Crystals of an m receptor antagonist, methods of making and uses thereof

Abstract

The main objective of this invention is to provide a novel crystal of a quaternary ammonium salt compound, (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclic [2,2,2]octane salt (hereinafter referred to as Compound I). The type A crystal of Compound I exhibits diffraction peaks at the following diffraction angles 2θ in its powder X-ray diffraction pattern: 5.7±0.2 degrees, 12.9±0.2 degrees, 16.7±0.2 degrees, 18.0±0.2 degrees, 19.5±0.2 degrees, 21.1±0.2 degrees, 22.3±0.2 degrees, and 23.3±0.2 degrees. The type B crystal of compound I exhibits diffraction peaks at the following diffraction angles 2θ: 5.2±0.2 degrees, 15.8±0.2 degrees, 16.9±0.2 degrees, 17.7±0.2 degrees, 19.5±0.2 degrees, 20.2±0.2 degrees, and 22.1±0.2 degrees, in its powder X-ray diffraction pattern. This invention also relates to a novel preparation method for compound I and the applications of the two novel crystals described above in the pharmaceutical field.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a novel crystal of a quaternary ammonium salt compound, (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane salt (hereinafter referred to as compound I), and its preparation method; this invention also relates to the application of the novel crystal of compound I in the pharmaceutical field. Background Technology

[0002] Asthma and chronic obstructive pulmonary disease (COPD) are the most common epidemics. Bronchodilators are the first-line drugs for the treatment of asthma and COPD. Commonly used bronchodilators include M receptor antagonists, such as ipratropium bromide and tiotropium bromide.

[0003] WO2015007073 discloses a class of long-acting compounds with selective antagonistic activity against M receptor subtypes. Compared with existing technologies, these compounds exhibit selective activity against M receptor subtypes in the treatment of asthma, COPD, allergic rhinitis, post-cold rhinitis, and gastric and duodenal ulcers, resulting in lower toxicity and side effects, as well as rapid onset and long-lasting effects. (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane salt (compound I) is a preferred compound, with the following structural formula:

[0004]

[0005] Specifically, compound I can be used to treat rhinitis, post-cold rhinitis, chronic bronchitis, high airway pressure, asthma, COPD, cough, urinary incontinence, urinary frequency, unstable bladder syndrome, bladder spasm, cystitis, and gastrointestinal diseases such as stress-induced colitis, spastic colitis, and duodenal and gastric ulcers. In particular, compared with existing technologies, it has the advantages of long-lasting efficacy, rapid onset of action, and low toxicity.

[0006] Compound I can also be used in combination with β2 receptor agonists, steroid hormones, anti-allergy drugs, anti-inflammatory drugs, anti-infective drugs, phospholipase 4 inhibitors, etc., to treat the above-mentioned respiratory diseases such as allergic rhinitis, post-cold rhinitis, asthma, and COPD.

[0007] As mentioned above, compound I is known to be used as a treatment for various diseases, but there is no record or information regarding the presence or absence of its crystals.

[0008] The inventors discovered that, regarding the synthetic process of compound I, WO2015007073, 1-phenyl-1-cyclopentylethylene oxide (intermediate) is prepared by reacting cyclopentylbenzophenone with dimethyl sulfate in the presence of sodium hydride (NaH); in the presence of NaH, the intermediate reacts with (R)-3-quinine alcohol to generate the diastereomer (2S,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2] Octane free base and (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2]octane free base; (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2]octane free base were obtained by column chromatography, and then reacted with 3-bromopropoxybenzene and the solvent was removed under vacuum to give a yellow oily substance. The addition of diethyl ether precipitated the substance to give an off-white solid (compound I). Although the above process has a shorter synthetic route, it has many drawbacks: (1) When preparing the intermediate 1-phenyl-1-cyclopentyl ethylene oxide, highly toxic or even genotoxic reagents such as dimethyl sulfate and dimethyl sulfide are required, and explosions are likely to occur when a large amount of NaH is used in this reaction; (2) When preparing the free base of (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2]octane, column chromatography separation is required, which makes the utilization rate of the expensive raw material (R)-3-quinine alcohol only 50%, increasing production costs and limiting the production scale; (3) The last step uses diethyl ether to obtain solid raw material. Since diethyl ether is a high-risk solvent, it is not suitable for modern industrial production.

