Eutectic compound of Tencapanol and application thereof

Abstract

The invention relates to a tenapanol meglumine eutectic crystal as shown in a formula (I), which obviously solves the problems of poor solubility and hygroscopicity of a prototype drug, and has the advantages of certain storage stability and bioavailability. The invention also provides application of the eutecticum in preparation of an adult constipation-type irritable bowel syndrome and a prevention and / or treatment agent for reducing the serum phosphate level of a dialysis patient.

Description

Technical Field

[0001] The present application relates to the field of solid forms of the drug tenapanor, particularly to a drug form that provides higher solubility for tenapanor, and more specifically, to the tenapanor N-methylglucamine cocrystal as a pharmaceutical drug form. Background Art

[0002] The crystallinity of a drug affects its physical and mechanical properties, such as solubility, hardness, compressibility, and melting point. Since these properties in turn affect the manufacture and efficacy of the drug, there is a need in the chemical and therapeutic arts to identify the crystalline forms of drugs and reproducible manufacturing methods.

[0003] Tenapanor Hydrochloride, common English name: Tenapanor Hydrochloride; Chinese chemical name: 17 - [[[[3 - [(4S)-6,8 - dichloro - 1,2,3,4 - tetrahydro - 2 - methyl - 4 - isoquinolinyl]phenyl]sulfonyl]amino] - N - [2 - 2 - [[2 - [[[3 - [(4S)-6,8 - dichloro - 1,2,3,4 - tetrahydro - 2 - methyl - 4 - isoquinolinyl]phenyl]sulfonyl]amino]ethoxy]ethoxy]ethyl] - 8 - oxo - hydrochloride; English chemical name: 17 - [[[3 - [(4S)-6,8 - dichloro - 1,2,3,4 - tetrahydro - 2 - methyl - 4 - isoquinolinyl]phenyl]sulfonyl]amino] - N - [2 - [2 - [2 - [[[3 - [(4S)-6,8 - dichloro - 1,2,3,4 - tetrahydro - 2 - methyl - 4 - isoquinolinyl]phenyl]sulfonyl]amino]ethoxy]ethoxy]ethyl] - 8 - oxo - hydrochloride; CAS No.: 1234365 - 97 - 9, and its structural formula:

[0004]

[0005] Molecular formula: C 50 H 66 Cl4N8O 10 S2·2HCl; Molecular weight: 1217.97. The first reported and publicly disclosed compound related to this product and

[0006] The crystalline forms are recorded in the following patent documents:

[0007]

[0008]

[0009] Tenapanor hydrochloride is a first-in-class small molecule drug developed by Ardelyx Inc and is an NHE3 inhibitor. It is used to treat hyperphosphatemia, chronic renal insufficiency, constipation, and irritable bowel syndrome. Its marketing information is as follows:

[0010] On September 12, 2019, tenapanor hydrochloride was approved by the US Food and Drug Administration (FDA) and is sold by Ardelyx Inc under the trade name

[0011] On September 25, 2023, tenapanor hydrochloride was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan and is sold by Kyowa Kirin Co., Ltd. under the trade names Fozevyl tablets 5mg / Fozevyl tablets 10mg / Fozevyl tablets 20mg / Fozevyl tablets

[0012] On February 20, 2025, tenapanor hydrochloride was approved by the National Medical Products Administration (NMPA) of China and is sold by Shanghai Fosun Pharmaceutical (Group) Co., Ltd. under the trade name

[0013] As is well known, water solubility is a key parameter affecting biological activity and is usually the rate-limiting step in the gastrointestinal absorption of drugs. Regardless of the intended route of administration, the active substance needs to dissolve or be solubilized in an aqueous medium at least at some point to achieve bioavailability or be applicable to patients. For example, the active substance in oral tablets should dissolve in gastrointestinal fluids. The main drawback of tenapanor hydrochloride is its very low oral bioavailability (at a dose of 10 mg / kg, when tenapanor hydrochloride is administered orally to male rats or male dogs once, at most time points, the concentration of tenapanor in plasma is less than the lower limit of quantification of 0.500 ng / mL).

[0014] As stated in the FDA Product Quality Review(s), tenapanor is classified as a Class 4 drug according to the Biopharmaceutics Classification System (BCS), which means it has low solubility and low permeability. Therefore, in order to achieve sufficient efficacy, it is crucial to find a form of tenapanor with the highest possible solubility and bioavailability. Tenapanor exists in polymorphic form 1 and an amorphous form, and the polymorph used in currently marketed tablets is amorphous powder. Although using the amorphous form of tenapanor overcomes the problem of polymorphic transformation, this approach also has some drawbacks: 1) The amorphous form is a metastable form and is generally less stable than the crystalline form in terms of storage, so a large amount of stabilizer is required to maintain the amorphous form; 2) There is always a risk of recrystallization during storage of the amorphous form; 3) Since the amorphous form in the tablet matrix has strong hygroscopicity, the tablet formulation requires protective packaging to prevent moisture absorption, and strong desiccants are added to currently marketed tablets. Therefore, it would be desirable to find an alternative crystalline form of tenapanor that can provide higher solubility, without the inherent poor stability problem of the amorphous form, and without the need to use stabilizers.

