of administration including, but not limited to, oral administration. Oral pharmaceutical compositions and dosage forms are exemplary dosage forms. Alternatively, the oral dosage form may be a solid dosage form such as a keying agent, an easy-to-swallow tablet, a hard capsule, a starch capsule, a hydroxypropylmethylcellulose (HPMC) capsule, or a soft elastic gelatin capsule. The lozenges of the present invention can be made by any method known in the art. Conventional methods for the preparation of tablets include direct compression ("dry mixing"), dry granulation followed by pressure 2 and wet granulation followed by drying and compression. Other methods include the use of rolling compaction techniques such as chilS0nat0r or drop rolling, or forming, or casting, or extrusion techniques. All of these methods are well known in the art and are described in detail in, for example, Lachman, et al., "The Theory and Practice of Industrial Pharmacy/5 Chapter 11, (3rd Ed. 1986), incorporated herein by reference. The invention also provides liquid dosage forms which include, without limitation, examples such as suspensions, solutions, saccharides or emulsions. The naphthostatin sulphate is administered by means of controlled or delayed release. It has a general goal of improving the efficacy of its non-controlled release drugs. Ideally, the optimally designed controlled release formulation is medically characterized by the lowest A PI (active pharmaceutical ingredient) release in the shortest time to cure or Control of the condition. Preferred controlled release pharmaceutical compositions generally include: 1) delayed API activity; 2) reduced dose frequency; 3) improved patient compliance; 4) less total AI > I dose; 5) reduction Local or systemic side effects; 6) Minimization of API accumulation; 7) Reduce fluctuations in blood concentration; 8) Improve treatment outcome; 9) Reduce enhancement effect or reduce API activity; and 1) Improve control The rate of control of the disease or condition. (Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 Technomic Publishing Lancaster, Pa.: 2000) ° In some embodiments of the invention, a typical daily dose includes tianap Sulfate, at a dose of from about 10·0 mg to about 5 mg, from about 12.5 mg to about 50.0 mg, from about 12.5 mg to 37.5 mg, or from about 25.0 mg to 37.5 g. In particular embodiments In this combination, the tianeptine sulfate is a saponin monohydrate hemisulfate. The dosages described herein are tianap, and the doses of the self-test do not include relative ions (such as sulfuric acid). Or the weight of any water-retaining agent molecule. 201029981 In another embodiment of the invention, a pharmaceutical composition, including oral tianeptine sulfate, is administered at a dose of from about 10.0 mg to about 50.0 mg, about 12.5 mg. To about 50.0 mg, about 25.0 mg to 50.0 mg, or about 37.5 mg to 50.0 mg of tianeptine. For example, about 12.5 mg, about 25.0 mg or about 37.5 mg. In one embodiment, the pharmaceutical composition comprises an orally available tianeptine sulfate at a dose of about 25.0 mg or about 37.5 mg. The total amount of the dose can be administered in a single or divided dose. In some embodiments, the dosage form is administered once a day. In some embodiments, the dosage form is administered multiple times per day. In another embodiment, each dose of the pharmaceutical composition comprises naproxen sulfate, which comprises up to 50.0 mg of tianeptine. In some embodiments, the daily dosage form of the invention comprises tianeptine sulfate at a dose of from about 25.0 mg to about 200.0 mg, from about 25.0 mg to about 150.0 mg, from about 25.0 mg to 100.0 mg, or about 25.0 mg. It is about 75.0 mg. In a particular embodiment, the tianeptine sulfate in the composition is tianeptine G-single monohydrate hemisulfate. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (e.g., sulfuric acid) or any water or solvent molecules. In another embodiment of the invention, a pharmaceutical composition comprising orally oral tianeptine sulfate, a necessary dose of from about 25.0 mg to about 200.0 mg, from about 25.0 mg to about 150.0 mg, from about 25.0 mg to about 100.0 Mg, about 25.0 mg to 75.0 mg, or about 50.0 mg to 75.0 mg of tianeptine. For example, about 25.0 mg, about 50.0 mg, or about 75.0 mg. In a specific embodiment of the invention, the pharmaceutical composition comprises an orally acceptable tianeptine sulfate at a dose of about 25.0 mg, about 50.0 mg, or about 75.0 mg. In another embodiment, a daily dosage of a pharmaceutical composition comprising tianeptine sulfate comprising up to 100.0 mg of indapeptin. In some embodiments of the invention, each dosage form comprises tianeptine sulfate, at a dose of from about 30.0 mg to about 200.0 mg, from about 30.0 mg to about 150.0 mg, from about 30.0 mg to 100.0 mg, or from about 30.0 mg to About 60.0 mg. In a specific embodiment, the tianeptine sulfate in the composition is tianeptine monohydrate hemisulfate. The dosage described herein is the dose of tianeptine free base, excluding the weight of the relative ion (e.g., citric acid) or any water or solvent molecule. In another embodiment of the invention, a pharmaceutical composition comprising orally oral tianeptine sulfate, a necessary dose of from about 30.0 mg to about 200.0 mg, from about 30.0 mg to about 150.0 mg, from about 30.0 mg to about 100.0 mg. , about 30.0 mg to 60.0 mg of tianeptine. For example, about 30.0 mg, about 60.0 mg, about 100.0 mg. In a specific embodiment, the pharmaceutical composition comprises an orally available tianeptine sulfate at a dose of about 30.0 mg, about 60.0 mg, and about 100.0 mg. In another embodiment, each dose of the pharmaceutical composition comprises tianeptine sulfate, which comprises up to no more than 100.0 mg of tianeptine. In another embodiment of the present invention, a pharmaceutical composition, including oral tianeptine sulfate, is administered at a dose of from about 1 mg to about 50.0 mg, from about 12.5 mg to about 50.0 mg, and about 25.0 18 201029981 mg to 50.0 mg, or about 37.5 mg to 50.0 mg of tianeptine. For example, about 12.5 mg, about 25.0 mg or about 37.5 mg. In a specific embodiment, the tianeptine sulfate is tianeptine monohydrate hemisulfate in this combination. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (e.g., sulfuric acid) or any water or solvent molecules. In another embodiment of the invention, a pharmaceutical composition, including oral tianeptine sulfate, is administered at a dose of from about 10.0 mg to about 50.0 mg, from about 12.5 mg to about 50.0 mg, and from about 25.0 mg to 50.0. About mM, or about 37.5 mg to 50.0 mg of tianeptine. For example, about 12.5 mg, about 25.0 mg or about 37.5 mg. In a particular embodiment, the pharmaceutical composition comprises an orally acceptable tianeptine sulfate at a dose of about 25.0 mg or about 37.5 mg. The total dose can be administered in a single or divided dose. In another embodiment, the daily dose of the pharmaceutical composition comprises tianeptine sulfate comprising up to 50.0 mg of tianeptine. In some embodiments, the daily dosage form of the invention comprises tianeptine sulfate at a dose of from about 25.0 mg to about 200.0 mg, from about 25.0 mg to about 150.0 mg, from about 25.0 mg to 100.0 mg, or about 25.0. The milligram is about 75.0 mg. In a particular embodiment, the tianeptine sulfate in the composition is tianeptine monohydrate hemisulfate. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (e.g., sulfuric acid) or any water or solvent molecules. In another embodiment of the present invention, a pharmaceutical composition comprising oral narnatine sulfate, the necessary dose of about 25.0 mg to 19 201029981 '1 about 200.0 mg, about 25.0 mg to about 150.0 mg, about 25.0 From milligrams to about 100.0 milligrams, about 25.0 milligrams to about 75.0 milligrams, or about 50.0 milligrams to about 75.0 milligrams of tianeptine. For example, about 25.0 mg, about 50.0 mg, or about 75.0 mg. In a specific embodiment, the pharmaceutical composition comprises an orally acceptable tianeptine sulfate at a dose of about 25.0 mg, about 50.0 mg, or about 75.0 mg. In another embodiment, a daily dosage of a pharmaceutical composition comprising tianeptine sulfate comprises up to no more than 100.0 mg of tianeptine. In some embodiments of the invention, the daily dosage form comprises tianeptine sulfate, at a dose of from about 30.0 mg to about 200.0 mg, from about 30.0 mg to about 150.0 mg, from about 30.0 mg to 100.0 mg, or about 30.0 mg. To about 60.0 mg. In a specific embodiment, the tianeptine sulfate in the composition is tianeptine monohydrate hemisulfate. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (e.g., sulfuric acid) or any water or solvent molecules. In another embodiment of the invention, a pharmaceutical composition comprising orally oral tianeptine sulfate, a necessary dose of from about 30.0 mg to about 200.0 mg, from about 30.0 mg to about 150.0 mg, from about 30.0 mg to about 100.0 mg, about 30.0 mg to 60.0 mg of tianeptine. For example, about 30.0 mg, about 60.0 mg, about 100.0 mg. In a specific embodiment, the pharmaceutical composition comprises an orally available tianeptine sulfate at a dose of about 30.0 mg, about 60.0 mg, and about 100.0 mg. In another embodiment, a daily dose of the medicinal composition 20 201029981 comprises a naproxen sulphate comprising up to no more than 100.0 mg of tianeptine. In other specific embodiments, the invention is directed to a pharmaceutical composition comprising the tianeptine sulfate described herein and one suitable for administration to a mammal for treating or preventing one or more of the symptoms described herein. Or a plurality of diluents, carriers and/or excipients. In some embodiments, a pharmaceutical composition comprises tianeptine monohydrate hemisulfate and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical combination is a controlled release pharmaceutical composition. In one embodiment, a ® tianeptine sulfate controlled release pharmaceutical composition requires less excipient mixed complex than other types of tianeptine pharmaceutical compositions. The tianeptine sulfate of the present invention can also be used in the preparation of a dosage form other than the above oral drug, such as a topical dosage form, an injection dosage form, a transdermal absorption dosage form and a mucosal dosage form. For example, these forms include creams, emulsions, solutions, suspensions, emulsions, ointments, powders, patches, suppositories, and the like. In other embodiments, the present invention is directed to a controlled release tableting agent comprising a pharmaceutically effective amount of tianeptine sulfate, particularly tianeptine monohydrate hemisulfate, and one or more The released polymer is controlled to provide an average maximum plasma concentration (Cmax) of tianeptine from about 100 ng/ml to 150 ng/ml when administered to a patient. In some embodiments, wherein the average highest plasma concentration (C m ax) of tianeptine is about 100 ng/ml to 120 ng/m tablet may be included when administered to a patient orally. A milligram dose of tianeptine. 21 201029981 In some embodiments, the controlled release lozenge is tested in vitro when using the United States Pharmacopoeia Dissolving Instrument Type II (paddle type) at 100 rpm in 900 ml of simulated gastric fluid (pH about 1.2) at 37 °C. Dissolution, after less than 14% release of tianeptine monohydrate hemisulfate after one hour, after 7 hours released between 45% to 80% of tianeptine monohydrate hemisulfate' and at 16 hours , releasing more than 90% of tianeptine monohydrate hemisulfate by weight. In other embodiments, 'When the U.S. Pharmacopeia Dissolution Apparatus Type II (paddle type) is in 900 mL of the gastric fluid (pH about 1.2), at about 37 ° C lOO rpm, less than 20% by weight of tianap The succinic monosodium sulphate salt is released after 2 hours, about 5% by weight to about 80% of tianeptine monohydrate hemisulfate is released after 8 hours, and after η hours, more than 90% by weight of tianeptine Monohydrate hemisulfate is released. In some embodiments, when the patient orally takes the tablet, the tablet provides a median mean plasma concentration (Tmax) of tianeptine for a period of about 2.5 to 3 hours. In a particular embodiment, the average area under the curve of the plasma concentration time curve is about 1170 to 1380 ng.hr/mL when the patient orally takes the tablet. The key contains tianeptine at a dose of 25 mg. In some embodiments, one or more controlled release polymers are included in the tablet: they comprise a cellulosic polymer, such as, but not limited to, hydroxypropylcellulose. Further, the one or more controlled release polymers comprise: a first hydroxypropylmethylcellulose having a viscosity of 80 to 120 cps (2% aqueous solution) and a second having a viscosity of 3,000 to 5,600 cps (2% aqueous solution) Hydroxypropyl cellulose. In a specific embodiment of 22 201029981, the ratio of the first to the second hydroxypropylmethylcellulose is from about 2:1 to about 4:1. In some embodiments, the controlled release matrix emollient further comprises a filler, such as microcrystalline cellulose. The tablet further comprises an excipient such as magnesium stearate. In a particular embodiment, the tablet further comprises a phthalic acid gel.