[0009] Through extensive and creative research, the inventors successfully solved the crystal form problem of compound I and also researched and determined a new production process for compound I. Summary of the Invention

[0010] Purpose of the invention

[0011] One of the objectives of this invention is to provide a novel method for preparing compound I.

[0012] Another object of the present invention is to provide a novel crystal of compound I, a method for preparing the novel crystal, and a pharmaceutical composition containing the crystal as an active ingredient, specifically as described in (1) to (4).

[0013] (1) A new method for preparing compound I.

[0014] (2) A type A crystal of compound I (hereinafter referred to as type A crystal of the present invention or crystal A), wherein the powder X-ray diffraction pattern shows diffraction peaks at at least the following diffraction angles 2θ: 5.7±0.2 degrees, 12.9±0.2 degrees, 16.7±0.2 degrees, 18.0±0.2 degrees, 19.5±0.2 degrees, 21.1±0.2 degrees, 22.3±0.2 degrees and 23.3±0.2 degrees, and the powder X-ray diffraction pattern is a pattern obtained by Cu Kα rays.

[0015] (3) A type B crystal of compound I (hereinafter referred to as type B crystal of the present invention or crystal B), wherein the type B crystal is a hydrate of compound I and 1.5 molecules of H2O, and its powder X-ray diffraction pattern shows diffraction peaks at at least the following diffraction angles 2θ: 5.2±0.2 degrees, 15.8±0.2 degrees, 16.9±0.2 degrees, 17.7±0.2 degrees, 19.5±0.2 degrees, 20.2±0.2 degrees and 22.1±0.2 degrees, wherein the powder X-ray diffraction pattern is a pattern obtained by Cu Kα rays.

[0016]

[0017] (4) A pharmaceutical composition containing any one of (2) to (3) as an active ingredient (hereinafter referred to as the pharmaceutical composition of the present invention).

[0018] When determining the diffraction angle 2θ of the diffraction peak in the embodiments and claims of the present invention, the obtained value should be understood to be within ±0.2 degrees, preferably within ±0.1 degrees.

[0019] Problem-solving methods

[0020] People hope that pharmaceutical raw materials are high-purity, stable products with therapeutic effects, and that they are environmentally friendly, safe, and inexpensive in industrial production. Therefore, the inventors conducted repeated and careful research and invented a new synthesis method for compound I and two new crystals of compound I, named crystal A and crystal B, respectively. Through experiments, it was unexpectedly discovered that: (1) compared with compound I, the residual solvent in crystals A and B is greatly reduced or even completely removed; (2) the crystallization process of crystals A and B can remove most of the impurities of compound I; (3) crystal A has strong hygroscopicity under various humidity conditions, while crystal B has very weak hygroscopicity even under high humidity conditions, making it more stable than crystal A and more conducive to industrial operation and storage.

[0021] The best way to realize an invention

[0022] 1. Preparation of compound I:

[0023] Step 1: Using cyclopentylmandelic acid or cyclopentylmandelic ester as the starting material, reduce it with sodium borohydride to obtain racemic 2-hydroxy-2-cyclopentyl-2-phenylethanol (Z02); the reaction solvent is selected from ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, etc., preferably ethylene glycol dimethyl ether, tetrahydrofuran, etc.; the molar ratio of sodium borohydride to the starting material is 2-5:1, preferably 2-3.5:1; a Lewis acid is added for catalysis when reducing cyclopentylmandelic acid (ester), the Lewis acid is selected from aluminum trichloride, boron trifluoride, zinc chloride, tin tetrachloride, titanium tetrachloride, etc., the molar ratio of Lewis acid to cyclopentylmandelic acid is 2-5:1, preferably 2.5-3:1.

[0024] Step 2: After esterification of Z02 with chiral acyl chloride, crystallization yields chiral carboxylic acid 2-hydroxy-2-cyclopentyl-2-phenylethanol ester (Z03). The chiral acyl chloride includes, but is not limited to, L-camphorsulfonyl chloride, D-camphorsulfonyl chloride, and mandelic acid derivative acyl chlorides. The molar ratio of Z02 to the chiral acyl chloride is 1:1 to 3, preferably 1:1.5 to 2. The reaction solvent is selected from dichloromethane, trichloromethane, tetrahydrofuran, dioxane, etc., preferably dichloromethane and tetrahydrofuran. The base is selected from organic bases such as triethylamine, pyridine, and N-methylmorpholine. The molar ratio of the base to the chiral acyl chloride is 1 to 4:1, preferably 1 to 2:1.