[0015] The most commonly used alternative crystalline forms for increasing the solubility of poorly soluble drugs are pharmaceutically acceptable salts. Crystalline salts are formed when a drug and a second component crystallize together to form a two-component crystalline complex, which are held together by ionic bonds with proton transfer between the two components. Compared with the pure crystalline drug, drug salts generally have more superior physical properties. However, all the salts of tenapanor reported are amorphous and highly hygroscopic. Therefore, forming co-crystals is an alternative two-component crystalline complex in which the drug and the second component are held together by non-ionic bonds such as hydrogen bonds or van der Waals bonds, and there is no proton exchange between the two components. The second component in the co-crystal is called a "co-ligand". Drug co-crystals have a unique crystal structure, and their crystallographic and spectroscopic properties are quite different from those of the drug and the co-ligand alone. These multi-component aggregates are being continuously explored and found to have uses, especially in the pharmaceutical field, because compared with the pure drug, drug co-crystals generally have more favorable pharmaceutical properties, which often make them more suitable for new dosing options that cannot be achieved by the pure crystalline drug or its amorphous form. This is because the co-crystal form may have improved properties, such as improved solubility or dissolution rate, or favorable storage stability, melting point, hygroscopicity, or other physicochemical properties. For the medicinal co-crystals of tenapanor to be acceptable as an alternative marketed form of tenapanor, the co-ligand used must be "inactive" and acceptable for use in pharmaceutical formulations from a regulatory perspective.

[0016] There remains an unmet need for a solid form of tenapanor with good physicochemical properties, desirable bioavailability, and favorable drug parameters.

[0017] By co-crystallizing an API or the salt of an API with a co-former (the other component of the co-crystal), a new solid form of the API can be produced, which has unique properties compared to the existing solid forms of the API or its salts. For example, the co-crystal may have different dissolution and / or solubilization properties from the active agent itself or its salt. Co-crystals containing the API can be used for the therapeutic delivery of the API. In some cases, new pharmaceutical formulations composed of the co-crystal of the API and a pharmaceutically acceptable co-former may have better performance than existing pharmaceutical formulations. However, the formation of co-crystals is unpredictable and not always possible in fact. In addition, the properties of a compound cannot be predicted before the formation of a specific co-crystal of the compound. Therefore, finding suitable conditions to obtain a specific co-crystal of a compound with pharmaceutically acceptable properties may require a large amount of time, effort, and resources. Summary of the Invention

[0018] An object of the present invention is to obtain solubility higher than that of the amorphous powder used in the prototype drug and good hygroscopicity by co-crystallizing tenapanor (used as a prophylactic and / or therapeutic agent for adult constipation-predominant irritable bowel syndrome and for reducing serum phosphate levels in dialysis patients), and to ensure permeability and bioavailability, and further inhibit the formation of solvates, facilitating the control of crystal forms that are important for the quality of drugs. This co-crystal is stable and reproducible on an industrial scale.

[0019] In order to attempt to achieve the above object, the present inventors conducted in-depth research and tried various different ligands (such as lysine, tyrosine, or phenylalanine, etc.). As a result, it was found that it was difficult for this compound to form co-crystals, and the substances obtained with some ligands could not crystallize out through various solvents (such as ethanol, methanol, toluene, ethyl acetate, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), acetonitrile, 1-butanol, water, or their mixtures, etc.). After trying various ligands and solvents, a tenapanor meglumine co-crystal was finally obtained, which significantly improved solubility, hygroscopicity, stability (physical stability and chemical stability), permeability, and bioavailability. The tenapanor meglumine co-crystal of the present invention significantly improved the physicochemical properties of the prototype drug tenapanor: it has certain advantages in terms of melting point, stability (physical stability and chemical stability), solubility, hygroscopicity, compressibility, permeability, and bioavailability, and is more suitable for oral use.

[0020] One aspect of the present invention provides a tenapanor co-crystal, characterized in that: the co-crystal is tenapanor meglumine shown in formula (I)

[0021] Among them, the molar ratio of tenapanor meglumine co-crystal is 1:1 of tenapanor and meglumine.

[0022] Among them, the X-ray powder diffraction pattern of tenapanor glucosamine eutectic has characteristic peaks at diffraction angles 2θ: 8.9±0.2, 12.2±0.2, 12.4±0.2, 17.2±0.2, 17.3±0.2, 19.2±0.2, 19.8±0.2, 20.6±0.2, 21.5±0.2, 26.2±0.2, 29.2±0.2, 32.6±0.2, 34.5±0.2°.

[0023] Among them, the endothermic temperature of the differential scanning calorimetry of tenapanor glucosamine eutectic is 124.9±3°C.

[0024] Preferably, the hygroscopicity of tenapanor glucosamine eutectic is lower than that of tenapanor base and tenapanor hydrochloride.

[0025] Preferably, tenapanor glucosamine eutectic has better water solubility than tenapanor base and tenapanor hydrochloride.

[0026] On the other hand, the present invention provides a drug containing tenapanor glucosamine eutectic.

[0027] Furthermore, the use of tenapanor glucosamine eutectic drug in the preparation of a prophylactic and / or therapeutic agent for adult constipation-predominant irritable bowel syndrome and reducing serum phosphate levels in dialysis patients.

[0028] The co-crystals of the present invention can be administered orally or parenterally as such or in the form of a mixture with a pharmaceutical carrier.

[0029] The oral dosage forms of the co-crystals of the present invention are, for example, tablets (including sugar-coated tablets, film-coated tablets), pills, granules, powders, capsules (including soft capsules, microcapsules), syrups, emulsions, suspensions, etc. The parenteral dosage forms are, for example, injections, infusions, drops, suppositories, etc. In addition, by combining the co-crystals with suitable bases (such as polymers of butyric acid, polymers of glycolic acid, copolymers of butyric acid and glycolic acid, mixtures of polymers of butyric acid and polymers of glycolic acid, polyglycerol fatty acid esters, etc.), sustained-release preparations can be effectively prepared. For the methods of preparing the above dosage forms of the co-crystals of the present invention, known preparation methods commonly used in the relevant field can be used. When preparing the above dosage forms, appropriate amounts of additives commonly used in the pharmaceutical field, such as excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifying agents, etc., can be added as needed. When preparing the co-crystals of the present invention into tablets, for example, they can be prepared by adding excipients, binders, disintegrants, lubricants, etc. When preparing pills or granules, they can be prepared by adding excipients, binders, disintegrants, etc. When preparing powders or capsules, they can be prepared by adding excipients, etc. When preparing syrups, they can be prepared by adding sweeteners, etc. When preparing...