The type of tianeptine sulfate of the present invention can be characterized by data such as: TGA, DSV, DVA, single crystal X-ray diffractometer data or any one, any two, any three, any four, any A single integer of five, any six, any seven, any eight, any nine, any ten or any of the ΡΧΚΧ>-2 Θ peaks or any combination of any of the above required data analysis techniques. The invention also relates to a novel tianeptine hydrochloride. The properties of tianeptine hydrochloride can be improved to one or more known forms of thiaprofen > butyl, such as tianeptine sodium free base or tianeptine sodium (currently thiabendidine) Form). Hydrochloride salts can include, but are not limited to, the following forms: hydrates and solvates, and the chemical equivalent ratio of several different ionized thiazepine to chlorine counterions. The invention also encompasses; the type of naproxen hydrochloride; the polymorph, the stereotype, but not limited to the above. The present invention also provides novel pharmaceutical compositions comprising the manufacturer's compounds, and related therapeutic methods for preparing such compounds. ~NT + put π bar containing 嚜 naproxen hydrochloride guanidine. In a further embodiment of the invention, 嗟Cai butyl hydrochloride can be combined into a pharmaceutical composition. In a specific embodiment of the invention, the guanidine and the sulphate hydrochloride can be combined into a controlled release pharmaceutical composition. 23 201029981 In another embodiment, tianeptine hydrochloride can be incorporated into a pharmaceutical composition comprising two or more layers of tianeptine hydrochloride, such that one layer of the organism is prior to the other freed. In another embodiment, tianeptine hydrochloride can be incorporated into a pharmaceutical composition which is in the form of a tablet and has a range and composition of different coatings such that the release time of tianeptine can be compared The currently available tianeptine (eg STABLON®) has a longer release time. In another embodiment, tianeptine hydrochloride can be incorporated into a pharmaceutical composition suitable for oral osmotic activity. Permeable active pharmaceutical compositions, osmotic pumps, osmotic drugs, osmotic drug release and sputum Other suitable osmotic techniques for oral administration may include, but are not limited to, 〇R〇s8 Push-Pull and 〇R〇S® three-layer pharmaceutical compositions. In another specific embodiment, tianeptine hydrochloride can be incorporated into a 〇R〇s8 drug delivery system. Such a controlled release pharmaceutical composition comprising tianeptine hydrochloride, such as a pharmaceutical composition suitable for oral osmotic activity, is more durable than the currently sold tianeptine sodium salt. In another embodiment, the invention comprises tianeptine hydrochloride. In another embodiment, the invention comprises a naphthoquinone; a guanidine hydrochloride salt wherein the hydrochloride salt comprises a wave front at a rate of 7 θ of about 7 23 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine hydrochloride' wherein the hydrochloride salt comprises a wave front at a Θ about 9.91 degrees in the PXRD diffraction pattern. In another embodiment, the invention comprises a guanidinium lamp hydrochloride wherein the hydrochloride salt comprises a wave front at a Θ about 14.53 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises a wave front in the PXRD diffraction pattern at a time of 2.23 degrees and 9.91 degrees at 2:00, 24,299,819. . In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises a wave front at each of about 9.43 degrees and 14.53 degrees in the PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises a wave front in the PXRD diffraction pattern at a concentration of about 7.23 degrees and 10.53 degrees. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride comprises a wave in the PXRD diffraction pattern at a concentration of about 7.23 degrees, 9.91 degrees, and 14.53 degrees. Front. In another embodiment, the present invention comprises tianeptine hydrochloride, wherein the hydrochloride is in the PXRD diffraction pattern at about 9.43 degrees, 10.53 degrees, 14.53 degrees, and 18.35 degrees at 2-Θ. Each contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt in the PXRD diffraction pattern is about 7.23 degrees, 9.91 degrees, 18.35 degrees, 21.39 degrees, and 23.93 at 2-Θ. Each time contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt in the PXRD diffraction pattern is at about 9.91 degrees, 14.53 degrees, 18.35 degrees, and 21.39 degrees at 2-Θ Each contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt in the PXRD diffraction pattern is about 7.23 degrees, 9.43 degrees, 1 〇 53 degrees, and 18.35 at 2-Θ Each time contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt in the PXRD diffraction pattern is at about 9.43 degrees, 9.91 degrees, 10.53 degrees, 14.53 degrees, and 21.39 at 2-Θ. Each time contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is in the PXRD diffraction pattern at about 2-3.2 degrees, 10.53 25 201029981 degrees, 14.53 degrees, 18.35 degrees in the PXRD diffraction pattern. At 21.39 degrees and 23.93 degrees each contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt in the PXRD diffraction pattern is at about 7.23 degrees, 9.43 degrees, 9.91 degrees, 10.53 degrees, 14.53 at 2-Θ. Degrees, 18.35 degrees, 21.39 degrees and 23.93 degrees each contain a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the PXRD diffraction pattern of the hydrochloride salt is substantially similar to that of Figure 5. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises an endothermic transfer at about 199 ° C in a DSC thermogram. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the DSC thermogram of the hydrochloride salt is substantially similar to that of Figure 6. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the TGA thermogram of the hydrochloride salt is substantially similar to that of Figure 7. In another embodiment, the invention comprises tianeptine hydrochloride wherein the hydrochloride vapor sorption (DVS) characteristic of the hydrochloride salt is substantially similar to that of Figure 8. In another specific embodiment, tianeptine hydrochloride is incorporated into a controlled release pharmaceutical composition. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is moisture resistant. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is moisture resistant and has a relative humidity of from about 10% to about 90%. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is moisture resistant and has a relative humidity of from about 20% to about 80%. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is moisture resistant and has a relative humidity of from about 30% to about 70%. In another embodiment, the invention comprises tianeptine hydrochloride, wherein 26 201029981 zhongzhi hydrochloride is completely stable. In another embodiment, the invention comprises tianeptine hydrochloride wherein the hydrochloride salt is fully stable ' has a relative humidity of from about 10% to about 90%. In another embodiment, the f invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is fully stable ' has a relative humidity of from about 20% to about 80%. In another embodiment, the invention comprises tianeptine hydrochloride wherein the hydrochloride salt is 'having a relative humidity of from about 30% to about 70%. According to the present invention, tianeptine hydrochloride may have different

Ο 隹 隹 办 塞 塞 萘 萘 萘 萘 塞 塞 塞 塞 塞 塞 塞 塞 塞 塞 塞 塞 塞 塞 塞 。 。 。 。 。 For example, the ratio of cation: anion is about 1: 1 ^ 2: 1 〇 ^ The present invention also includes other chemical ratios. In another embodiment, the invention comprises tianeptine hydrochloride and its manufacture and in another embodiment the invention comprises a hydrate of a naproxetine salt. In another embodiment, the invention comprises a solvate of the intermediate naproxen hydrochloride. In another embodiment, the invention comprises one or more morphologies of thiaeptine hydrochloride or a hydrate or solvate of thiaeptine hydrochloride. In another embodiment, the invention comprises a co-crystal of a thiabendazole: salt salt. In another embodiment, the invention is a non-shaped body of naphthylpyridinium hydrochloride and a method of making and using same. /, · In another specific embodiment, The serpineptine hydrochloride salt may be in the form of an anhydrous form or a solvate, but is not limited to the above form. The form of 5 Hydration or solvate has a chemical equivalent ratio of ionized naproxet to water or solvate molecules, such as: 1: 1: 1 '5, 2. 1 or 1: 2, But not limited to the above ratio. 27 201029981 In another embodiment, the present invention provides a method of producing tianeptine hydrochloride, comprising: (C) providing tianeptine or a sodium salt thereof; and (d) the tianap The sodium salt or its sodium salt is contacted with hydrochloric acid to crystallize the tianeptine hydrochloride. In a particular embodiment, the tianeptine is in the form of a sodium salt. In another embodiment, a solvent is added to the tianeptine or its sodium salt prior to the hydrochloric acid treatment. In another embodiment, step (b) is carried out in the presence of a solvent such that a solution is formed prior to crystallization of the hydrochloride salt. In another embodiment, step (b) is carried out in the presence of a solvent such that a suspension is formed prior to crystallization of the hydrochloride salt. In certain embodiments, a solvent is selected from the group consisting of acetone, ethanol, methyl nitrate, decyl alcohol, acetonitrile, di-methane, water, and tetrahydrofuran (THF). In another embodiment, a solvent comprises a mixture of any two or more solvents including, but not limited to, acetone, ethanol, nitroxanthene, decyl alcohol, acetonitrile, dichloropurine, water, and tetrahydrofuran. The tianeptine free base and tianeptine sodium can be prepared by one or more methods in the art, including, but not limited to, the method of U.S. Patent No. 3,758,528. In a particular embodiment of the invention, the mammal is orally administered with an effective amount of tianeptine hydrochloride which modulates the physiological function of the mammal and/or treats the mammal. In the dosage portion, oral tianeptine hydrochloride is sufficient to affect the modulation of physiological functions and/or treatment of mammals. In another embodiment, a method of treating a mammal suffering from depression comprising administering to the mammal an effective amount of tianeptine hydrochloride is administered. In another embodiment, a method of treating a mammal suffering from stimulating bowel syndrome comprising administering an effective amount of a naproxen hydrochloride to the mammal is provided. In another embodiment, a method of treating a mammal suffering from attention deficit hyperactivity disorder is provided, which comprises administering to the mammal an effective amount of a naproxetine hydrochloride. In another embodiment, a method of treating a caring disorder suffering from asthma is provided, comprising administering to the mammal an effective amount of tianeptine hydrochloride. In another embodiment, the mammal is a human. In another embodiment, the invention comprises the preparation of a medicament comprising tianeptine hydrochloride. The agent can be used to treat depression, irritating bowel syndrome, attention deficit hyperactivity disorder or asthma, and is used in mammals in need of such treatment. In another embodiment, the mammal is a human. The pharmaceutical dosage form of guanidinium hydrochloride can be administered in several ways including, but not limited to, oral administration. Oral pharmaceutical compositions and dosage forms are exemplary dosage forms. The oral dosage form may optionally be in the form of a solid dosage form such as a lozenge, an oval tablet, a hard gelatin capsule, a starch capsule, a hydroxypropyl decyl fiber (HPMC) capsule or a soft and elastic gelatin capsule. Dosage forms include, but are not limited to, suspensions, solutions, syrups or emulsions. The tianeptine hydrochloride is administered as a controlled or delayed release method. Release control pharmaceutical products often have the same goal of improving the treatment of drugs by releasing uncontrolled counterparts. In medical therapy, an ideally designed release control preparation is characterized by the use of minimal API (active pharmaceutical ingredient) substances to treat or control the condition, and the advantages of achieving a release control bark composition in the shortest day-to-day interval usually include: (1) delay in API activity; (2) decrease in the number of doses; (3) increase = 29 201029981 '. human compliance; (4) less use of total sputum; (5) reduce local or systemic side effects; 6) reduce the accumulation of API; (7) reduce the fluctuation of blood concentration; (8) improve the efficacy of treatment; (9) reduce the multiplication or loss of API activity; and (10) improve the speed of disease or state control ( Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa.: 2000) The representative daily dose of the present invention comprises from about 10.0 mg to 50.0 mg, from 12.5 mg to 37.5 mg or 25.0 mg to 37.5 mg of tianeptine hydrochloride. The dosages described herein indicate that the dose of 嚷neptine free test does not include relative ions (e.g., chlorine) or the weight of any water and @solvent molecules. ~ In another specific embodiment of the present invention, a pharmaceutical composition containing a naphthoquinone hydrochloride hydrochloride which is administered orally in an amount of from 10.0 mg to 50.0 mg, 12.5 mg to 5〇.〇mg, 25〇 to 50, 〇mg or 37.5 mg to 50 mg of tianeptine. For example, H 12.5 mg, 25.0 mg or 37.5 mg. In a particular embodiment, a pharmaceutical composition comprising sennapeptin hydrochloride can be administered orally to about 25 ounces or 37.5 mg. This dose can be administered in a single or divided dose. In another embodiment of the present invention, the daily dose of the pharmaceutical composition comprising singapore 'butyrate hydrochloride is up to about 50.0 mg of thiaprofen. In another specific embodiment, the present invention relates to a composition comprising the naproxetine hydrochloride as described in the above, and one or more diluents, carriers and/or excipients suitable for oral administration to a mammal. To treat or prevent one or more of the conditions described herein. In a specific embodiment, the sputum sputum, the hydrochloride salt release control pharmaceutical composition is compared with other medicinal compositions containing bismuth; two = 30 201029981 medicinal composition - its need - less complex excipients can also be salt The acid salt is in addition to the above-mentioned dosage forms, dosage forms, and other medical dosage forms, such as: topical dosage forms, non-oral lotions, agents, and adhesive dosage forms. Examples of such dosage forms are as follows: emulsifiable concentrates, agents, and the like. Reading, suspension, lotion, ointment, powder, patch and inspection