[0025] Step 3: Z03 is treated with an alkali to obtain R-1-phenyl-1-cyclopentylethylene oxide (Z04). The alkali includes, but is not limited to, NaH, potassium tert-butoxide, butyllithium, sodium amide, etc., with NaH and potassium tert-butoxide being preferred. The molar ratio of alkali to Z03 is 1 to 3:1, preferably 1 to 1.5:1; the reaction solvent is selected from dichloromethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, etc., with dimethyl sulfoxide and tetrahydrofuran being preferred.

[0026] Step 4: Z04 reacts with R-(-)3-quinol to obtain (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2]octane free base (Z05). The base includes, but is not limited to, NaH, potassium tert-butoxide, butyllithium, sodium amino groups, etc., with NaH and potassium tert-butoxide being preferred. The molar ratio of R-(-)3-quinol to the base is 1–3:1, preferably 1–1.5:1; the reaction solvent is selected from dichloromethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, etc., with dimethyl sulfoxide and tetrahydrofuran being preferred.

[0027] Step 5: After Z05 undergoes a quaternization reaction with 3-phenoxy-1-bromopropane (Z06), (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octium salt (compound I) is obtained.

[0028]

[0029] In the preparation of compound I, the compounds used as raw materials can be commercially available or prepared according to publicly available methods.

[0030] 2. Preparation of Type A and Type B crystals of the present invention (hereinafter collectively referred to as the crystals of the present invention)

[0031] (1) Preparation of type A crystal of the present invention:

[0032] Step 1: Dissolution Process

[0033] This process involves heating to dissolve compound I in a solvent. Suitable solvents for this process include, for example, alcohols, acetonitrile, dichloromethane, and chloroform. Suitable alcohols for this process are C1-C5 small molecule alcohols, preferably, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or 3-methyl-1-butanol, with ethanol being the most preferred.

[0034] As a good solvent capable of dissolving compound I in this process, the amount used is preferably in the range of 1 to 10 times (mL / g) relative to compound I, more preferably in the range of 1 to 5 times (mL / g), and even more preferably in the range of 2 to 3 times (mL / g). The dissolution temperature varies depending on the type and amount of solvent used, and is generally carried out with stirring below the boiling point of the solvent or by reflux at the boiling point of the solvent, preferably in the range of 20°C to 100°C, and more preferably in the range of 60°C to 90°C.

[0035] In this process, the solution of compound I can be subjected to activated carbon adsorption and filtration as needed to remove insoluble matter. To prevent crystal precipitation during filtration, filtration is preferably carried out under pressure using a funnel equipped with a heating device. The filtered solution is maintained at a certain temperature, preferably in the range of 20°C to 100°C, and more preferably in the range of 60°C to 90°C.

[0036] Step 2: Adding antisolvent for crystallization process

[0037] Based on solubility tests, the antisolvents for compound I include saturated hydrocarbons, such as straight-chain or branched C6-C8 alkanes or C5-C8 cycloalkanes, specifically but not limited to cyclopentane, pentane, heptane, octane, cyclohexane, cycloheptane, and cyclooctane. The antisolvents for compound I include ketones, such as straight-chain or branched C3-C8 ketones, specifically but not limited to acetone, 2-butanone, and methyl isobutyl ketone. The antisolvents for compound I include esters, specifically but not limited to ethyl formate, ethyl acetate, isopropyl acetate, and butyl acetate. The antisolvents for compound I include ethers, specifically but not limited to isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and methyl tetrahydrofuran. Other antisolvents for compound I include, specifically but not limited to, toluene. Preferred antisolvents for this process include ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate, acetone, and butanone, with ethyl acetate being the most preferred.

[0038] Under stirring conditions, the selected antisolvent is slowly added to the solution filtered in step 1. The antisolvent is preferably in the range of 1 to 20 times (mL / mL) of the compound I solution, more preferably in the range of 5 to 15 times (mL / mL), and even more preferably in the range of 8 to 10 times (mL / mL).

[0039] During the preparation of type A crystals, all steps must strictly prevent contact with moisture. The solvent used must be anhydrous, and the containers must be dry.

[0040] Step 3: Cooling and crystallization process

[0041] This process involves cooling the solution prepared in step 2 above to precipitate type A crystals of the present invention. Preferably, a crystallization device with heating and stirring functions is used in this process.