[0030] When preparing a milk agent or suspension, it can be prepared by adding a suspending agent, a surfactant, an emulsifier, etc. Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate, etc.

[0031] etc. Examples of binders include 5 - 10 wt% starch liquid paste, 10 - 20 wt% gum arabic solution or gelatin solution, 1 - 5 wt% astragalus

[0032] gum solution, carboxymethyl cellulose solution, sodium alginate solution, glycerol, etc. Examples of disintegrants include starch, calcium carbonate, etc. Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, purified talc powder, etc. Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerol, simple syrup, etc. Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyethylene 40 stearate, etc. Examples of suspending agents include gum arabic

[0033] gum, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite, etc. Examples of emulsifiers include gum arabic, tragacanth

[0034] gum, gelatin, polysorbate 80, etc. In addition, when preparing the above dosage forms of the cocrystals of the present invention, appropriate amounts of colorants, preservatives, fragrances, corrective agents, stabilizers, thickeners, etc. typically used in the pharmaceutical field can be added according to requirements.

[0035] Although the content of the cocrystals of the present invention in the pharmaceutical agents of the present invention varies according to the form of the pharmaceutical preparation, it is generally about 0.01 to 100 wt%, preferably about 2 to 85 wt%, more preferably about 5 to 70 wt% relative to the entire preparation.

[0036] As described above, tenapanor is known in the art to be useful for treating various diseases, disorders, and conditions. The tenapanor N - methylglucamine

[0037] cocrystals of the present invention and pharmaceutical compositions containing them can also be used to treat such diseases, disorders, and conditions. Diseases, disorders, or conditions that can be treated with the tenapanor N - methylglucamine

[0038] cocrystals of the present invention include but are not limited to: for reducing the serum phosphorus level in adult patients with chronic kidney disease (CKD), as an additional treatment for patients who are insufficient responders to phosphate binders or intolerant to any dose of phosphate binder treatment.

[0039] The tenapanor N - methylglucamine

[0040] cocrystals of the present invention can also be used to treat such diseases, disorders, and conditions.

[0041] Accordingly, the present invention relates to a method for treating such diseases, disorders or conditions, which comprises the step of administering to a patient in need thereof a therapeutically effective amount of the tenapanor N-methylglucamine cocrystal of the present invention, or the step of administering to a patient in need thereof a therapeutic composition containing the tenapanor N-methylglucamine cocrystal of the present invention.

[0042] On the other hand, the present invention provides a method for preparing a tenapanor cocrystal. Tenapanor and N-methylglucamine are heated to a eutectic state under the protection of an inert gas, stirred for a period of time while maintaining the temperature, slowly cooled to solidify, then a first organic solvent is added and the mixture is heated to reflux until clear, slowly cooled to 0-5 °C, stirred for a period of time until crystallization is complete, then filtered, the filter cake is washed with a second organic solvent, and dried to obtain the target product.

[0043] Wherein, the inert gas is selected from nitrogen.

[0044] Wherein, the first organic solvent is selected from methanol, ethanol, isopropyl ether, isopropanol, ethyl acetate or a mixture thereof.

[0045] Wherein, the second organic solvent is selected from isopropyl ether.

[0046] Wherein, the molar ratio of tenapanor to N-methylglucamine is 1.5:1 to 1:1.5, preferably 1:1.

[0047] Wherein, the temperature for heating to the eutectic state is 130-180 °C, preferably 150-175 °C, more preferably 155-160 °C.

[0048] Wherein, the time for the first heat preservation and stirring is 20-60 minutes, preferably 25-35 minutes, preferably 30 minutes; the

[0049] The time for the second heat preservation and stirring is 4-8 hours, preferably 5-7 hours, more preferably 6 hours.

[0050] Wherein, the drying time is 2-7 hours, preferably 4-6 hours, more preferably 4 hours. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0052] Figure 1 It is the chemical structure of the tenapanor N-methylglucamine cocrystal in Example 1.

[0053] Figure 2For the eutectic of tinapano meglumine in Example 1 1 1H spectrum.

[0054] Figure 3 For the eutectic of tinapano meglumine in Example 1 13 13C spectrum.

[0055] Figure 4 IR spectrum of the eutectic of tinapano meglumine in Example 1.

[0056] Figure 5 DSC spectrum of the eutectic of tinapano meglumine in Example 1.

[0057] Figure 6 TG spectrum of the eutectic of tinapano meglumine in Example 1.

[0058] Figure 7 XRPD spectrum of the eutectic of tinapano meglumine in Example 1.

[0059] Figure 8 Solubility curves of the eutectic, physical mixture, and tinapano. Detailed implementation manners

[0060] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0061] The present invention will be further explained and described below in combination with specific implementation manners.

[0062] Example 1:

[0063] 1.0 g of tinapano and 0.17 g of meglumine were added to a 50 ml reaction flask, protected by nitrogen, heated to 155 - 160 °C for eutectic melting, and kept stirring for 30 min. After stirring, the temperature was slowly lowered to 25 - 30 °C for solidification, 10 ml of methanol was added, the temperature was raised to reflux until clear, and then slowly lowered to 0 - 5 °C, and kept

[0064] stirring for 6 h. After crystallization, filtration was carried out, the filter cake was washed with isopropyl ether, and dried at 50 - 60 °C for 4 hours to obtain 0.7 g of a pale yellow solid, with a yield of 59.82% and a melting point of 113 - 120 °C.