Characteristics of the Γ Γ 硫酸 硫酸 硫酸 顾 顾 顾 顾 顾 顾 顾 顾 C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C ~ Any combination of eight, any seven, any eight, any nine, any single integer of 1^_2Θ peaks and any of the above data analysis techniques. This invention relates to a novel naproxetine acid salt. Compared with one or more known types of tianeptine, the characteristics of tianeptine can be improved. For example, tianeptine free base or tianeptine sodium (Minute 1J dexamepeptine) Available types). The phosphate may comprise the following types: hydrates and solvates, and stoichiometric ratios of several different ionized tianeptine to gas relative ions, but are not limited to the above. The invention also includes other tian naproxes. Plastics such as phosphonates include, but are not limited to, allotropes, co-crystals, and amorphous forms. The invention also provides novel pharmaceutical compositions comprising such compounds, methods of making such compounds, and related methods of treatment. In a particular embodiment, the invention comprises a naphthostatin sulphate. 4 201029981 In further embodiments, tianeptine phosphate can be incorporated into a pharmaceutical composition. In a further embodiment, the tianeptine phosphate can be incorporated into a release controlled pharmaceutical composition. In another embodiment, the tianeptine wall salt can be incorporated into a pharmaceutical composition comprising two or more layers of tianeptine phosphate in which one layer is released prior to the other. In another embodiment, the tianeptine phosphate can be incorporated into a pharmaceutical composition that is in the form of a sheet and has a range and composition of different coatings such that the release of tianeptine can be compared to current The tianeptine obtained (eg STABLON®) has a longer release time. In another embodiment, the tianeptine phosphate can be incorporated into an osmotically active pharmaceutical composition suitable for oral administration. Osmotic active pharmaceutical compositions, osmotic pumps, osmotic drugs, osmotic drug release and other suitable oral permeation techniques may include, but are not limited to, OROS® Push-Pull and 〇R〇s® three-layer pharmaceutical compositions. In another specific embodiment, tianeptine phosphate can be incorporated into a 〇R〇S® drug delivery system. A controlled release pharmaceutical composition comprising tianeptine phosphate, such as an osmotically active pharmaceutical composition suitable for oral administration, 10 which provides a longer lasting therapeutic effect than the currently sold tianeptine sodium salt. In a specific embodiment, the invention comprises guanidinium >, a butylate. In another embodiment, the invention comprises a naproxen hydrochloride salt wherein the phosphate contains a wave front at a PXRD diffraction pattern of about 6.83 degrees. In another embodiment, the invention comprises tianeptine phosphate wherein the phosphate comprises a wave front at a Θ about 9.27 degrees in a PXRD diffraction pattern. In another embodiment 32 201029981, the invention comprises tianeptine phosphate wherein the phosphate contains a wave front at a Θ about 11.95 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate comprises a wave front at each of about 6.83 degrees and 9.27 degrees in the PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine phosphate' wherein the hydrochloride salt in the PXRD diffraction pattern each contains a wave front at about 2-95 Å and 13.53 degrees. In another embodiment, the invention comprises tianeptine phosphate wherein the phosphate comprises a wave front in the PXRD diffraction pattern at a level of about 0.131 and 17.35 degrees. In another embodiment, the invention comprises tianeptine phosphate ' wherein the phosphate comprises a wave front at each of about 6.83 degrees, 11.95 degrees and 13.53 degrees in the PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate is in a PXRD diffraction pattern at a temperature of about 0.131 degrees, about 35 degrees, 18.47 degrees, and 20.93 degrees. Contains a wave front. In another embodiment, the present invention comprises tianeptine hydrochloride, wherein the acid salt in the PXRD diffraction pattern is at about 6.83 degrees, 9.27 degrees, U.95 degrees, 13.53 degrees in 2?? At 16.31 degrees each has a wave front. In another embodiment, the invention comprises u-inopidine, wherein the sulphate is in the PXRD diffraction pattern at about 2-93 93, 21.49 degrees, 22.77 degrees, and 23.67. Each has a wave front. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate comprises one in each of the 2-x, about 6.83, 13.83, 17.35, and 18.47 degrees in the pxrd diffraction pattern. Wave front. In another embodiment, the invention comprises a naphthostatin phosphate, wherein the phosphoric acid is in the PXRD diffraction pattern at about 2.27 degrees, U.95 degrees, 13.53 degrees, 16.31 at 2 to θ 33 4 4201029981. Degrees and 18.47 degrees each contain a wave front. In another embodiment, the invention comprises a naphthostatin phosphate, wherein the acidate in the pxrd diffraction pattern is at about 6.83 degrees, 11.95 degrees, 16.31 degrees, 17% degrees at 2-Θ, 20.93 degrees and 22.77 degrees each contain a wave front. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate is in the PXRD diffraction pattern 'at 2-Θ about 6.83 degrees, 9.27 degrees, 11.95 degrees, 13.53 degrees, 13.83 degrees, 15.93 degrees, 16.31 degrees, Π·35 degrees, 18.47 degrees, 20.93 degrees, 21.49 degrees, 22.77 degrees, and 23,67^ degrees each contain a wave front. In another embodiment, the invention comprises tianeptine phosphate wherein the PXRD diffraction pattern of the phosphate is substantially similar to that of Figure 9. In another embodiment, the invention comprises tianeptine phosphate wherein the phosphate comprises a endothermic transfer at about 211 °C in a DSC temperature map. In another embodiment, the invention comprises tianeptine phosphate' wherein the DSC thermogram of the acidate is substantially similar to Figure 10. In another specific embodiment, the invention comprises tianeptine phosphate wherein the TGA temperature record of the phosphate is substantially similar to that of Figure 11. In another embodiment of the invention, the invention comprises tianeptine phosphate wherein the dynamic vapor adsorption (DVS) characteristic of the acidate is substantially similar to that of Figure 12. In another embodiment, The naproxen hydrochloride is incorporated into a controlled release pharmaceutical composition. In another embodiment, the invention includes a naproxen phosphate wherein the phosphate is completely stable. In another specific embodiment, the invention comprises an 11 lane neptin sulphate wherein the phosphate is completely stable at a relative humidity of from about 10% to about 90% 34 201029981. In another embodiment, the invention includes a tianeptine phosphate wherein the phosphate is fully stable at a relative humidity of from about 20% to about 80% relative humidity. In another embodiment, the invention includes a tianeptine phosphate wherein the phosphate is fully stable at a relative humidity of from about 30% relative humidity to about 70% relative humidity. According to the present invention, the naproxen phosphate may have a different stoichiometric ratio of ionized tianeptine (cation) to phosphate relative ion (anion). Cation: The ratio of negative ions can be 1:1 or 2:1. ® other equivalent ratios are also included in the present invention. In another embodiment, the invention includes tianeptine phosphate and methods of making and using same. In another specific embodiment, the invention includes hydrates of naproxen sulphate and methods of making and using same. In another embodiment, the invention comprises a solvate of thiaprofen:nr phosphate. In another embodiment, the invention consists of one or more tianeptine phosphate polymorphs, or one or more poly-sigma naproxen>, butyrate hydrate or solvate polymorphs.另一 In another embodiment, the invention comprises a co-crystal of tianeptine discate. In another embodiment, the invention includes an amorphous form of tianeptine phosphate and methods of making and using same. In another embodiment, a tianeptine phosphate form may be present, for example, but not limited to, in the form of an anhydrous form, a monohydrate, a dehydrated form or a monosolvate. Such hydrate and solvate forms may have different stoichiometric equivalents of the tianeptine ion to the water or solvate molecule, such as, but not limited to, about 1:1, 1:15, 2:1 or 1:2. 35 201029981 In another embodiment, the invention provides a process for the preparation of tianeptine hydrochloride, comprising: (e) providing tianeptine or a sodium salt thereof; and (f) tianeptine or The sodium salt acts with phosphoric acid to form a crystallized tianeptine phosphate. In a particular embodiment, wherein the naproxen is in the form of a sodium salt. In another embodiment, a solvent is added to the sennapeptine or its sodium salt prior to the addition of hydrochloric acid. In another embodiment, step (b) is carried out in the presence of a solvent such that the phosphate forms a solution prior to crystallization. In another embodiment, step (b) is carried out in the presence of a solvent such that the phosphate forms a suspension prior to crystallization. In certain embodiments, the solvent is selected from the group consisting of: acetone, ethanol, nitromethane, decyl alcohol, acetonitrile, dichlorodecane, water, and tetrahydrofuran (THF). In another embodiment, a solvent may be a mixture of any two or more solvents including, but not limited to, acetone, ethanol, nitrodecane, decyl alcohol, acetonitrile, dichlorodecane, water. And tetrahydrofuran. The tianeptine free base and tianeptine sodium can be prepared by one or more methods available in the art, including, but not limited to, the method of U.S. Patent No. 3,758,528. In a particular embodiment of the invention, a physiologic and/or therapeutically effective amount of a naphthotropine " citrate salt is administered to the mammal. In another aspect, an effective amount of thiaprofen, butyrate, which is sufficient to affect the physiology and/or treatment of the mammal, is administered. 36 201029981 In another embodiment, a method of treating a mammal suffering from depression comprising administering an effective amount of tianeptine phosphate to the mammal is provided. In another embodiment, a method of treating a mammal suffering from intestinal tract is provided, comprising administering to the mammal an effective amount of tianeptine phosphate. In another embodiment, a method of treating a mammal having attention deficit hyperactivity disorder comprising administering an effective amount of a naproxen phosphate to the mammal is provided. In another embodiment, a method of treating a mammal having a sputum is provided, comprising administering to the mammal an effective amount of tianeptine phosphate. In another specific embodiment, the mammal is a human. In another embodiment of the invention, the preparation of a medicament comprising tianeptine phosphate is included. This agent can be used in mammals in need of such treatment to treat diseases such as depression, intestinal cramps, attention deficit hyperactivity disorder or asthma. In another embodiment, the mammal is a human. Pharmaceutical dosage forms of tianeptine phosphate may be administered in a variety of ways including, but not limited to, oral. Oral pharmaceutical compositions and dosage forms are in an exemplary dosage form. The oral dosage form is desirably in the form of a solid dosage form such as a lozenge, an easy-to-swallow tablet, a hard capsule'-starch capsule, a hydroxypropyl-mercaptocellulose (hpMc) capsule, or a soft elastic gelatin capsule. The invention also provides liquid dosage forms including, without limitation, suspensions, solutions, syrups or emulsions. - tianeptine phosphate is administered by means of controlled or delayed release. Controlled-release pharmaceutical products usually have the general goal of improving the efficacy of their non-controlled release drugs. Ideally, the use of the 37 201029981 controlled release formulation designed on demand is characterized by the lowest API (active drug ingredient), which is released in the shortest possible time to cure or control the condition. The advantages of controlled release pharmaceutical compositions generally include: 〇 delayed Αρι activity; 2) reduced dose frequency; 3) improved patient compliance; 4) less total API dose; 5) reduced local or systemic side effects 6) Minimize the accumulation of API; 7) Reduce fluctuations in blood concentration; 8) Improve treatment outcome; 9) Reduce enhancement or reduce API activity; and 10) Improve control of disease or symptoms. (Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa.: 2000). The typical daily dose of the present invention comprises tianeptine phosphate's at a dose of from about 10.0 mg to about 50.0 mg, from about 12.5 mg to 37.5 mg' or from about 25.0 mg to 37.5 mg. The dosages described herein are those of the naproxen free base, excluding the relative ions (e.g., phosphorus) or the weight of any water or solvent molecules. In another embodiment of the present invention, the oral administration of a pharmaceutical composition comprising a naproxetine hydrochloride salt is carried out at a dose of from about 1 〇.〇mg to 50.0 mg, and about 12.5 mg to 50.0 post. About 25.0 mg to 50·〇mg, or about 37.5 mg to 5〇·〇mg or so. For example, about 12.5 mg 'about 25 〇 mg or about 37.5 mg. In a specific embodiment, the pharmaceutical composition comprises 7 oral tianeptine phosphate at a dose of about 25. mg or about 37.5 mg. The total amount can be applied in single or divided doses. In another embodiment, the parental dose of the pharmaceutical composition comprises guanidinium; butyrate, which comprises sennapeptin up to a maximum of 5 〇·〇 mg. In other specific embodiments, the invention is directed to a pharmaceutical composition comprising 38 201029981 as described herein, and suitable for administration to a mammal for treating or preventing one or more of the compositions described herein. One or more diluents, carriers, and/or excipients of the condition. In one embodiment, a stanopeptine phosphate controlled release pharmaceutical composition requires a less complex mixture of excipients than other types of tianeptine pharmaceutical compositions. The tianeptine sulfate of the present invention can also be used in the preparation of a dosage form other than the above oral drug, such as a topical dosage form, an injection dosage form, a transdermal absorption dosage form and a mucosal dosage form. For example, these forms include creams, emulsions, solutions, suspensions, emulsions, ointments, powders, patches, suppositories, and the like. The tianeptine phosphate form of the present invention can be characterized, for example, by TGA, DSC, DVS, single crystal X-ray diffractometer data, or by any one, any two, any three, any four , any five, six, seven, eight, nine, ten, or any single integer PXRD 2-Θ peak, or a combination of data from any of the above analytical techniques. While the invention has been described in terms of various embodiments, the invention can be embodied in various embodiments without departing from the spirit and scope of the invention. [Examples] Example Example 1 tianeptine hemisulfate monohydrate (7-[(3-chloro-6,11-dihydro-6-fluorenyldibenzo[c,f][l, 2] thiazepine-11-yl)amino]heptanoic acid, S,S-dioxide hemisulfate monohydrate) 39 201029981 · Example 1 a 15 STABLON® (Sennaeptin sodium) lozenge It was ground in a mortar and mixed with 15 mL of tetrahydrofuran (THF) to extract tianappropane; These mixtures were mixed by shaking and sonication. Filtered in a Buchner funnel and insoluble. The THF solvent was evaporated from the clean solution of hydrazine, and the remaining composition was dissolved in 丨5 deionized water. Four equivalents of sulfuric acid were added to crystallize the tianeptine hemisulfate monohydrate. Example lb Sennalpeptin sodium (1054.16 g) was dissolved in vinegar @acid.water (4 L) at 50:50 at 50 ° C to give a colorless solution. This solution was filtered hot and at 95. In the case of (:, sulfuric acid (66 ml) is added in about three minutes. In the case of 953⁄4, the crucible 丁 普 半 半 sulphate monohydrate is produced within one hour. Then the temperature is gradually Adjust to 104. (:, 100 minutes, 8 ° C, 220 minutes, 25 ° C for 40 minutes, and 5 C, 100 minutes. Then allow the mixture to stir at 5 ° C overnight (about 20 hours). Filter the solids, and Use acetic acid: water 5 〇: 5 〇 (2 x 1 liter) 'water (3 x 1 liter), acetone (lx 6 〇〇 ml), rinse dry. Dry the solid at 40 ° C in vacuo. Example 1 c at room temperature Sennaeptin sodium (100 g) was dissolved in: isopropanol: water (500 liters) at 50:50 to give a colorless solution. This solution was filtered and 45.4% sulfuric acid solution (73.2 ml) was added. It is filtered, in which case the crystalline naproxetine hemisulfate monohydrate will completely crystallize within two hours. Use 5 〇: 5 〇 isopropanol: water (5 〇〇 ml) 40 201029981 and water (300 ML) Wash the solid and then dry the solid overnight in the surrounding environment. Xylapeptin hemisulfate monohydrate The ratio of a tianeptine ion to sulfate counterion to water is 1:0.5:1. The tianeptine hemisulfate monohydrate crystal represents the method by which any of the examples la to lc are completed. The properties can be characterized by PXRD, DSC, TGA, Dynamic vapor sorption (DVS), single crystal X-ray diffractometer, UV/absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy. The PXRD diffraction pattern exhibited by Putin hemisulfate monohydrate includes diffraction peaks of 2-Θ which are about 8.25, 8.97, 11.49, 13.91, 14.73, 16.95, 18.07, 19.39, 20.59, 21.99, 22.83, and about 23.27 degrees ( See Figure 1.) DSC exhibits an endothermic transfer at approximately 193 degrees Celsius (see Figure 2 for yTGA analysis showing that tianeptine hemisulfate monohydrate loses about 5.0 percent between about room temperature and about 160 degrees Celsius The weight (see Figure 3). Dynamic gas phase adsorption (DVS) completes the analysis of ruthenium naphthalate hemisulfate monohydrate at about 25 ° C and relative humidity from about zero to 90% (see Figure 4). DVS analysis showed that 嗟 naproxil; butyl hemisulfate monohydrate was A relative humidity of about 10% is stable to a relative humidity of about 90%. This is a typical non-hygroscopic material. Below 10% relative humidity, the water mass has been lost. Single crystal data · 2 (carbon η hydrogen nCiN2 oxygen 4 sulfur]). (sulfur oxygen 4).2 (hydrogen 2 oxygen); Μ = 503.99; monoclinic crystal, p2(i)/n; a = 9.3816(4) angstrom; b = 25.2869( 10) angstrom; c = 19.9621 (7) angstrom; α = 90 degrees; β = 103.144 (2) degrees; γ = 90 degrees; V = 4611.6 (3) cubic angstroms; 41 4 201029981 T = 100 (2) K; Z = 8; Dc = 1.452 g/cm Å; λ = 0.71073 angstroms. The tianeptine hemisulfate monohydrate exhibits an ultraviolet/absorption spectrum comprising a maximum absorbance (λ max), for example, at about 208 nm 'and a weak absorbance, for example, at about 275 nm (see Figure 13). ). The tianeptine hemisulfate monohydrate exhibits an FTIR spectrum comprising diffraction peaks, for example, at about 1351, 1713, 1732, 2855, 2916, 2939, 3193, and 3540 cm-1 (see Figure 14). The tianeptine hemisulfate monohydrate exhibits a Raman spectrum comprising peak waves, for example, at about 286, 339, 582, 672, 695, ❹ 1053, 1099, 1163, 1182, 1300, and 1586 cm1 (see Figure 15). The following are the analytical techniques used. The DSC analysis of each sample of the scanning thermal differential was performed using a Q1000 scanning thermal differential (TA Instruments, Newcastle, Delaware, USA), which used the advantage QW-Series 'Version 1.0.0.78, Thermal Advantage Release 2.0 (©2001 TA © Instrument-Water Company)' and the following components: QDdv.exe version 1.0.0.78 build 78.2; RHBASE.DLL version 1.0.0.78 build 78.2; RHCOMM.DLL version 1.0.0.78 build 78.0; RHDLL.DLL version 1.0 .0.78 build 78.1; — TGA.DLL version 1.0.0.78 build 78.1. In addition, the analysis software used is a general analysis 2 for Windows 95/95/2000/NT, version 3.1E; Jianshi history 3.1.0.40 (©2001 TA Instruments-Water Company), or the illustration in the present invention Or other versions specified by other locations. 42 201029981 For all DSC analyses, a divisible sample is used, in a standard aluminum weighing pan (the weighing pan section #9〇0786.〇91; cover part #900779.901) or a sealed aluminum weighing pan (the weighing pan section) #9〇〇793 9〇1 Cover Section # 900794.901 (TA Instruments, Newcastle, Delaware, USA):| Weighing in the middle. Unsolvated samples are loaded into standard pans and sealed to dry the samples using shrink wrap. The wet sample (such as mud) is sealed by crimping. The solvent sample (including hydrate) is packed into the sealing disk and sealed. The sample weighing pan is equipped with an AQ1000 scanning thermal differential, equipped with an autosampler and controlled by The software is separately heated separately to obtain a thermogram with a heating rate of 10. (: / min from Tmin (typically 3 (rc) to Tmax (t is usually 300. 〇, using an empty aluminum weighing pan as a reference. Drying) Nitrogen (compressed nitrogen 'Class 4.8 (BOC gas, Murray Hill, NJ, USA)) was used as a sample purge gas and the flow rate was set at 50 mL/min. Thermal transfer was observed and analyzed using analytical software provided by the instrument. Analysis The thermogravimetric analysis (TGA) of the sample uses a Q500 thermogravimetric analyzer (TA Instruments, Newcastle, Delaware, USA), which uses the advantage qW_Series 'Version 1.0.0.78, Thermal Advantage Release 2.0 (©2001 TA Instruments - Water Company). In addition, the analysis software used is Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.1E; Construction 3.1.0.40 (©2001 ΤΑ Instruments-7jc), or the illustration or Other versions specified by other premises. 43 201029981 For the TGA experiment 'use dry nitrogen as the purge gas, balance the purge gas to 40 mL/min of nitrogen 2, and sample purge gas to 60 mL/min of nitrogen 2. The sulfate is placed in a platinum plate for TGA. The initial temperature is generally about 2 degrees Celsius, the heating rate is 1 degree Celsius per minute, and the end temperature is 3 degrees Celsius. Powder X-ray diffraction utilizes one. D/maximum fast X-ray diffractometer to obtain powder xenon diffraction pattern (Rigaku/MSC, Woodlandes, Texas, USA) @ D/Maximum fast Xenon ray diffractometer equipped with a copper source (copper/unloading) 1.51.5406Α), manual χ-y stage' And a 0 3 mm collimator. The sample is placed in a 0.3 mm quartz capillary by slicing the closed end of the capillary and placing a small capillary open end on a powdered sample layer or on a beating sample deposit. Dinner Company, Natick, Miami, USA) The placed capillary is placed in a holder mounted on the x_y stage. A diffraction pattern requires control software (RINT fast control software, Rigaku Express / XRD, version i.〇.〇 (©i999 Rigaku ❹ c〇.)) 'Environmental conditions for the transmission mode power set at 40mA is 46 kV, and The Omega-axis oscillation is from 〇5 degrees to 丨度/sec, and the phi-axis rotation is over 360 degrees at 2 degrees/second. The exposure time was 15 minutes unless otherwise stated. The obtained diffraction pattern is integrated from 2 to 4 degrees 2·θ and from 0 to 36 degrees, and the step length is 〇·〇2 degrees chi (l segment), and uses the RINT fast display software provided by Rigaku Instruments. (RINT fast display software, version 1.18 (Rigaku / MSC)) in the coffee as a utility. According to Rigaku's 44 201029981, the calibration of each system sets the value of the dark count to 8. Integration is not used for normalization or offset by OMEGA, chi or phi. The diffraction diagrams included in this article show the raw data (without subtracting the background). The relative intensity of the diffraction peaks in a diffraction pattern is not necessarily a limitation of the pxrd mode because the peak intensity varies with the sample, for example, due to crystalline impurities. In addition, each diffraction peak will have a different angle 'about +/- 0.1 degrees, or about + / _ 〇. 〇 5. The diffracted peaks of the entire mode or most of the modes may also vary from approximately +/_〇1 degrees to approximately © +/- 0·2 degrees due to different calibrations, settings, and different factors between the instrument and the operator. All of the reported PXRD diffraction peaks in the figures, the examples, and elsewhere in this specification have an error of 2-Θ approximately: ±: 〇·ι degrees. Unless otherwise stated, all diffraction patterns are done at room temperature (approximately 24 degrees Celsius to 25 degrees Celsius). Early-crystal X-ray diffraction uses 100(2)K on a Bmker KAPPA APEX II CCD device to detect X-ray intensity data. 'This detection system is equipped with a graphite monochromator and a MoKafine-focus seal. Tube (λ = 〇·71073Α), operating power is 1.5 kW (5〇kV, 30mA). Eight molecules prepare Pu'er to form unit cells. The sulfate ion forms a salt on the secondary amine of the two sennapeptine molecules. Hydrogen bonds can be found between the two naproxen molecules and the carboxylic acid tail and sulfate ion of one water molecule. UV/Absorption Spectra 45 4 4201029981 Ultraviolet/absorption spectra were measured using a Kalah 50 UV/Vis spectrometer (Vankel, Palo Alto, Calif.). The tianeptine hemisulfate monohydrate was dissolved in methanol:water (0.150 mg/mL) 50:50), passed through a filtered 0.45 um syringe filter' and then in the same solvent (final concentration 0.075 mg/mL) Dilute 2 times. Add 1.0 mL of sample to a quartz colorimetric tube with a 1.0 cm diameter. Fourier Transform Infrared Spectroscopy FTIR analysis is the use of one of the thermoelectric companies Nexus 47〇 FTIR instrument (Pennsylvania, Philadelphia). The tianeptine hemisulfate monohydrate Lu and the potassium bromide are ground together and compressed into a translucent circular plane. The analysis was performed using 32 scans in the E.S.P. mode. A fresh background measurement was collected prior to sample analysis. Raman spectroscopy Raman luminescence is performed using the Nicolai Raman system, one of the thermoelectric companies, equipped with a 785 nm laser microscope unit and a 1 倍 objective lens. Xiang: 3G wire collection of sub-exposure 4 seconds window to collect the scattered Raman spectrum. Collect - fresh background measurements before sample analysis. Example 2 tianeptine hydrochloride (7_[(孓chloro^丨^dihydro-^bis[c,f][l,2]thiazepine-7-yl)amino]heptanoic acid, s, s-di-I-salt hydrochloride) 31 STABLON® (嗟Naproxine nano-crush was sampled in a spider) and mixed with 23 mL of tetrahydrogen (THF) to extract 嗟46 201029981 Zep juice. The mixture was mixed by shaking and sonication, filtered through a Buchner funnel, and the non-dissolved components were evaporated from the filtered clean solution, and the remaining composition was dissolved in 4 mL of deionized water. Four equivalents of hydrochloric acid were added to crystallize the thiophene. Naproxen hydrochloride. Crystallization represents the obtained by the above method, and its characteristics can be characterized by PXRD, DSC, TGA, dynamic moisture adsorption analysis (DVS). The pxRD winding of tianeptine hydrochloride The projections include diffraction peaks of 2_θ of about 7.23, 9.43, 9.91, 10.53, 14.53, 18.35, 21.39, and about 23.93 degrees (see Figure 5). £> DSC exhibits an endothermic transfer at about 199 degrees Celsius (see Figure 6). TGA analysis showed that tianeptine hydrochloride lost about 2.9 percent by weight between about room temperature and about 14 degrees Celsius (see Figure 7). Dynamic moisture adsorption analysis (DVS) of tianeptine hydrochloride at a relative humidity of from about 0 to about 90% at 25 ° C (see Figure 8). Dynamic moisture adsorption analysis (DVS) showing tianeptine salt The acid salt is stable up to a relative humidity of up to about 90%. The naproxen hydrochloride absorbs less than 2.5% of the water weight over the entire humidity range. Example 3 tianeptine phosphate (7-[ ( 3-Chloro-6,n_dihydro-6-nonylbiphenyl brigade [c,f][l,2]thiazepine-11-yl)amino]heptanoic acid, s,s_dioxide Phosphate) 15 STABLON® (Sennalpeptin sodium) tablets were ground in a spider and mixed with 15 mL of tetrahydrofuran to extract tianeptine. These mixtures were mixed by spreading and sonication. The non-dissolved fraction was filtered through a Buchner funnel. The THF solvent was evaporated from the filtered clean solution, 47 201029981 and the remaining composition was redissolved in 2.5 mL of THF. Five equivalents of phosphoric acid were added to crystallize the celenapride phosphate. The properties obtained by the above method can be characterized by PXRD, DSC, TGA, dynamic moisture adsorption analysis (DVS). PX presented by tianeptine phosphate The RD diffraction pattern includes 2-Θ which are diffraction peaks of about 6.83, 9.27, 11.95, 13.53, 13.83, 15.93, 16.31, 17.35, 18.47, 20.93, 21.49, 22.77 and about 23.67 degrees (see Figure 9). °DSC in Celsius An endothermic transfer was exhibited at about 193 degrees (see Figure 10). TGA analysis showed that the naproxen wall salt lost about 3.7 percent by weight between about room temperature and about 199 degrees Celsius (see Figure 11). Dynamic moisture adsorption analysis (DVS) is about 0 to about 90% of tianeptine phosphate at a relative humidity of 25 degrees Celsius (see Figure 12). Dynamic water adsorption (D V S) analysis showed that tianeptine phosphate absorbed about 25% by weight of water at a relative humidity of about 90%. Example 4 Relative Dynamic Moisture Adsorption Analysis (DVS) Data for Sennaeptin Sodium Figure 16 shows relative DVS data for tianeptine sodium (at about 25 degrees Celsius) and tianeptine sulphate in Figure 4. Comparison of the number of DVS of monohydrates. The tianeptine sodium begins to deliquesce at a relative humidity of about 60% and absorbs about 38% of the water (by weight) at a relative humidity of about 90%. Example 5 Aqueous Solubility of Thinaeptidine Hemisulfate Monohydrate 48 201029981 An excess of tianeptine hemisulfate monohydrate (from Example 1) was added to the solution and equilibrated for 24 hours with continuous mixing, then The aqueous solubility of tianeptine hemisulfate monohydrate was measured at room temperature. Three solutions were used, including 10 mM HCl solution, a buffer solution of pH 6.5 (50 mM sodium phosphate), and deionized water. The remaining solids were removed from each solution and analyzed in solid form. The thiophene > succinic sulphate fresh hydrate did not show any conversion to the free zwitterionic form. In all three solutions +, the solubility of naphthoquinone monosulfate monohydrate is less than 丨mg/mL. Figure 17 shows tianeptine hemisulfate monohydrate, tianeptine hydrochloride and tianap The solubility of statin phosphate is compared. Example 6 A formulation of two tianeptine sulfates was made. The composition is described below.