[0042] The cooling temperature (the temperature at which the precipitated crystals are collected) is preferably in the range of -10°C to 50°C, more preferably in the range of -5°C to 20°C, and even more preferably in the range of 0°C to 10°C. In this process, it is preferable to cool slowly over a period of 0.5 h to 10 h until this cooling temperature is reached. Alternatively, the solution prepared in step 1 above can be partially evaporated under heating and stirring to promote the precipitation of crystal A.

[0043] Furthermore, seed crystals of type A crystals of the present invention can be added to this process; when adding seed crystals of type A crystals of the present invention, it is preferable to add them when the solution is cooled to a temperature range of 40°C to 80°C. There is no particular limitation on the amount of seed crystals of type A crystals of the present invention added, but it is preferably in the range of 1% (g / g) to 5% (g / g) relative to compound I.

[0044] Step 4: Crystal collection and drying process

[0045] This process involves collecting the precipitated crystals obtained in step 3 above and drying them using methods such as filtration and centrifugation.

[0046] The drying process can be carried out by conventional methods such as vacuum drying or drying with a desiccant, preferably under reduced pressure, and more preferably under conditions of 20℃~70℃ and below 10mmHg for 1h~48h to obtain type A crystals.

[0047] (2) Preparation of type B crystal of the present invention:

[0048] Method 1: Dissolution process involves adding a certain amount of purified water to a good solvent.

[0049] Step 1: Dissolution Process

[0050] This process involves heating to dissolve compound I in a solvent. Suitable solvents for this process include, but are not limited to, small molecule alcohols (C1-C5) or acetonitrile, preferably methanol, ethanol, n-propanol, or isopropanol, with ethanol being the most preferred. These solvents are mixed with a certain amount of water to serve as the solvent for compound I. The ratio of water to the solvent is preferably 2% (ml / ml) to 10% (ml / ml), and most preferably 4% (ml / ml) to 6% (ml / ml).

[0051] The amount of the mixed solvent used to dissolve compound I in this process is preferably in the range of 1 to 10 times (mL / g) relative to compound I, more preferably in the range of 2 to 5 times (mL / g). The dissolution temperature varies depending on the type and amount of solvent used, and is generally below the boiling point of the solvent by stirring or reflux at the boiling point, preferably in the range of 20°C to 100°C, more preferably in the range of 60°C to 90°C.

[0052] In this process, the solution of compound I can be subjected to activated carbon adsorption and filtration as needed to remove insoluble matter. To prevent crystal precipitation during filtration, filtration is preferably carried out under pressure using a funnel equipped with a heating device. The filtered solution is maintained at a certain temperature, preferably in the range of 20°C to 100°C, and more preferably in the range of 60°C to 90°C.

[0053] Step 2: Adding antisolvent for crystallization process

[0054] Preferred antisolvents for this process include esters, water, ethers, ketones, liquid cycloalkanes or aromatics, with ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate, 2-butanone, methyl isobutyl ketone, water, isopropyl ether, and methyl tert-butyl ether being the most preferred.

[0055] When water is used as the antisolvent, the good solvent in step 1 can be used without adding water. In addition to alcohol and acetonitrile in step 1, the good solvent can also be dichloromethane or trichloromethane, which are immiscible with water.

[0056] Under stirring conditions, the selected antisolvent is slowly added to the solution filtered in step 1. The antisolvent is preferably in the range of 3 to 20 times (mL / mL) of the compound I solution, more preferably in the range of 5 to 15 times (mL / mL), and even more preferably in the range of 8 to 10 times (mL / mL).

[0057] Step 3: Cooling and crystallization process

[0058] This process involves cooling the solution prepared in step 2 above to precipitate the type B crystals of the present invention. Preferably, a crystallization apparatus equipped with heating and stirring functions is used for this process.

[0059] The cooling temperature (the temperature at which the precipitated crystals are collected) is preferably in the range of -10°C to 50°C, more preferably in the range of -5°C to 20°C, and even more preferably in the range of 0°C to 10°C. In this process, it is preferable to cool slowly over a period of 0.5 h to 10 h until the cooling temperature is reached.

[0060] Furthermore, seed crystals of type B of the present invention can be added to this process; when adding seed crystals of type B of the present invention, it is preferable to add them when the solution is cooled to a temperature range of 40°C to 80°C. There is no particular limitation on the amount of seed crystals of type B of the present invention added, but it is preferably in the range of 1% (g / g) to 5% (g / g) relative to compound I.