[0065] 1 1H-NMR(400MHz,DMSO / TMS,ppm):

[0066] Δδ 7.68 - 7.49 (11H, m, for the benzene ring and sulfonamide of tenapanor); δ 6.88 - 6.86 (2H, d, for the benzene ring of tenapanor); δ 5.91 - 5.76 (4H, m, -NH-CO-NH-); δ 4.41 - 4.38 (4H, m, -OH); δ 3.72 - 3.33 (31H, t, -CH2-, -CH-, sulfonamide, -NH-); δ 3.13 - 3.09 (4H, m, -OH, -CH3); δ 2.95 - 2.81 (11H, m, -CH-, -CH2-); δ 2.68 - 2.55 (4H, m, -CH2-); δ 2.37 (6H, s, -CH3);

[0067] δ 2.27 (2H, s, -CH2-); δ 1.31 (4H, s, -CH2-);

[0068] 13 C-NMR (400 MHz, DMSO / TMS, ppm):

[0069] 158.51, 145.97, 141.38, 141.23, 133.31, 132.75, 132.69, 131.70, 129.71, 128.42, 126.99, 125.25, 71.75, 71.44, 71.06, 71.00, 70.65, 70.06, 69.94, 69.54, 64.32, 59.21,

[0070] 55.46, 53.26, 45.76, 44.66, 42.83, 36.41, 28.07, 23.32;

[0071] XRD:

[0072] Test conditions: XRD: Conducted on a Shimadzu 6100 diffractometer using Cu-Kα X-rays with a wavelength of 1.54 nm, 40 KV, and 30 mA. Before testing, the instrument performance was checked using corundum. The test sample was placed on a non-reflective plate at room temperature. Test conditions: Scanning range 5 - 90°, 10° / min.)

[0073] Table 1 2θ angle

[0074]

[0075]

[0076] IR:

[0077] Table 2 IR

[0078]

[0079] Example 2:

[0080] 1.0 g of tinapano and 0.17 g of meglumine were added to the grinding process, and rapidly ground for 30 min. After grinding, 10 ml of methanol was added, heated to reflux until dissolved clearly, slowly cooled to 0 - 5 °C, and kept stirring for 6 h. After crystallization, filtered, the filter cake was washed with isopropyl ether, and dried at 50 - 60 °C for 4 hours to obtain 0.68 g of light yellow solid, with a yield of 58.12% and a melting point of 115 - 119 °C.

[0081] Example 3:

[0082] 1.0 g of tinapano and 0.17 g of meglumine were added to a 50 ml reaction flask, protected by nitrogen, heated to 155 - 160 °C for eutectic melting, and kept stirring for 30 min. After stirring, slowly cooled to 25 - 30 °C for solidification, 10 ml of ethyl acetate was added, heated to reflux, slowly cooled to 0 - 5 °C, and kept stirring for 3 h. After stirring ended, filtered, the filter cake was washed with isopropyl ether, and dried at 50 - 60 °C for 4 hours to obtain 0.92 g of light yellow solid, with a yield of 78.62% and a melting point of 113 - 119 °C.

[0083] Example 4:

[0084] 1.0 g of tinapano and 0.17 g of meglumine were added to a 50 ml reaction flask, protected by nitrogen, heated to 155 - 160 °C for eutectic melting, and kept stirring for 30 min. After stirring, slowly cooled to 25 - 30 °C for solidification, 10 ml of acetone was added, heated to reflux until dissolved clearly, slowly cooled to 0 - 5 °C, and kept stirring for 6 h, with no solid precipitation.

[0085] Example 5:

[0086] 1.0 g of tinapano and 0.17 g of meglumine were added to a 50 ml reaction flask, protected by nitrogen, heated to 155 - 160 °C for eutectic melting, and kept stirring for 30 min. After stirring, slowly cooled to 60 - 70 °C for solidification, 10 ml of methanol was added and stirred until dissolved clearly, slowly cooled to 0 - 5 °C, and kept stirring for 6 h. After crystallization, filtered, the filter cake was washed with isopropyl ether, and dried at 50 - 60 °C for 4 hours to obtain 0.76 g of light yellow solid, with a yield of 64.96% and a melting point of 113 - 116 °C.

[0087] Example 6:

[0088] 1.0 g of tenapanor and 0.17 g of N-methylglucamine were added to a 50 ml reaction flask. Under nitrogen protection, it was heated to 155 - 160 °C for melting. After keeping the temperature for stirring for 30 min, it was slowly cooled to 60 - 70 °C for solidification. 10 ml of ethyl acetate was added and refluxed with stirring for 30 min. After filtration, the filter cake was washed with isopropyl ether and dried at 50 - 60 °C for 4 hours to obtain 0.86 g of a pale yellow solid, with a yield of 73.50% and a melting point of 115 - 120 °C.

[0089] Example 7:

[0090] 10 g of tenapanor and 1.7 g of N-methylglucamine were added to a 250 ml reaction flask. Under nitrogen protection, it was heated to 155 - 160 °C for melting. After keeping the temperature for stirring for 30 min, it was slowly cooled to 25 - 30 °C for solidification. 100 ml of methanol was added, heated to reflux until clear, and then slowly cooled to 0 - 5 °C. After keeping the temperature for stirring for 6 h, crystallization was completed. After filtration, the filter cake was washed with isopropyl ether and dried at 50 - 60 °C for 4 hours to obtain 7.56 g of a pale yellow solid, with a yield of 64.61% and a melting point of 116 - 120 °C.

[0091] Example 8:

[0092] 100 g of tenapanor and 17 g of N-methylglucamine were added to a 2000 ml reaction flask. Under nitrogen protection, it was heated to 155 - 160 °C for melting. After keeping the temperature for stirring for 30 min, it was slowly cooled to 25 - 30 °C for solidification. 1000 ml of methanol was added, heated to reflux until clear, and then slowly cooled to 0 - 5 °C. After keeping the temperature for stirring for 6 h, crystallization was completed. After filtration, the filter cake was washed with isopropyl ether and dried at 50 - 60 °C for 4 hours to obtain 65.43 g of a pale yellow solid, with a yield of 55.92% and a melting point of 117 - 120 °C.