Ingredient composition •-. Each tablet content (mg) ------ ---****"' --- F1 F2 F3 tianeptin pentasulfate monohydrate active molecule 28.84 mg 28.84 mg ___-******* 28.84 mg Avicel PH200 Filler Methocel Controlled Release Polymer Grade K100 LV CR 60,00 rag 108.66 mg 60.00 mg 81.50 mg 60.00 ^ 54.33 Nag Methocel Premium K4M CR Controlled Release Polymer 0.00 mg 27.16 mg 54.33 mg Magnesium Stearate Glue Lubricant Lubricant Glidant 2.00 mg 50, 50 rng 200.00 mg 2.00 mg 0.50 mg 200.00 mg 2.00 rag 0.50 Mg 200.00 mS Example 7 49 201029981 The pH solubility curve of the following β-spinpactin form is measured: β-spinapetine hydrochloride; tianeptine-sulphate monohydrate; terpene thiophene Ting; tianeptine free form (type II zwitterion, as described and identified in US Publication No. US 2008/0221081 Α1, its PXRD diffraction pattern is depicted in Figure 18); and tianeptine, sodium sulphate. The tianeptine sulfonate used in this example was prepared by the following procedure. The tianeptine free form II (2.072 grams) was combined with p-methyl sulfonic acid (0.923 grams). Acetonitrile (5 Torr) was added to the solid mixture. The mixture is heated to produce a clear solution. Allow this solution