[0061] Step 4: Crystal collection and drying process

[0062] This process involves collecting the precipitated crystals obtained in step 3 above and drying them using methods such as filtration and centrifugation.

[0063] The drying process can be carried out by conventional methods such as vacuum drying or drying with desiccant, preferably under reduced pressure, and more preferably under good ventilation conditions of 20℃~70℃ for 1h~48h to obtain type B crystals.

[0064] Method 2: The B-type crystal of this invention can also be obtained by the method of transforming the A-type crystal.

[0065] The type A crystals of this invention are added to a reaction vessel, along with purified water. The weight ratio of water to type A crystals is 3 to 30 times (g / g), preferably 5 to 20 times (g / g), and most preferably 8 to 12 times (g / g). The mixture is stirred and slurried, with the temperature preferably controlled at 10℃ to 50℃, and most preferably 20℃ to 30℃. The slurrying time is preferably 0.3 h to 10 h, and most preferably 0.5 h to 5 h. The mixture is then filtered, and the solid is dried in a forced-air dryer at 40℃ to 80℃ until constant weight is achieved, yielding type B crystals. The drying time is 2 to 24 h.

[0066] 3. Pharmaceutical uses; pharmaceutical composition of the present invention

[0067] Any pharmaceutical composition containing crystal A or crystal B of compound I is within the scope of this invention. Compound I of this invention has excellent M receptor antagonistic activity, selective action on M receptor subtypes, strong action on M3 receptors and weak action on M2 receptors, thus exhibiting glandular secretion inhibition, tracheal dilation, and bronchodilatory effects. Therefore, the crystals and pharmaceutical compositions of this invention can be used to treat various diseases such as allergic rhinitis, post-cold rhinitis, asthma, COPD, and gastric and duodenal ulcers (see patent document WO2015007073). Therefore, another object of this invention is to provide pharmaceutical compositions containing crystal A and crystal B (hydrates of compound I), including acceptable pharmaceutical carriers. The aforementioned pharmaceutical compositions of crystal A and crystal B may optionally contain other therapeutic ingredients, such as, but not limited to, steroidal anti-inflammatory drugs, phosphodiesterase 4 inhibitors (PDE-4), β2 receptor agonists, histamine receptor antagonists, etc.

[0068] When administering the crystals of the present invention as a medicine, the crystals of the present invention may be administered directly, or administered in a pharmaceutically permissible non-toxic inert carrier in a range of, for example, 0.001% to 99.9%.

[0069] The carrier for the above composition may be a solid, semi-solid, or liquid diluent, filler, or other formulation adjuvant. One or more of these carriers may be used.

[0070] The pharmaceutical compositions of this invention can be in solid, semi-solid, or liquid dosage forms: for example, powder inhalers (DPIs), inhalation solutions, metered-dose inhalers (or soft inhalers: SMIs), and metered-dose inhalers (MDIs) for treating asthma and COPD; nasal drops and nasal sprays for treating post-cold rhinitis, seasonal allergic rhinitis, and perennial allergic rhinitis; oral preparations such as capsules, tablets, granules, powders, suspensions, solutions, syrups, and elixirs for treating gastric and duodenal ulcers; and injectable formulations for intraoperative muscle relaxation or excessive tracheal secretion. Of particular importance are the preparations for treating asthma, COPD, post-cold rhinitis, allergic rhinitis, and gastric and duodenal ulcers.

[0071] When preparing solid dosage forms, the crystals of this invention can be made to meet the appropriate particle size requirements using pulverizing equipment.

[0072] The powder form allows the crystals of this invention to be ground to an appropriate degree, and then mixed with a similarly ground pharmaceutical carrier such as starch or mannitol, and granulated. Flavoring agents, preservatives, dispersants, coloring agents, and fragrances can be added as desired.

[0073] Tablets can be prepared by adding excipients to the powdered crystals of the present invention to form a powder mixture, granulating or pulverizing, or pressing into large tablets and then pulverizing, and then adding disintegrants or lubricants before tableting.

[0074] The powder mixture can be prepared by mixing appropriately pulverized crystals of the present invention with a diluent or matrix. Binders (e.g., sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), dissolution delay agents (e.g., paraffin wax), adsorbents (e.g., bentonite, kaolin), etc., can be added as needed.