[0093] Example 9:

[0094] 1.0 g of tenapanor and 0.17 g of N-methylglucamine were added to a 50 ml reaction flask. Under nitrogen protection, it was heated to 155 - 160 °C for melting. After keeping the temperature for stirring for 30 min, it was slowly cooled to 25 - 30 °C for solidification. 10 ml of isopropyl alcohol was added, heated to reflux until clear, and then slowly cooled to 0 - 5 °C. After keeping the temperature for stirring for 6 h, crystallization was completed. After filtration, the filter cake was washed with isopropyl ether and dried at 50 - 60 °C for 4 hours to obtain 0.77 g of a pale yellow solid, with a yield of 65.81% and a melting point of 119 - 120 °C.

[0095] Example 10:

[0096] 1.0 g of tenapanor and 0.17 g of meglumine were added to a 50 ml reaction flask, protected by nitrogen, heated to 155 - 160 °C for melting, kept warm and stirred for 30 min. After stirring, the temperature was slowly lowered to 25 - 30 °C for solidification, 20 ml of methanol was added, heated to reflux until clear, slowly cooled to 0 - 5 °C, and kept warm and stirred for 6 h. After crystallization, filtration was carried out, the filter cake was washed with isopropyl ether, and dried at 50 - 60 °C for 4 hours to obtain 0.41 g of a pale yellow solid, with a yield of 35.04% and a melting point of 115 - 121 °C.

[0097] Example 11:

[0098] 1.0 g of tenapanor and 0.17 g of meglumine were added to a 50 ml reaction flask, protected by nitrogen, heated to 155 - 160 °C for melting, kept warm and stirred for 30 min. After stirring, the temperature was slowly lowered to 25 - 30 °C for solidification, 30 ml of methanol was added, heated to reflux until clear, slowly cooled to 0 - 5 °C, and kept warm and stirred for 6 h. After crystallization, filtration was carried out, the filter cake was washed with isopropyl ether, and dried at 50 - 60 °C for 4 hours to obtain 0.21 g of a pale yellow solid, with a yield of 17.94% and a melting point of 117 - 120 °C.

[0099] Example 12:

[0100] 1.0 g of tenapanor and 0.17 g of meglumine were added to a 50 ml reaction flask, protected by nitrogen, heated to 155 - 160 °C for melting, kept warm and stirred for 30 min. After stirring, the temperature was slowly lowered to 25 - 30 °C for solidification, 20 ml of isopropyl ether was added, heated to reflux, slowly cooled to 0 - 5 °C, and kept warm and stirred for 6 h. After stirring ended, filtration was carried out, the filter cake was washed with isopropyl ether, and dried at 50 - 60 °C for 4 hours to obtain 1.05 g of a pale yellow solid, with a yield of 89.74% and a melting point of 113 - 120 °C.

[0101] Comparative Example 1:

[0102] 0.13 g of L-lysine was used instead of meglumine, and the melting preparation method was the same as in Example 1 to obtain 0.79 g of a yellow solid, with a yield of 69.91% and a melting point of 78 - 121 °C. The product could not crystallize with solvents such as methanol, ethanol, isopropanol, and acetone.

[0103] Comparative Example 2:

[0104] 0.16 g of L-tyrosine was used instead of meglumine, and the melting preparation method was the same as in Example 1 to obtain 0.84 g of a yellow solid, with a yield of 72.41% and a melting point of 88 - 131 °C. The product could not crystallize with solvents such as methanol, ethanol, isopropanol, and acetone.

[0105] Comparative Example 3:

[0106] 0.15 g of phenylalanine was used to replace meglumine, and the co - melting preparation method was the same as that in Example 1. 0.69 g of yellow solid was obtained, with a yield of 60.0% and a melting point of 92 - 127 °C. The product could not be crystallized out with solvents such as methanol, ethanol, isopropanol, and acetone.

[0107] Example 13: Investigation of in vitro dynamic solubility

[0108] Substances to be measured: The ternapano meglumine cocrystal prepared according to the method of Example 1, a physical mixture of ternapano and meglumine (source: Macklin, batch number C16441044) (molar ratio 1:1) (hereinafter referred to as the mixture), and ternapano (self - prepared in the applicant's laboratory).

[0109] For most drugs, the solubility is generally determined at 48 - hour saturated solubility. However, since the dissolution behavior of cocrystal drugs conforms to the "bounce - parachute model", its specific dissolution mechanism is as follows: (1) The intermolecular force of the cocrystal is destroyed: The hydrogen bonds between the API and the cocrystal former in the drug cocrystal are destroyed in a short time (from a few minutes to one hour) in the biological medium. (2) Diffusion of API or ligand: With the dissociation of the cocrystal, the more water - soluble API or cocrystal former in the drug cocrystal diffuses from the lattice into the biological medium. (3) Re - establishment of the interaction between the cocrystal components and solvent molecules in the solution to form supersaturated clusters: The other component with lower water - solubility in the cocrystal also detaches from the lattice and becomes supersaturated in the biological medium, forming loosely aggregated clusters. This kind of nanomolecular cluster is similar to the amorphous drug phase, having partial order but lacking all fixed characteristics. This amorphous drug form generated by cocrystal dissociation can show the same peak in drug solubility as the amorphous drug dispersed in the polymer matrix. Therefore, the "spring" effect is achieved by dissociating the cocrystal into an amorphous drug form. Thus, strictly grasping the dissolution of cocrystal drugs at each time period is of great significance for better utilization of this drug.