The liquid was cooled to room temperature' and then sputum was added to the benzene sulphate; butyl (about 5 mg). The solution was allowed to stand overnight to produce a complete product crystallized. The suspension was then cooled to (TC and separated to isolate the white crystalline solids 0 to (iv) the order of the flavonoid 1f sulfamate sulfonate. The naproxen (442·0 mg) and p-toluene acid ( 199 3 Add acetic acid and a stupid 1:1 to the mixture. The Wei compound is briefly super

In the process, observe _ into white (10). The entire lion's rafts are clearly crystallized. It was then dried for 6 hours at 75X: vacuum. The following k is used for another one to prepare the A. Combine the free form of 嗟 普 ί , 夂 丁 Μ (Μ )). Add acetonitrile (1 ( gram) and p-toluene to the mixture and gently heat the "output = ' to the temperature and place! hours. Use the broken bar to the inner surface of the bottle containing 50 201029981. The crystallization is induced and about The completion was completed after 15 minutes. The solid was collected by filtration and characterized as tianeptine tosylate. Procedure for measuring the solubility curve of pH: The parental Seychelles format was added to the glass bottle. Add a stir bar to the buffer and close the glass bottle. Incubate the sealed glass bottle at 37 ° C for 24 to 36 hours. After incubation, remove the remaining solution by centrifugation using a 0.2 μm pore size filter. Solid. Just measure the pH of each filtrate, then dilute the solution 2 to 10 times and analyze the content of tianeptine by HPLC (UV detection). Qualify the remaining solids by powder X-ray diffraction to determine each Solid form (balanced form) produced in glass bottles. Data for each form of tianeptine can be found in Tables 1 to 5 below. Table _1, tianeptine hydrochloride in different buffer solutions Salt dissolution

Buffer System Initial Buffer Solution pH Test Temperature CC) Solubility (mg/mL) Final pH Balanced Form 100mM HC1 1 f\ /r ττ/^ι ~ 1 37 3.15 1.4 HC1 lUmM rlCl 2 37 7.47 2.2 HC1 lOOmM Gas Acetate Pound 1 Λ Π wn Λ >f 3 37 3.81 2.5 Form II iUUniM Miscellaneous 5 37 0.06 4.4 Form II lOOmM pyridazine 6 37 0.03 5.3 Form II ΐϋυιηΜ Research fee 7 37 0.02 6.4 1 Form II lUDmM diethanolamine 8 37 0.34 7.4 Form II lOOmM glycine, 10 37 2.75 8.7 Form II Table 2, β-Sennapene starting from different buffer solutions; D-Sulphate monohydrate __ Solubility buffer system Initial buffer solution pH Experimental temperature Rc) Solubility (mg/mL) Final pH Balanced Form 100 mM HC1 —· — 1 37 0.33 1.4 Sulfate 51 201029981

10 mM HC1 2 37 0.20 2.4 Sulfate 1 OO mM oxime acetate 3 37 0.25 3.0 Sulfate 1 OO mM acetate 5 37 0.12 4.7 Form II lOO mM trace ° Qin 6 37 0.10 5.5 Form II 1 OO mM phosphate 7 37 0.10 6.6 Form Π lOOmM triethanolamine 8 37 0.36 7.6 Form II 1 OO mM glycine 10 37 3.61 8.7 Form II Table 3. The solubility of tianeptine sulfonate starting from different buffer solutions

Buffer System Initial Buffer Solution pH Test Temperature (°c) Solubility (mg/mL) Final pH Balanced Form 100 mM HC1 1 37 0.96 1.03 Tosylate 10 mM HC1 2 37 0.88 2.05 Toluene Sulfate 100 mM Chloroacetic Acid Salt 3 37 1.01 3.02 Toluenesulfonate 100 mM acetate 5 37 0.06 4.61 Form II lOOmM ° bottom ° Qin 6 37 0.04 5.65 Form II lOOmM phosphate 7 37 0.05 6.76 Form II lOOmM triethanolamine 8 37 0.32 7.67 Form II 1 OOmM Gan Amino acid 10 37 9.14 8.88 Form II Table 4. The solubility of tianeptine Form II starting in different buffer solutions

Buffer system initial buffer solution pH test temperature rc) Solubility (mg/mL) Final pH equilibrium form lOOmM HC1 1 37 1.36 1.17 HC1 10mM HC1 2 37 2.66 2.47 Form II lOOmM gas acetate 3 37 0.83 3.08 Form II lOOmM acetate 5 37 0.04 5.06 Form II lOOmM pie ° Qin 6 37 0.04 6.01 Form II lOOmM acid salt 7 37 0.06 7.08 Form II lOOmM triethanolamine 8 37 0.40 7.98 Form II 1 OOmM glycine 10 37 9.72 9.61 Form II 5, narnatine sodium solubility buffer system starting from different buffer solutions initial buffer solution pH test temperature rc) solubility (mg / mL) final pH equilibrium form lOOmM HC1 1 37 1.86 1.68 HC1 52 201029981 lOOmM HC1 ___ 1 37 7.898 9.10 Form II 10 mM HC1 w ----- 37 7.46 9.17 Form I and II lOmM HC1 2 37 66.192 9.250 na lOOmM acetate acetate __^3 37 ] 0.06 4.63 Form I and II lOOmM chloroacetate 3 -------- 37 60.54 9.41 Form II lOOmM acetate.__ 5 37 1.50 8.45 Form I and ίι lOOmM. Bottom ° Qin 37 0.27 7.75 Form II lOOmM acid salt 7 37 39.53 9.40 Form II lOOmM triethanolamine 8 ----- Γ 37 85.43 8.92 Form II 1 OOmM glycine 10 ------ 37 43.56 10.20 No Indicates that there is not enough residual solids so it is not suitable ❹ 噻 The tianeptine sodium sample described in Table 5 was repeated under three pH conditions (initial pH 1, 2 and 3) and had different drug target concentrations. For example, 6 〇 to 7 〇 mg of tianeptine sodium to 1 〇 () rnMHCl is added at a pH of 1. For the second sample, 60 to 7 mg of tianeptine sodium to 100 mM HCl was added, followed by the addition of additional 嗔nupeptin steel salt until the suspension appeared. This is done to achieve supersaturation of the drug. Therefore, because the sodium concentration in the second sample towel is higher, after the Putinna salt is converted to an equilibrium form, the final pH value is not good.终 The final pH and form will affect the solubility. °. The different forms of 嗟 naproxen (4) positivity solubility data in the attack of 19 are based on the graph has a roughly gradual solubility curve 'smoke from yang 1 his form of 嗟 naproxen, statin is lower than pH 4 ', its high In the case of a dissolved release dosage form which has a large decrease in solubility after pH 4.5, it is preferred for oral administration. If in the stomach two: 3⁄4 53 201029981 variability (this 9 e resolution curve can be other than the presence of food) such a solution; butyl hydrochloride case = tyrosine absorption variability. For example, in 嗟 time may cause such as W, the data shows prolonged retention in the stomach. Conversely, the intestine dissolves and dissolves, thus limiting absorption. Line, can reduce the variation of the dog = relatively consistent solubility curve is favorable. Ice 2 for controlled release dosage forms may be ^ X which significantly affects the observed absorption variability. Example 8 ^ In Vitro Dissolution Study A lozenge comprising a spirulina sulphate monohydrate was prepared using three formulations (except for the acid-cut gel) defined as FI, F2 and F3 from Example 6. Tablets were also prepared using a formulation similar to Fi, F2 and theirs in Example 6 except that the alumite gel was omitted and the cerium citrate salt was used as the active molecule in place of the flavondetine hemisulfate monohydrate. These tablets were tested in the United States Pharmacopoeia II instrument to assess the effect of salt form on drug release. ❹ The required amount of tianeptine hemisulfate monohydrate, Avicel PH200, and Methocel K4M and/or Methocel K100 in the FI, F2 and F3 formulations, respectively Mix in a suitably sized glass vial using a Turbula blender for 10 minutes. Magnesium stearate was then added and the blend was additionally mixed for 5 minutes. A typical powder dressing batch size is 4 grams. 54 201029981 Manually compressed tablets (10) 5 mg) using a 0.8 mm flat circular die, typically compressed kgf (approximately 130 MPa). J is 65 〇 The same experiment was carried out to prepare a two-cylinder transfer experiment containing 嗟Cepspotin steel salt (from CF Pharmaceutical Company of Budapest (batch number HAT-357AB)). In one experiment, ^ has been sold with naphthalene, butyl sulphate monohydrate tablet (7), and drug release. In the second smashing test, F3), in an experiment, the drug 1 was released containing tianeptine sodium Ο ❹ (F1, F2 & F3). In each experiment, the drug release was measured using a US-based brain W (paddle). The specific instrument is a Varian VK7-faced US Pharmacopoeia Dissolving Instrument II (rotary paddle). Use Varian Kari (Varian

Cary) 50 UV spectrophotometer to quantify the sample. A 1 〇 umPE full flow filter was used in the sample line of the automatic pumping. The dissolution conditions are as follows: Medium and amount: Degassing: Type of container: Temperature. Paddle 13⁄4 degrees: Stirring rate: Detection '· Time point:

900mL simulated gastric fluid (SGF), pH of about 1.2 900mL simulated intestinal fluid (SIF), pH of about 6.5 without degassing tip container 1 37.3 ± 0.5 °C paddle to the tip of the container about 10 mm 100 rpm pipeline · medium continuous, UV absorption at 208 nm is achieved every 6 minutes until 2 hours, then every 12 minutes until 3 hours, then every 30 minutes until 30 hours or until the maximum absorption plateau is established. μ 55 201029981 Add 2.0 g of NaCi and 7.0 ml of concentrated HC1 to sufficient water to make a 1000 ml solution, and then weigh the appropriate amount to prepare an SQF dissolution medium. Add 6.8 g of potassium dihydrogen phosphate (KH2p〇4) and g66 g of sodium hydroxide (NaOH) to sufficient water to make a 1 ml solution (produced pH of about 6.5), and then weigh the appropriate amount Prepare a SIF dissolution medium. The normalized release profile was calculated according to the following: (absorbance) / (absorbance at the last time point) X 100 ° /. = Percentage of normalized dissolution The experimental results of 喧naprofen > butyl hemisulfate monohydrate are shown in Table 6 below. The results of the three replicates of each recipe in each medium were averaged to obtain the "release percentage" values in Table 6. Table 6 Percent release SGF SIF Time FI (Thioeptine semi-sulfate monohydrate) F2 (Thioproxen hemisulfate monohydrate) F3 (Thioproxil hemisulfate monohydrate) F1 (喽Naphthalene) Putin hemisulfate monohydrate) F2 (Thioproxil hemisulfate monohydrate) F3 (Thioproxil hemisulfate monohydrate) V 4 ^ / 〇〇〇0.59 0.80 0.43 0.30 0.39 0.28 vl · \/ V/ 〇1 0 0.09 0.28 0.21 0.44 0.30 0.42 〇〇〇0.61 0.79 0.68 1.31 0.82 1.02 ν/ · Ζλ \J 0 fly 0 1.33 1.42 1.05 2.42. 1.36 • 1.46 〇40 2.19 2.11 1.49 3.41 1.97 2.12 〇3.26 2.86 1.90 4.57| 2.85 2.69 \j. \j 〇/;〇4.41 3.67 2.43 5.97 3.50 3.26 〇7〇5.72 4.60 2.951 6.95 4.28 3.88 〇c〇7.02 5.60 3.551 8.52 5.08 4.59 〇Q〇8.38 6.59 4.14 9.73 6.08 5.17 1.00 9.82 ^ 7.62 4.76 11.19 7.24 5.88 56 201029981