[0110] Due to the "bounce - parachute" situation in dissolution, in order to understand the dissolution of the prepared cocrystal, dynamic solubility tests were carried out on both the cocrystal sample and the raw drug to master the whole process of dissolution. Equal amounts of the active ingredient of the ternapano meglumine cocrystal of the present invention, the physical mixture of ternapano + meglumine, and the raw drug ternapano were placed in a constant - temperature shaker at 37 °C and 100 rpm, and samples were taken at 5 min, 15 min, 30 min, 60 min, 120 min, and 240 min (n = 3) respectively for the dynamic solubility test. The results are shown in Table 3. After the measurement, a dynamic dissolution curve was plotted with the sampling time as the abscissa and the solubility as the ordinate ( Figure 8 ).

[0111] Table 3 Solubility results

[0112]

[0113] The experimental results show that the solubility of the invention of tenapanor meglumine cocrystal is higher than that of the raw material drug tenapanor within 30 minutes, and the highest reaches 20 times that of the raw material drug.

[0114] Example 14: Hygroscopicity investigation

[0115] Substances to be tested: Tenapanor meglumine cocrystal prepared according to the method of Example 1, a physical mixture (hereinafter referred to as the mixture) of tenapanor and meglumine (source: Macklin, batch number C16441044) (molar ratio 1:1), and amorphous powder of tenapanor hydrochloride (self-made in the R & D laboratory of the applicant) (hereinafter referred to as tenapanor hydrochloride).

[0116] 1 The test was carried out with reference to the guiding principle for the hygroscopicity test of drugs (General Principles 9103, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0117] Take this product and spread it flat in a stoppered glass weighing bottle that has been pre-saturated (outer diameter 50 mm, height 15 mm), weigh it precisely, place the weighing bottle with the mouth open in a suitable constant temperature and humidity dryer (25°C ± 1°C, relative humidity 80% ± 2%) for 24 hours, cover the lid of the weighing bottle, weigh it precisely, and calculate the weight gain due to hygroscopicity.

[0118] 2 The results of the hygroscopicity test are shown in the following table:

[0119] Table 4 Results of the hygroscopicity test

[0120] Sample Tenapanor N-methylglucamine cocrystal Mixture Tenapanor hydrochloride Weight of weighing bottle after saturation (g) 44.2473 43.3051 43.0732 Sample weight (g) 0.20067 0.29723 1.02300 Sample weight after 24 h (g) 44.4486 43.6422 44.2277 Moisture absorption weight gain (%) 0.31％ 13.41％ 11.28％

[0121] Referring to the hygroscopicity determination criteria in the guiding principle for the hygroscopicity test of drugs in General Principles 9103, Volume IV, Chinese Pharmacopoeia 2020 Edition, it can be known that tenapanor meglumine cocrystal is basically non-hygroscopic; both the physical mixture and tenapanor hydrochloride have strong hygroscopicity.

[0122] Example 15: Stability investigation

[0123] 1 As an important part of stability research, the stress testing is particularly important in the process of drug research and development. We investigated the inherent stability of the cocrystal of the present invention under high temperature, high humidity, and strong light irradiation (appearance, moisture, chiral purity, microstructure, solubility, content, related substances).

[0124] 2.1 High temperature stress testing

[0125] The sample (tenapanor N-methylglucamine cocrystal prepared by the method of Example 1) was placed at a temperature of 60 °C, and samples were taken on the 0th day, 1st day, 5th day, and 10th day to observe the properties and detect whether the solubility changed by injecting samples. The results are shown in the following table:

[0126] Table 5 Results of the investigation on the influence of high temperature on stability

[0127] Time Appearance Moisture content (%) Chiral purity Microstructure Solubility in 15 min Content Related substances Day 0 White crystals 0.03 99.9％ Needle-like crystals 786 μg / mL 99.8％ 0.21％ Day 1 White crystals 0.03 99.9％ Needle-like crystals 788 μg / mL 99.8％ 0.22％ Day 5 White crystals 0.02 99.9％ Needle-like crystals 790 μg / mL 99.7％ 0.24％ Day 10 White crystals 0.01 99.9％ Needle-like crystals 791 μg / mL 99.7％ 0.24％

[0128] The experimental results show that the tenapanor cocrystal of the present invention is not easily decomposed at high temperature. The appearance color was not changed by naked-eye observation, and no new impurities were detected by high performance liquid chromatography. There were no obvious changes in moisture, chiral purity, microstructure, and solubility at 15 min, indicating that this product is relatively stable at high temperature.

[0129] 2.2 Experimental on the influencing factors of high humidity

[0130] The sample (tenapanor N-methylglucamine cocrystal prepared by the method of Example 1) was placed at 75% and 90% humidity, and samples were taken on the 0th day, 1st day, 5th day, and 10th day to observe the properties and detect whether the solubility changed by injecting samples. The results are shown in the following table:

[0131] Table 6 Results of the investigation on the influence of high humidity on stability

[0132] Time Appearance Moisture content (%) Chiral purity Microstructure Solubility in 15 min Content Related substances Day 0 White crystals 0.03 99.9％ Needle-like crystals 786 μg / mL 99.8％ 0.21％ Day 1 White crystals 0.04 99.9％ Needle-like crystals 794 μg / mL 99.8％ 0.22％ Day 5 White crystals 0.05 99.9％ Needle-like crystals 796 μg / mL 99.7％ 0.24％ Day 10 White crystals 0.06 99.9％ Needle-like crystals 801 μg / mL 99.7％ 0.24％

[0133] The experimental results show that the tenapanor cocrystal of the present invention is not easily decomposed at high humidity. The appearance color was not changed by naked-eye observation, and no new impurities were detected by high performance liquid chromatography. There were no obvious changes in moisture, chiral purity, microstructure, and solubility at 15 min, indicating that this product is relatively stable at high humidity.

[0134] 2.3 Experimental on the influencing factors of strong light

[0135] The sample (tenapanor N-methylglucamine cocrystal prepared by the method of Example 1) was placed under strong light of 4500 Lx ± 500 Lx, and samples were taken on the 0th day, 1st day, 5th day, and 10th day to observe the properties and detect whether the solubility changed by injecting samples. The results are shown in the following table:

[0136] Table 7 Results of the investigation on the influence of strong light on stability

[0137]

[0138]

[0139] The experimental results show that the tenapanor eutectic of the present invention is not easily decomposed under strong light, the appearance color has not changed as observed with the naked eye, and no new impurities are detected by high performance liquid chromatography. There are no obvious changes in moisture, chiral purity, microstructure, and solubility at 15 min, indicating that this product is relatively stable under strong light.

[0140] Example 16: Permeability study

[0141] The permeability study was carried out using an artificial bionic membrane permeation plate with a completely phospholipid-based lamellar structure. In the study of this example, the experiment was carried out for 8 h, and the drug permeation rate across the entire membrane was measured every hour. According to the formula:

[0142]

[0143] In the above formula, J (Flux) is the permeation rate, that is, the amount of drug passing through a unit membrane area per unit time (μg·h -1 ·cm -2 ), dc / dt is the change rate of the drug concentration in the receptor chamber per unit time (μg·mL -1 h -1 ); V is the volume of the buffer solution in the receptor chamber (mL); A is the area of the artificial membrane (cm 2 ). The permeation rate per hour of tenapanor and the tenapanor N-methylglucamine eutectic was obtained, and the total permeation amount was obtained by cumulatively summing the permeation rate per hour. The permeation rate per hour of tenapanor and the tenapanor N-methylglucamine eutectic through the artificial bionic permeation membrane is shown in Tables 8 and 9. The total permeation amount of tenapanor and the tenapanor N-methylglucamine eutectic through the artificial bionic permeation membrane after 8 h is shown in Table 10. These data indicate that, compared with tenapanor, the tenapanor N-methylglucamine eutectic enhances the penetration ability of tenapanor through the artificial membrane.

[0144] Table 8 Tenapanor permeation rate

[0145] Time (h) 1 2 3 4 5 6 7 8 <![CDATA[Tinapano-1 (μg / h·cm 2 )]]> 44.32 50.55 47.65 51.02 53.02 48.39 49.22 50.32 <![CDATA[Tinapano-2 (μg / h·cm 2 )]]> 38.33 40.96 42.57 40.36 44.56 46.32 46.23 44.69 <![CDATA[Tinapano-3 (μg / h·cm 2 )]]> 44.66 38.35 39.34 45.54 46.39 38.94 40.61 40.02 <![CDATA[Average value (μg / h·cm 2 )]]> 42.44 43.29 43.19 45.64 47.99 44.55 45.35 45.01 STDEV (%) 3.56 6.42 4.19 5.33 4.45 4.97 4.37 5.16

[0146] Table 9 Tenapanor N-methylglucamine eutectic permeation rate

[0147]

[0148]

[0149] Table 10 Cumulative permeation amount of tenapanor and the tenapanor N-methylglucamine eutectic of the present invention

[0150] Time (h) <![CDATA[Tinapano (μg / cm 2 )]]> <![CDATA[Inventive tenapanor N-methylglucamine cocrystal (μg / cm 2 )]]> 1 42.44 185.86 2 85.73 287.24 3 128.92 394.99 4 174.56 502.74 5 222.55 610.22 6 267.10 720.56 7 312.45 821.72 8 357.46 919.87

[0151] Example 17: Pharmacokinetic study in rats

[0152] 1 Test objective: To investigate the plasma concentration level and pharmacokinetic characteristics of tenapanor after a single oral administration of the amorphous powder of the original research medicinal crystal form of tenapanor and the tenapanor glucosamine methanesulfonate cocrystal of the present invention in rats at the same dosing dose.

[0153] 2 In vivo high performance liquid chromatography analysis method

[0154] Chromatographic column: End-capped octadecylsilyl silica gel column (250×4.6 mm; 5 μm)

[0155] Column temperature: 35 °C

[0156] Mobile phase: Mobile phase A: 0.01 mol / L diammonium hydrogen phosphate (adjusted to pH 7.5 with phosphoric acid); Mobile phase B: acetonitrile

[0157] Table 11 Mobile phase

[0158] Time (min) Mobile phase A (%) Mobile phase B (%) 0→5 80 20 5→20 80→20 20→80 20→25 20 80 25→30 20→80 80→20 30→35 80 20

[0159] Flow rate: 1.0 ml / min

[0160] Detection wavelength: 210 nm

[0161] Injection volume: 2 μl

[0162] Solvent: Methanol - acetonitrile (1:1)

[0163] 3 Materials and methods

[0164] 1) Test drugs: Amorphous powder of tenapanor hydrochloride (hereinafter referred to as "original research medicinal crystal form"), provided by the self-synthesized laboratory of Anhui Yipuke Medical Technology Development Co., Ltd., white solid, purity: 98.26%; The tenapanor glucosamine methanesulfonate cocrystal of the present invention was obtained by laboratory preparation using optimized process parameters, off-white solid, purity: 99.93%;

[0165] 2) Test animals: 12 SD rats, 6 males and 6 females, body weight 220 - 240 g;

[0166] 3) Sampling method: After the test drug was formulated into a uniform suspension of 1.25 mg / kg with corn oil, it was immediately orally administered to rats at a volume of 4 ml / kg, and 0.1 ml of jugular vein blood was collected before and 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 24 h after administration, placed in an EDTA-K2 tube, centrifuged at 3000 r / min for 10 min to separate plasma, and stored frozen at -80 °C in a refrigerator;

[0167] 4) LC / MS / MS Bioanalysis of Biological Samples: Mix 50 μl of plasma with 5 μl of working solution or blank diluent, add 150 μl of acetonitrile precipitant containing internal standard, vortex for 2 min, centrifuge at 12000 r / min for 10 min, take 2 μl of the supernatant and mix it with 200 μl of pure water: acetonitrile (1:1), and then inject 3 μl for analysis.