1.10 11.47 8.70 5.35 12.53 7.95 6.58 1.20 12.83 9.75 5.96 14.08 8.98 7.28 1.30 14.28 10.86 6.61 15.18 9.94 7.96 1.40 15.76 11.97 7.27 16.56 10.87 8.64 1.50 17.39 13.04 7.97 17.88 11.91 9.41 1.60 18.77 14.13 8.63 19.03 12.85 10.16 1.70 20.31 15.25 9.33 20.44 13.88 10.91 1.80 21.87 16.31 10.04 21.69 14.80 11.61 1.90 23.41 17.37 10.77 22.95 15.79 12.31 2.00 24.88 18.49 11.55 24.17 16.77 13.03 2.20 27.83 20.60 13.07 26.74 18.67 14.47 2.40 30.98 22.67 14.67 29.38 20.63 15.86 2.60 34.07 24.77 16.32 32.22 22.51 17.35 2.80 36.87 26.79 18.13 34.70 24.49 18.84 3.00 39.60 28.78 19.76 37.11 26.51 20.31 3.50 45.91 33.85 24.16 42.52 31.30 24.12 4.00 51.43 38.59 28.34 47.47 35.69 27.88 4.50 56.64 43.23 32.58 52.16 39.77 31.49 5.00 61.59 48.18 36.54 56.67 43.99 34.82 5.50 66.23 52.51 40.13 60.91 47.70 37.83 6.00 70.71 56.38 43.55 64.84 51.19 40.69 6.50 74.74 59.98 46.96 68.72 54.34 43.40 7.00 78.39 63.52 50.04 72.28 57.57 46.10 7.50 81.75 66.93 53.19 75.68 60.81 48.79 8.00 84.70 70.11 56.16 78.80 64.00 51.68 8.50 87.58 73.16 59.11 81.80 66.98 54.46 9.00 90.24 76.25 61.92 84.51 69.83 57.22 9.50 92.99 79.12 64.80 86.90 72.51 59.89 10.00 94.80 81.94 67.57 89.03 75.14 62.55 10.50 96.69 84.59 70.39 90.94 77.55 65.13 11.00 97.72 86.88 72.84 92.80 79.96 67.76 11.50 98.41 89.02 75.29 94.61 82.07 70.66 96.07 90.92 77.66 96.07 83.92 72.43 12.50 99.21 92.48 79.81 97.07 85.67 74.62 13.00 99.84 93.90 81.85 97.74 87.41 76.83 13.50 99.67 95.23 83.96 98.27 89.13 78.84 14.00 99.63 96.23 85.97 98.53 90.75 80.72 14.50 99.57 97.12 87.96 98.84 92.52 82.55 15.00 99.65 97.79 89.93 99.04 94.25 84.41 15.50 99.74 98.31 91.88 99.31 95.61 86.07 16.00 99.70 98.67 93.57 99.56 96.51 87.68 16.50 99.87 99.08 94.94 99.64 97.24 89.22 57 201029981 17.00 100.00 99.27 96.09 99.84 97.65 90.55 17.50 100.16 99.40 96.97 100.12 98.01 91.66 18.00 99.49 97.62 98.30 92.70 18.50 99.56 98.14 98.51 93.79 19.00 99.46 98.49 98.15 94.66 19.50 99.55 98.53 98.38 95.67 20.00 99.57 98.79 98.68 96.46 20.50 99.61 98.96 98.91 97.06 21.00 99.73 99.11 99.14 97.54 21.50 99.81 99.07 99.34 97.87 22.00 99.86 99.25 99.61 98.28 22.5 99.97 99.32 99.77 98.59 23 100.00 99.35 100.00 98.90 23.5 100.08 99.45 100.19 99.13 24 99.57 99.29 24.5 99.71 99.56 25 99.73 99.69 The experimental results of Putin sodium salt are shown in Table 7 below. The results of a repeated experiment in each medium for each formulation are taken as the "release percentage" values in Table 7. Time (hours) release percentage SGF SIF F1 (Thannapeptin sodium salt) F2 (Thioprofen sodium salt) F3 (Thnaproxil sodium salt) F1 (Thioprofen sodium salt) F2 (Thioprofen sodium) Sodium salt) F3 (tianapeptin sodium salt) 0.00 0.62 0.63 0.46 0.23 0.35 0.29 0.10 5.14 5.03 3.91 4.20 3.33 4.21 0.20 8.66 7.98 '6.31 6.30 4.97 6.64 0.30 11.30 10.14 8.11 7.84 6.17 8.52 0.40 13.60 11.92 9.59 9.30 7.24 9.86 0.50 15.65 13.48 10.97 10.68 8.43 11.15 0.60 17.60 15.17 12.26 12.29 9.59 12.34 0.70 19.58 16.73 13.45 13.95 10.87 13.48 0.80 21.58 18.14 14.62 15.59 12.21 14.55 0.90 23.42 19.56 15.72 17.25 13.55 15.62 201029981

1.00 25.09 21.01 16.92 18.69 14.95 16.63 1.10 26.87 22.43 17.90 20.34 16.04 17.62 1.20 28.66 23.73 18.93 21.87 17.40 18.56 1.30 30.20 25.11 19.91 23.39 18.66 19.67 1.40 31.80 26.52 21.01 24.71 19.74 20.73 1.50 33.38 27.70 21.99 26.20 20.86 21.77 1.60 34.87 29.06 23.46 27.58 21.94 22.74 1.70 36.34 30.27 23.90 29.00 23.04 23.67 1.80 38.03 31.52 24.77 30.33 24.15 24.68 1.90 39.03 32.73 25.69 31.65 25.13 25.54 2.00 40.53 33.96 26.56 32.92 26.16 26.42 2.20 43.07 36.18 28.32 35.51 28.25 28.15 2.40 45.61 38.59 30.06 37.93 30.26 29.78 2.60 47.99 40.82 31.63 40.20 32.04 31.41 2.80 50.37 42.95 33.25 42.40 34.03 33.03 3.00 52.54 45.16 34.82 44.67 35.96 34.58 3.50 57.87 50.35 38.62 49.71 40.64 38.24 4.00 62.80 55.10 42.17 54.63 45.08 41.71 4.50 67.20 59.47 45.54 59.79 49.44 45.06 5.00 70.94 63.87 48.72 64.71 53.46 48.30 5.50 74.56 68.16 51.87 70.10 57.37 51.37 6.00 77.84 72.07 55.20 72.47 62.05 54.40 6.50 80.86 75.44 58.32 76.17 66.55 57.20 7.00 84.20 78.52 61.79 79.74 70.01 60.07 7.50 86.84 81.37 64.85 82.88 73.28 63.27 8.00 89.38 83.91 67.87 85.57 76.17 66.45 8.50 91.54 86.23 70.18 87.94 79.32 69.32 9.00 93.34 88.39 72.79 90.09 82.11 72.15 9.50 95.28 90.25 74.94 91.81 84.72 74.60 10.00 96.67 92.05 77.59 93.21 87.08 76.94 10.50 97.77 93.60 79.35 94.62 89.23 79.06 11.00 98.13 95.09 81.30 96.06 90.97 81.11 11.50 98.06 96.07 83.44 97.99 92.57 83.12 12.00 98.34 97.08 85.48 98.46 94.05 85.02 12.50 98.41 97.60 86.95 98.50 95.18 86.96 13.00 98.60 98.10 88.45 98.65 96.08 88.59 13.50 98.56 98.30 89.83 98.64 96.84 90.29 14.00 98.71 98.70 90.91 98.85 97.54 91.58 14.50 98.79 98.84 91.94 98.76 98.86 92.92 98.89 98.42 98.25 92.73 98.89 98.42 94.25 15.50 98.93 99.04 93.62 99.00 98.72 95.17 16.00 99.13 98.95 94.34 99.11 98.85 96.10 59 201029981 16.50 99.31 99.01 95.45 99.16 99.10 96.96 17.00 99.36 99.16 96.89 99.28 99.23 97.57 17.50 99.26 99.28 97.92 99.42 99.17 98.08 18.00 99.46 99.33 98.42 99.45 99.27 98.69 18.50 99.54 99.43 99.04 99.54 99.48 99.0 7 19.00 99.70 99.61 98.41 99.63 99.57 99.50 19.50 99.63 99.64 99.57 99.67 99.61 99.62 20.00 99.83 99.77 99.57 99.78 99.65 99.91 20.50 99.90 99.80 99.61 99.94 99.90 99.92 21.00 99.99 99.93 99.43 99.91 99.94 100.06 21.50 100.09 99.91 99.71 100.00 99.96 100.12 22.00 100.00 100.00 100.00 100.00 100.00 100.00 As shown by these results, the sodium salt (amorphous) is more soluble in SGF and in SIF than the hemisulfate monohydrate salt. Specifically, as shown in FIG. 20 and FIG. 21, it depicts a comparison result of a bond containing tianeptine sulphate monohydrate and a tablet containing guanidin and timinate, and a tablet prepared by using a sodium salt. Faster, especially in the early stages of dissolution time. In order to further emphasize the difference in release kinetics between tablets prepared with tianeptine sodium salt and tablets prepared with tianeptine sulphate monohydrate salt, time is taken from the corresponding release curve data. The first derivative is calculated to calculate the release rate. As shown in Figure 22 (using the suspect formulation F2 for each salt as an example), the release rate of the formulation based on the hemisulfate monohydrate salt was higher than the sodium salt based formulation during the entire dissolution experiment. It will be much more stable. This difference is particularly seen when the X-axis (time) is presented in logarithmic coordinates, as shown in Figure 23. Example 9 Biological Assay 60 201029981 Behavioral Despair Test in Mice (IP Administration) The behavioral despair test in mice, also known as forced swimming test, is an acute in vivo assay that detects the antidepressant activity of test compounds. The method for detecting antidepressant activity is in accordance with Porsolt et al. {Behavioural Despair in Mice: A Primary Screening Test for Antidepressants, Arch. Int. Pharmacodyn., 229, 327-336, 1977). Mice that are forced to swim in a situation where a mouse cannot escape quickly will become immobile. Antidepressants reduce the amount of time that persists. 〇 Animals: Male Rj NMRI mice (I冓 from Elevage Janvier, France) with a body weight ranging from 20 to 28 grams were transported and placed on a wooden padded material with free access to water and food. The clones (MACROLON) cages (25 X 19 X 13 cm, 10 animals per cage) were stable for at least 5 days (SAFE Code 11-3). These animals q were placed under artificial lighting (12 hours) at a controlled ambient temperature of 21 ± 3 °C with a relative humidity between 30% and 80%. After the test, all animals were sacrificed by exposure to a mixture of 〇2/C02 (20%/80%) followed by CO2 or a broken neck. Formulation and Test Compounds In Study A, white powdered tianeptine hemisulfate monohydrate was dissolved in physiological saline. A white powder of thiaprofen > butadiene (commercially available) was dissolved in physiological saline and adjusted to a pH of 8.62. The control group is a vehicle, that is, physiological saline. Reference will be made to the reference 61 201029981 Compound of white powdered imiamine hydrochloride (purchased from Sigma) dissolved in physiological saline. In Study B, the white powdered tianeptine hemisulfate monohydrate was dissolved in physiological saline and adjusted to a pH of 81 (Research B). The control group is a vehicle, that is, physiological saline. White powdered imiamine hydrochloride (purchased from Sigma) as a reference compound was dissolved in physiological saline. Formulation excipients added included 1N hydrochloric acid, 2M sodium hydroxide, and physiological saline (purchased from Laborat〇ire Aguettant). © Formulation of naproxetine hemisulfate monohydrate, tianeptine sodium and imiamine hydrochloride at ambient temperature (close to +20 C). Store the media at approximately +4 °C. Test animals were administered 1 ml/kg of test compound, reference compound and vehicle. All formulations were administered in an amount of 10 ml/kg body weight. Verification procedure: At the beginning of the assay, a single dose of vehicle, reference compound, tianeptine sulphate monohydrate or each mouse in each sputum group was administered 30 minutes before entering the swimming room. The dose of celecoxib sodium is as detailed below. After 30 minutes, the mice were individually placed in a cylinder containing 1 〇 of water (22 C) (height = 24 cm; 13 cm in diameter) from which the mice could not escape. The mice were placed in water for 6 minutes and the duration of the remaining 4 minutes was measured. One mouse was studied in each group. This test was carried out by eye. Use the viewpoint dynamic image to track the time when the software records are not moving. 62 201029981 Study Design: Insulin naphthylsulfate monohydrate was evaluated in two studies of behavioral despair assays as detailed below. In Study A, one of the six groups was assigned 1 animal. The three groups were treated with tianeptine pentasulfate monohydrate and given 1 mg/kg, 150 mg/kg and 200 mg/kg, respectively. The tianeptine pentasulfate monohydrate was administered intraperitoneally 30 minutes prior to the test and compared to the vehicle to which the vehicle was administered. One group was treated with tianeptine sodium, and 15 mg/kg was administered intraperitoneally 30 minutes before the test. One group was treated with the reference compound (imamine hydrochloride), and 32 mg/kg was administered by intraperitoneal injection 3 minutes before the test, and the sixth group was treated with control vehicle, and administered intraperitoneally 3 hours before the test. ----- As the mother group of τ is assigned 1 animal. The two groups were treated with guanidinium and semisulfur (tetra) monohydrate, and given % and 6G mg/kg, respectively. Sulfate monohydrate was administered by intraperitoneal injection 3 minutes before the test, and treated with the reference medium (imamine hydrochloride) as the sputum and sputum for the animals given the vehicle liquid. 'Before the test 30 minutes ago, take a bribe.> 32 mg/kg was administered intraperitoneally, and the fourth dose was given. 4 Intraperitoneal injection 30 minutes before each test according to the above procedure and listed in the table below. Use Situ^Animals' to measure the day of continuous immobility (4) Values with * indicate statistically * 乂 character verification to evaluate measurement results, humiliation has 4 differences' ρ value is less than 0.001 < 201029981