[0168] 4 Experimental Results

[0169] After single oral administration to male and female rats, the average (ng·mL -1 ) of tenapanor in plasma at different times was measured. The sampling and detection results are shown in Tables 12 and 13. Then, the average drug concentration-time curves in plasma after single oral administration to male and female rats were plotted. The main pharmacokinetic parameters were obtained by fitting and analyzing the data using the non-compartmental model and statistical moment analysis method, as shown in Tables 14 - 15.

[0170] Table 12 Sampling Results of Average Plasma Drug Concentration after Single Oral Administration to Female Rats

[0171] Sampling time / h Original research drug crystal form (ng / ml) This invention (ng / ml) 0 0 0 0.25 512.5±352.3 4012.2±653.3 0.5 1294.6±778.1 4055.3±882.5 1 1669.2±1115.5 4125.3±1024.2 1.5 1805.2±784.2 4598.2±1001.1 2 1514.2±885.3 3864.3±569.8 4 1554.6±653.3 2223.1±555.6 6 1987.3±698.2 2024.3±784.2 8 1901.2±785.3 1699.4±662.3 24 302.5±222.1 205.6±51.2

[0172] Table 13 Sampling Results of Average Plasma Drug Concentration after Single Oral Administration to Male Rats

[0173] Sampling time / h Original research drug crystal form (ng / ml) This invention (ng / ml) 0 0 0 0.25 1541.3±258.6 5021.8±986.7 0.5 2321.1±365.2 5101.5±925.3 1 3025.5±1899.5 8132.4±2536.1 1.5 2864.5±1995.3 5024.1±1584.6 2 3456.8±2321.2 3854.6±2125.3 4 2864.8±1125.5 1854.6±824.5 6 1021.5±663.2 1354.9±654.2 8 685.4±425.3 826.4±352.8 24 75.2±16.2 82.6±31.6

[0174] Table 14 Main Pharmacokinetic Parameters after Single Oral Administration to Female Rats

[0175] Parameter Unit Original research drug crystal form This invention AUC(0-t) h*mg / L 24241±1125 44543±2125 AUC(0-∞) h*mg / L 26954±1312 49512±1862 MRT(0-t) h 4.24±0.26 2.42±0.15 MRT(0-∞) h 36.21±0.12 40.22±0.21 Cmax mg / L 3541±563 8369±663 Tmax h 6.31±0.10 4.11±0.10 t1 / 2 h 5.22±0.15 1.15±0.05 Vz / F L / kg 3542±542 8542±642 CLz / F L / h / kg 0.65±0.05 0.31±0.06

[0176] Table 15 Main Pharmacokinetic Parameters after Single Oral Administration to Male Rats

[0177] Parameter Unit Original research drug crystal form This invention AUC(0-t) h*mg / L 32241±2254 54655±3021 AUC(0-∞) h*mg / L 35922±1562 60757±2053 MRT(0-t) h 7.68±0.15 1.86±0.05 MRT(0-∞) h 36.95±0.05 41.38±0.32 Cmax mg / L 5021±841 9135±768 Tmax h 5.31±0.05 5.11±0.00 t1 / 2 h 1.22±0.03 1.15±0.04 Vz / F L / kg 3848±642 10242±822 CLz / F L / h / kg 0.57±0.04 0.38±0.03

[0178] The results of pharmacokinetic studies show that the bioavailability of the product obtained in the present invention is significantly improved compared with the amorphous powder of the original drug, having a certain bioavailability advantage.

Claims

1. A tenapanor co-crystal, characterized in that: The eutectic is the tenapanor N-methylglucamine eutectic structure represented by formula (I):

2. The tenapanor eutectic according to claim 1, wherein The tenapanor N-methylglucamine eutectic is tenapanor and N-methylglucamine with a molar ratio of 1:

1.

3. The tenapanor eutectic according to claim 1, wherein The X-ray powder diffraction pattern of the tenapanor N-methylglucamine eutectic has characteristic peaks at diffraction angles 2θ: 8.9±0.2, 12.2±0.2, 12.4±0.2, 17.2±0.2, 17.3±0.2, 19.2±0.2, 19.8±0.2, 20.6±0.2, 21.5±0.2, 26.2±0.2, 29.2±0.2, 32.6±0.2, 34.5±0.2°.

4. The tinapano meglumine cocrystal according to any one of claims 1 to 3, characterized in that, The endothermic temperature of the tenapanor N-methylglucamine eutectic by differential scanning calorimetry is 113-120 °C.

5. A pharmaceutical composition, characterized in that, Containing the co-crystal according to claim 1 and a pharmaceutically acceptable carrier.

6. Use of the tenapanor co-crystal according to claim 1 or the pharmaceutical composition according to claim 5 in the preparation of a drug for preventing / treating reduction of serum phosphate level, hyperphosphatemia, chronic renal insufficiency, constipation and irritable bowel syndrome in dialysis patients.

7. The use according to claim 6, wherein the irritable bowel syndrome is adult constipation-predominant irritable bowel syndrome.

8. The preparation method of the tenapanor eutectic according to claim 1, characterized in that, Tenapanor and N-methylglucamine are heated to a eutectic state under the protection of an inert gas, stirred for a period of time while maintaining the temperature, slowly cooled to solidify, then the first organic solvent is added and heated to reflux until clear, slowly cooled to 0-5 °C, stirred for a period of time until crystallization is complete, then filtered, the filter cake is washed with the second organic solvent and dried to obtain the target product.

9. The preparation method according to claim 8, characterized in that, The first organic solvent is selected from methanol, ethanol, isopropyl ether, isopropyl alcohol, ethyl acetate or a mixture thereof.

10. The preparation method according to claim 8, characterized in that, The second organic solvent is selected from isopropyl ether.

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