Table 8: Study A treatment with intraperitoneal administration for a period of 30 minutes before the test was continued > F time (seconds) Mean soil sem P value compared with the control group. Percentage change medium 203.2 ± 5.5 _ tianeptine half Sulfate monohydrate (100 mg/kg) 83.1 ± 21.2* <0.0001 -59% tianeptine hemisulfate monohydrate (150 mg/kg) 115.5 ± 13.6* <0.0001 -43% thiaprofen Tetrasulfate monohydrate (200 mg/kg) 108.8 ± 19.8* 0.0002 -46% tianeptine sodium (150 mg/kg) 102.0 ± 13.0* <0.0001 -50% imiamine (32 mg/kg) 64.1 ± 16.1* <0.0001 -68%

100 mg/kg, 150 mg/kg, and 200 mg/kg of tianeptine hemisulfate monohydrate reduced the duration of immobility (-59%, -43%, and compared with animals given vehicle). -46%, p is less than 0.001). All animals showed a Straub tail reaction, high activity and circling behavior. Several animals had difficulty swimming; two animals were drowned, one in the 100 mg/kg group and the other in the 200 mg/kg sputum group. The data for these animals are not included in the results. 150 mg/kg of naproxen sodium also reduced less than 〇1) when compared to animals given vehicle. All move 'shows Straub's tail reaction, high activity and circling behavior. Several animals had difficulty swimming; two animals were drowned' and the data for these animals were not included in the results. 64 201029981 In contrast, animals treated with imamine hydrochloride (32 mg/kg) also reduced the duration of immobility (-68%, p less than 0.001) compared to the vehicle-administered control group. Results (Study B): Animals 5 were tested according to the procedure described above to measure the duration of the performance and are listed in the table below. The measurement results were evaluated using the Stuart t-character test, with a value of * indicating a statistically significant difference with a p-value less than 0.001.

Table 9: Study B Treatment time by intraperitoneal administration for a period of 30 minutes before the test (seconds) Mean ± sem P value Percentage change compared to the control group 179.5 ± 12.1 . - tianeptine sulphate Monohydrate (30 mg/kg) 25.8 ± 8.7* &lt;0.0001 -86% tianeptine hemisulfate monohydrate (60 mg/kg) 29.7 ± 9.7* &lt;0.0001 -83% imiamine (32 Mg/kg) 20.9 ± 8.5* &lt;0.0001 -88% 30 mg/kg and 60 mg/kg of naproxen sulphate monohydrate, which is less persistent than animals given vehicle Time (-86% and -83%, p less than 0.001). In both doses, abnormal behavior was observed in all 10 mice before the test (‘including Straub tailing and circling behavior). In contrast, animals treated with imamine hydrochloride (32 mg/kg) also reduced the duration of persistence (-88%, p less than 0.001) compared to the vehicle-administered control group. 65 201029981 The results of studies A and B showed that there was antidepressant activity in 11 sinaputin hemisulfate monohydrates administered intraperitoneally between 3 〇 mg/kg and 200 mg/kg. Example 10 Clinical Trial Study, Pharmacokinetics of Indole Naphthal; Ding Formula The following clinical trials evaluated single dose pharmacokinetics (PK) in formulation screening, which were double-blind, random, four-processing sequence, and four Period cross-age group 'Each treatment sequence (sample number 3) based on computer-generated random schedule' in random order accepts three π-spinoprene, thiosulfate monohydrate controlled release (CR) lozenges A commercially available sin naproxen STABLON® immediate release (IR) formulation with a formulation of 25 and a 25 mg dose (two 12.5 mg tablets). Twelve subjects were recruited to the trial. The subjects were healthy males or healthy non-lactating women from 21 years old to 55 years old. Clinical chemistry, hematology, and urinalysis tests are within normal allowable limits (if they are out of range, they should be considered clinically excluded) and are performed within 21 days of receiving the first study drug. The body mass index ranges from ❹ 18kg/m2 to 30kg/m2. After resting for 5 minutes in a supine position, the vital signs were normal (95 mm <systolic pressure &lt; 140 mm Hg, 50 mm Hg < diastolic pressure &lt; 9 〇 mm Hg, 45 bpm <heart rate &lt; 90 bpm). 12-lead automatic electrocardiogram (ECG; incomplete right bundle branch block can be connected to the party) Normal: 120 ms &lt;PR&lt;2l〇ms, QRS&lt;120 ms, QTc (Bazett) male is less than Equal to 430 msec and female less than or equal to 450 msec. Subjects who did not experience vomiting, completed all assessments, did not reach 66 201029981 to the exit criteria, and completed 24 hours of ρκ blood sample collection during the four treatment periods were considered The subject completed the study. Research drug information and management: The clinical formulation containing tianeptine desulfate monohydrate is taken once a day, and the controlled release matrix is composed of hydroxypropyl fluorenyl cellulose as a speed controlling polymer and micro-etchable filler. Crystalline cellulose is made up. Three CR recordings were used in the study; the formulation of F (F2 and F3) as provided in Table 6 has an in vitro release profile close to 9, respectively.

90% of drug release was shown at 12 and 15 hours). The composition of the Sanyan formulation is approximately the same except for the ratio of the release polymer Methocel K100LVCR to the Methocel K4M CR. The three CR formulations were white to a white round lozenge containing 25 mg of tianeptine (equivalent to &lt;8.84^ng of tianeptine hemisulfate monohydrate). The placebo agent is a complex lozenge that does not contain 3 tianeptine. STABLON® IR Recording: (Jingzhou) is two 125 white to nearly white tablets (a total of 魄 is a product on sale. Store all tianeptine sulphate research products in appropriate locks The room temperature is between 15 c and ij IR L and is the responsibility of the researcher. STABLON® is stored according to the sales soap: do not store under 25 art, avoid light. 8 Research drugs are in the first 4, 7 and 10 days close to the morning, the sour water was used by the non-carbon person in the fasting condition under the fasting condition of 240 mL. In order to keep the treatment given, it is invisible, test, close your eyes. And open the mouth, the two tablets (2 67 201029981 12.5 mg STABLON® bond or a 25 mg CR formula)

Add a matching placebo tablet) on their tongue and ask them to swallow. The study drug was swallowed entirely without being smothered, divided, dissolved or crushed. Subjects maintained an upright position from the time the study drug was administered until 4 hours after the study drug was administered. About 2 hours after the administration (but not earlier), the subject drank a glass of water (about 24 〇 mL); from then on until after, drinking water was allowed. Four hours after the ingestion of the drug, a standardized lunch was given to all subjects on the first day. The lunch is the same on all days of dosing. The exact start time for lunch and dinner (9 hours after dosing) and any deviations from lunch and dinner time are recorded in the CRF. During the study period, it was forbidden to study prescription or over-the-counter medicines (including vitamins and herbal medicines, aids) other than drugs. Acetylamine was allowed to be used 3 days before the start of the administration of the _J parent. During the study period, the use of up to 3 doses of 5 〇〇 mg of acetaminophen per day was used to treat headache or pain, but not more than 3 grams per week. Subjects were given medication on days 14, 7 and 1; follow-up inspections were conducted within 2 days of the 丨7 soil.

Musical Dynamics (PK) Assessment 2·4 was administered to subjects on days 1, 4, 7 and 1 of s, and blood samples were taken at dogs, 70, 8, 1 and 11 days (each time) 4 plasma) was evaluated as ρκ. Specifically come to Weng. Lotte's administration (t=0) and post-administration 0.25, 0.5, .2.0, 2.5, 3.〇, 4.0, 6.0, 8〇, 1〇〇, 12〇, ^ 68 201029981 16.0, 24.0, 28.0 , 32.0 and 36·〇 hours samples were stored at _2 (TC. 咏 样本 samples. These will be analyzed in the ICON development solution (Manchester Governor, _ (surface) bioanalytical analysis of blood damage sample Ting Concentration. 嗔 naproxil (10) quantitation limit (L〇Q) is hi. “ Data analysis: ❽ All available data are included in the data list. PK analysis group contains all received at least, no major deviations in the intake of study drugs Accepted; = not all _) missing data m (d) during the period (but estimated: two of the t-moisture time data) using the following tianeptine PK parameters in the treatment of the actual sampling:

Cmax Tma ❹ , maximum plasma concentration (ng/mL) observed [Limited time: concentration, interval (hours) AUC24h AUCjast interval (hours) analyte concentration exceeds the quantitation pole at the dosing interval (24 hours) , σ right rR ? m 2 degree versus time curve two (ngh / m) L) using the trapezoidal method to calculate blood AUC ί 3 from the dose after 0 to t, ast hours of the area, to line time ° to unlimited The area of time, root %AUC^qx ί = AUC-+c-^(ng.h/mL), ^ 2 is the percentage of AUC〇° pushed to t, calculated by the following equation: 69 201029981 λζ ίΐ/2,λ Frel The first reaction poem associated with the terminal part of the curve ^ ^ ^ ^ time curve terminal logarithm. The linear phase of the negative rate n - by the music &amp; degree · and the semi-log drug concentration-time curve terminal 咎n lifetime, calculated as 0.693/λζ Slope (λζ) related to the elimination of semi-relative bioavailability: The drug administered is Jixian~ Calculated as: _CWAUC two 5 liters, the systemic qi ratio J treatment is non-intravenous administration. Test: F (jJef)f(test))]*i〇〇, reference Test: IR formula. H, F2 and F3CR formulas; 参 ❹ Use non-compartment reading to calculate the ph ph. In the actual processing, after the money is sampled, the neck of the money is analyzed. The average enthalpy concentration was calculated using each stream to be used as a graph. Use validated pharmacokinetics and statistical software κ analysis and narrative statistics. Take the (:_ and Tmax values directly from the data. Calculate the blood concentration _ time curve terminal logarithm _ post-stage g Η Η negative slope as a semi-logarithmic plot to eliminate the relative time of each check with the 22nd check concentration Determine the range of data used. Use at least three data to calculate λζ. Use the above green to calculate other ΡΚ parameters. 〇Results: Of the 12 subjects recruited, 12 completed the average age of 37.7 years, range At 23蛊^, the test was between the ages of 55 and the age of 15. The 12th place was a male (5〇.0%). The 4 people who were dealing with the deviation of the process were her. The difference was excluded. Outside of the analysis. * The difference between the actual sampling time after the processing of the sample and the scheduled sampling time of 70 201029981 is taken as the difference between the actual sampling time and the scheduled sampling time. It is not considered as a reason for exclusion. The elimination rate constant λζ and the half-life ί1/2, λ are calculated only when the coefficient of determination (R2adj) used to estimate the terminal elimination phase is higher than 0.80. If AUC〇〇, the percentage of ex exceeds 20%, then calculate ACUo 'but it does not Included in narrative statistics. The mean plasma concentration-time curves for the four treatments are shown in Figure 24, and the concentration scale is linear. Table 10 below lists 25 mg of naproxen and statin administered as STABLON® IR tablets, respectively. And the mean (±SD) tianeptine pharmacokinetic parameters of the naproxen sulphate monohydrate CR tablet formulation FI, F2 and F3. Table 1 〇: Pharmacological mechanics spring number parameter STABLON® (n =12) FI (n=i2, F2 (n=12) F3 (n=ll) Cmaxj ng/mL 464 ± 104 149 ± 71 111 ± 56 100 ± 41 1.50 2.50 2.51 3.00 Ί max, hour (1.00 - 2.00) (1.50 ~ 4.00) (1.50 - 4.00) (2.00 - 12.0) AUCiast, ngh/mL 1535 ± 354 1350 ± 3〇i 1290 ± 453 1073 ± 458 AUC〇〇, ngh/mL 1571 ± 382 1383 ± 293 1377 ± 442 1172 ± 537 FreI, % 100 90.9 ± 18.0 89.5 ± 20.2 73.0 ± 26,4 11/2, hour Γ 3.0 ±0.6 5.3 ± 0.9 5.7 ± 2.3 5.9 ± 3.6 C24h, ng/mL BQL 18.8 ± 8.4 22.3 ± 12.0 16.1 ± 14.7 cmax is the maximum plasma concentration; Tmax is the time to reach the maximum plasma concentration 'AUC? is the area under the plasma concentration_time curve to infinity time, A UC丨ast is the area under the plasma concentration_time curve from the post-dose to t]^ small area, 1/2 is the elimination half-life; Ffei is the relative bioavailability; BQL refers to the lower limit of quantification; Ding Long: the median (Minimum-Maximum) 201029981 The results of this study can be summarized as follows. After oral administration of the STABLON® IR lozenge formulation, tianeptine was rapidly absorbed and showed a peak plasma concentration 1 to 2 hours after administration. The tianeptine mortar concentration decays with a terminal half-life of about 3 hours. All three tianeptine hemisulfate monohydrate CR formulations (FI, F2 and F3) showed a plasma concentration level after a delay time of 0.3 to 0.4 hours with a peak at about 2.5 to 3 hours (F3 vs. F1 and F2) The concentration of the maximum tianeptine at a later time &gt; F1 is about three times lower than that of the STABLON® IR formula, while the peak plasma concentration of tianeptine in F2 and F3 is four to five times lower than that of the STABLON® IR formulation. The plasma concentration of the statin was attenuated to about 8 hours and then gradually increased to the second concentration peak, which was observed about 12 hours after administration. This second plasma concentration peak was about 0.4 times the initial Cmax of F1, and F2 and F3. Cmax is 0.5 to 0.6 times. After this second peak, the plasma concentration further decays with the estimated half-life, which is 5.3 hours in F1, 5.7 hours in F2, and 5.9 hours in F3, up to 36 hours after administration. The average 24-hour concentration of F1 is 0.13 times Cmax, F2 is 0.20 times Cmax, and F3 is 0.16 times Cmax, and the most limited peak-to-valley ratio of F2 after repeated administration of QD is predicted. With STABLON® IR Compared with the formula, the relative bioavailability of tianeptine of F1 is 91%, F2 90% for F3 and 73% for F3. Inter-individual variability (expressed as a percentage of CV) exposed to tianeptine has an increasing tendency from CR formulations F1 to F2 to F3. STABLON® IR Lozenges Formulation PK features consistent with those known in the literature were: rapid absorption, peak plasma concentrations 1 to 2 hours after dosing, and half-life decay with about 3 hours. 72 201029981 About 2.5 after administration The median time of 3 hours, the naproxen sulphate monohydrate CR formula (FI, F2 and F3) showed much lower plasma concentration peaks than the STABLON® IR formula (Κ3 is slightly longer than Η and F2) The peak concentration of tianeptine in the FI CR formulation is higher than that in the F2 and F3 CR formulations. After Cmax, the naphthoquinone is continuously absorbed from the CR formula (F Bu F2 and F3), resulting in The second peak after about 10 to 16 hours after the drug. The difference between the first and second peaks is in F1 (the second peak is about 0.4 times Cmax) than in F2 and F3 (the second peak is Cmax 0.5 to 0.6 times) large. Plasma concentration 衰减 decays with half-life of 5 to 6 hours. The difference between 仏仙 and Cmax is in F1 and F3 (CWC^ ratio别13 and 〇16) are larger than F2 (C24h/Cmax ratio is 0.20), which predicts the minimum peak-to-valley ratio of F2 after repeated administration. Cr formula F2 shows the most limited peak-to-valley ratio And high bioavailability. In summary, the β-sinaprofen sulphate monohydrate CR formula (pi, F2 and F3) showed a gentle absorption after treatment, as compared to the STABLON® IR formula. Peak time, lower Cmax, • and more gradual attenuation. Compared to the STABL®&gt;^IR formulation, the first C_ post-嗟 naproxen was continuously absorbed from the CR formulation, resulting in a second peak of about 10 to 16 hours after administration. [Simple description of the figure] ^ Figure 1 PXRD diffraction pattern of tianeptine monohydrate hemisulfate. Figure 2_DSC temperature chart of sinaprofen monohydrate hemisulfate. Figure 3 - TGA temperature record of thiophene > Ding monohydrate hemisulfate. Figure 4 - dvs data for tianeptine monohydrate hemisulfate. 73 201029981 Figure 5 - PXRD diffraction pattern of tianeptine hydrochloride. Figure 6 - DSC thermogram of tianeptine hydrochloride. Figure 7 - TGA thermogram of tianeptine hydrochloride. Figure 8 - DVS data for tianeptine hydrochloride. Figure 9 - PXRD diffraction pattern of tianeptine phosphate. Figure 10 - DSC thermogram of tianeptine phosphate. Figure 11 - TGA thermogram of tianeptine phosphate. Figure 12 - DVS data for tianeptine phosphate. Figure 13 - Ultraviolet/absorption spectra of tianeptine monohydrate hemisulfate. Figure 14 - Infrared spectrum of tianeptine monohydrate hemisulfate. Figure 15 - Raman spectrum of tianeptine monohydrate hemisulfate. Figure 16 - DVS data for tianeptine sodium. Figure 17 - Solubility of different tianeptine salts. Figure 18 - PXRD diffraction pattern of tianeptine formula (II). Figure 19 - Solubility data for various buffers of various forms of tianeptine at 37 °C. Figure 20 - Drug release (in SGF) of tianeptine sodium salt and tianeptine monohydrate hemisulfate tablet. Figure 21 - Drug release (in SIF) of tianeptine sodium salt and tianeptine monohydrate hemisulfate tablet. Figure 22 - Drug release rate (in SGF) of tianeptine sodium salt and tianeptine monohydrate hemisulfate. Figure 23 - Drug release rate (in logarithmic coordinates, in SGF) of tianeptine sodium salt and tianeptine monohydrate hemisulfate tablet. Figure 24 - Linear mean plasma concentration time curve of STABLON® tablets compared to tianeptine monohydrate hemisulfate tablets. 74 201029981

Claims (1)

201029981 VII. Scope of application for patents 1. A 7-[(3-chloro-6,1-dihydro-6-fluorenyl) and [c,f][l,2] as shown in the formula (Π) Sulphur azepine-11-yl)amino]heptanoic acid S,S-dioxide hemisulfate monohydrate: 2. 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][l,2]thiazepine-11-yl according to item 1 of the scope of application Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, which is a crystalline form. 3. 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][l,2]thiazepine-11-yl according to the scope of patent application Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate exhibits at least measurable crystals 7-[(3-chloro-6,11- Dihydro-6-mercaptodibenzo[c,f][l,2]thiazepin-11-yl)amino]heptanoic acid S,S-dioxide hemisulfate monohydrate. 4_7-[(3-chloro-6,11-dihydro-6-fluorenyldibenzo[c,f][l,2]thiazepine-11-yl according to item 3 of the patent application scope Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the crystalline hemisulfate monohydrate has a weight of from about 20% to about 100% by weight of the hemisulfate monohydrate . 76 201029981 5. 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][l,2]thiazepine-11 according to the scope of patent application -amino)heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by an X-ray powder diffraction pattern comprising a peak at a 2-Θ angle of about 8.97 Degree 6. According to the scope of patent application No. 1 7-[(3-chloro-6,11-dihydro-6-mercaptodibenzo[c,f][l,2]thiazepine-11 -amino)heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by a beta X-ray powder diffraction pattern comprising a peak at a 2-Θ angle of about 11.49 degrees. 7. According to the scope of patent application No. 1 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][l,2]thiazepine-11-yl Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by an X-ray powder diffraction pattern comprising peaks at a 2-Θ angle of about 8.25 and about 8.97 degree. ❿ 8. According to the scope of the patent application, 7-[(3- gas-6,11-dihydro-6-methyldibenzo[c,f][l,2]thiazepine-11- Alkyl]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by a line powder diffraction pattern comprising a peak at a 2-Θ angle of about 8.25, about 13.91 And about 14.73 degrees. 9. 7-[(3-chloro-6,11-dihydro-6-mercaptodibenzo[c,f][l,2]thiazepine-11-yl according to the scope of patent application Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by 77 201029981 X-ray powder diffraction pattern comprising a peak at a 2-Θ angle of about 8.97, About 18.07, about 19.39 and about 20.59 degrees. 10. 7-[(3-Ga-6,11-dihydro-6-methyldibenzo[c,f][l,2]thiazepine-11-yl according to the scope of patent application Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by an X-ray powder diffraction pattern comprising a peak at a 2-Θ angle of about 8.97, about 11.47 , about 13.91, about 18.07, about 19.39 and about 20.59 degrees. 11. 7-[(3-Gas-6,11-dihydro-6-mercaptodibenzo[c,f][l,2]thiazepine-11-yl according to the scope of patent application Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by an X-ray powder diffraction pattern comprising a peak at a 2-Θ angle of about 8.25, about 8.97 , about 11.49, about 13.91, about 14.73, about 16.95, about 18.07, about 19.39, about 20.59, about 21.99, about 22.83, and about 23.27 degrees. 12. 7-[(3-Gas-6,11-dihydro-6-fluorenyldibenzo[c,f][l,2]thiazepine-11- according to the scope of patent application Alkyl]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 13. 7-[(3-Chloro-6,11-dihydro-6-mercaptodibenzo[c,f][l,2]thiazepine-11-yl according to the scope of patent application Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate special 78 201029981 is a scanning thermal differential temperature record comprising an endothermic transition at about 193 °C. 14. 7-[(3-Chloro-6,11-dihydro-6-mercaptodibenzo[c,f][l,2]thiazepine-11-yl according to the scope of patent application Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is measured by dynamic moisture adsorption analysis at a relative humidity of about 10% to about 90 at 25 °C. % is moisture resistant. ® 15. 7-[(3-Chloro-6,11-dioxin-6-mercaptodibenzo[c,f][l,2]thiazepine-11- according to the scope of patent application Alkyl]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein 7-[(3-gas-6,11-dihydro-6-mercaptodibenzo[c,f][ l, 2] thiazepine-11-yl)amino]heptanoic acid The ratio of S,S-dioxide to upper sulfuric acid to water is about 2:1:2. 16. — Crystalline 7-[(3-chloro-6,11-dihydro-6-mercaptodibenzo[c,f][ 1,2]thiazepine-11-yl)amino]g Acid S,S-dioxide hemisulfate monohydrate® characterized by an X-ray powder diffraction pattern comprising peaks at a 2-Θ angle of about 8.97, about 11.49, about 14.73, about 20.59, about 22.83, and about 23.27 degrees. . 17. A 7-[(3-chloro-6,11-dihydro-6-fluorenyldibenzo[c,f][l,2]thiazepine-11- of the formula (II) Method for the base of amino] heptanoic acid S,S-dioxide hemisulfate monohydrate: 79 201029981 It comprises the step (a) dissolving 7-[(3-chloro-6,11-dihydro-6-fluorenyldibenzo[c,f][l,2]thiazepine in a mixture of water and acetic acid. -11-yl)amino]heptanoic acid S,S-dioxide or its sodium salt; (b) adding a sulfuric acid solution containing only water or a solvent comprising water in combination with acetic acid to the reaction mixture of step (a); c) Crystallization of the compound of formula (II). 18. The method of claim 17, further comprising the steps of: (d) isolating the compound of formula (II) obtained in the reaction mixture of step (c); (e) washing with a mixture of water and acetic acid a compound of formula (II); (f) further washing the compound of formula (II) with water; and (g) drying the compound of formula (II). 19. The method of claim 17, wherein the method does not separate the intermediate product of the formula: 80 201029981 20. A method of treating a mammal suffering from depression comprising administering to said mammal an effective amount of 7-[(3-chloro-6,11-dioxin-6-) of claim 1 Mercaptodibenzo[c,f][l,2]thiazepin-11-yl)amino]heptanoic acid S,S-dioxide hemisulfate monohydrate. 21. A kind of 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][l,2]thiazepine-11 containing the scope of patent application. -Acidyl]heptanoic acid S,S-dioxide hemisulfate monohydrate and a pharmaceutically acceptable carrier pharmaceutical composition. 22. The composition of claim 21, wherein the pharmaceutical composition is a controlled release pharmaceutical composition. 23. A controlled release interstitial lozenge comprising: a pharmaceutically effective amount of 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][l,2 Thiazol-11-yl)amino]heptanoic acid S,S-dioxide hemisulfate monohydrate; and one or more release controlling polymers, 201029981 · wherein when the tablet is administered orally to a patient , 7_[(3_chloro_611_dihydro-6-methyldibenzo[ Ming[1,2]thiazepin-11-yl)amino]heptanoic acid s,s-dioxide The average maximum plasma concentration (Cmax) is from about 100 ng/mL to about 150 ng/mL. 24. The lozenge according to claim 23, wherein the lozenge uses a USP dissolution apparatus type II (paddle) at about 37 ° C, 100 rpm, 900 mL simulated gastric juice (pH about i.2) The in vitro dissolution rate measured in less than 14% by weight after 7 hours of release of 7-[(3-chloro-6,11-dioxin-6-methyldibenzothiazepine-u-yl) Amino]heptanoate s S,S-monooxide hemisulfate monohydrate, after 7 hours of release, at 45% to 80% by weight of 7-[(3-chloro-6,11-dihydro-6-A) Dibenzo[[;;,£][1,2]thiazepine-11-yl)amino]heptanoic acid S,S-dioxide hemisulfate monohydrate between 'and 16 hours of release More than 90% by weight of 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[(), £][1,2]thiazepine-11-yl)amine The sulphate S, S-dioxide hemisulfate monohydrate. The tablet according to claim 23, wherein the tablet is 7-[(3) when administered to a patient orally. -Chloro-6,11-dihydro-6-mercaptodibenzo[c,f][l,2]thiazepine_h_yl)amino]heptanoic acid S,S-dioxide average The highest plasma concentration (Cmax) is from about 100 ng/mL to about 120 The ng/mL. The tablet according to claim 23, wherein the tablet is 7-[(3-chloro-6,11-dihydro-6-mercaptodiphenyl) when administered orally to a patient. And [c,f][l,2]shiquanzazao-11-yl)amino]heptanoic acid §, S-dioxide reaches |J 82 201029981 median time of mean highest plasma concentration (Tmax) The tablet is in the range of from about 2.5 hours to about 3.0 hours. 27. The tablet according to claim 23, wherein the tablet has a mean area under the curve of the plasma concentration time curve ranging from about 1170 ng when administered to a patient. Hr/mL to about 1380 ng.hr/mL 28. The lozenge according to claim 23, wherein the one or more release controlling polymers comprise hydroxypropyl fluorenyl cellulose. 〇 29. The tablet of claim 23, wherein the one or more release controlling polymers comprise first hydroxypropyl methylcellulose (2% solution dissolved in water) having a viscosity of 80 to 120 cps and a viscosity of 3,000 to 5,600 Cps second hydroxypropyl decyl cellulose (2% solution dissolved in water) 30. According to the scope of claim 29: agent, Propyl group via said first and second Yue hydroxypropyl cellulose ratio to the cellulose Yue ❿ from about 2: 1 to about 4: 1.83