[0075] The powder mixture can be prepared as follows: First, it is moistened with a binder such as syrup, starch paste, gum arabic, cellulose solution, or polymer solution, stirred and mixed, then dried and pulverized to form granules. Adding stearic acid, stearate, talc, mineral oil, etc., as lubricants to the granules prepared in this way can prevent them from adhering to each other.

[0076] In addition, tablets can be manufactured without the above-mentioned granulation or pulverization process, by directly compressing the crystals of the present invention with a free-flowing inert carrier.

[0077] For the tablets produced, film coating or sugar coating can be applied.

[0078] Capsules can be prepared by filling the outer shell of capsules such as gelatin capsules with crystals or pulverized crystal powder as described above, in the form of powders or granulated materials as described in the tablet section. Alternatively, the micronized powder of the crystals of this invention can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and surfactant, and then encapsulated in gelatin sheets to form soft capsules.

[0079] For example, other oral preparations such as liquid formulations, syrups, lozenges, and elixirs can also be formulated in a way that contains a certain amount of the crystals of this invention.

[0080] Syrups can be manufactured by dissolving the crystals of the present invention in a suitable flavored aqueous solution. Efficacy can be manufactured using a non-toxic alcoholic carrier.

[0081] The suspension can be manufactured by dispersing the crystals of the present invention in a non-toxic carrier. Depending on the requirements, solubilizers or emulsifiers (e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (e.g., peppermint oil, saccharin), etc., can be added.

[0082] If necessary, the dosage units for oral administration can be microencapsulated.

[0083] The pharmaceutical compositions of the present invention can also be in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and releases the drug in the rectum. Such materials include cocoa butter, beeswax, polyethylene glycol, stearic acid, and / or hydrogenated coconut oil glycerides.

[0084] Non-oral formulations can be in the form of liquid preparations for subcutaneous, intramuscular, or intravenous injection, such as solutions or suspensions. These non-oral formulations can be prepared by suspending or dissolving a certain amount of the crystals of the present invention in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and then sterilizing the suspension or solution. Furthermore, stabilizers, preservatives, emulsifiers, etc., may be added. Preferably, the injection solution is prepared at a pH of 4.5 to 7.5.

[0085] Alternatively, the crystals of compound I of the present invention can be administered locally rather than systemically. The composition of the crystals of the present invention can be formulated for administration to mammals, preferably for humans. The composition consisting of the crystals of the compound of the present invention and suitable excipients can be administered repeatedly, or the composition can be administered continuously. Suitable sites of administration include, but are not limited to, the nasal cavity, lungs, trachea, and bronchi.

[0086] The composition of the drug crystals of the present invention can be in the form of nasal drops, nasal sprays, inhalation solutions, DPIs, solution-type metered-dose inhalers, suspension-type metered-dose inhalers, SMIs, etc.

[0087] This invention comprises a composition of the inventive crystals administered via nebulizer. Nebulizers typically generate a high-speed airflow that atomizes the pharmaceutical composition containing the active ingredient, allowing it to be inhaled into the respiratory tract by a patient. Therefore, the active ingredient is usually dissolved in a suitable solvent to form a solution placed in the nebulizer. Alternatively, the active ingredient is micronized and combined with a suitable carrier to form a micronized particle suspension suitable for inhalation. Micronization is generally defined as having more than 90% of the solid particles having a diameter of less than 10 μm. Suitable nebulizers are commercially available. Representative solvents for the composition are physiological saline or ethanol solutions.

[0088] This invention relates to a composition containing the crystals of the invention, administered via inhalation using a metered-dose inhaler. A metered-dose inhaler that uses mechanical force to atomize a drug solution is called a metered-dose inhaler (SMI), and SMI uses an isotonic aqueous solution as the solvent. A metered-dose inhaler (MDI) that uses the propellant force to quantitatively release a therapeutic drug is called a metered-dose inhaler. The composition administered via a metered-dose inhaler is contained in a solution or suspension. Both types of metered-dose inhalers are commercially available. The MDI containing Compound I crystals has a co-solvent including, but not limited to, anhydrous ethanol, glycerol, and one or more glycols, including, but not limited to, ethylene glycol, propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 800. Its propellant includes, but is not limited to, tetrafluoroethane (HFA-134a) and heptafluoropropane (HFA-227ea), or a mixture thereof. Its surfactants include, but are not limited to, oleic acid; oligolactic acid (OLA); dehydrated sorbitols, such as span20, span65, span80, and span85; polyoxyethylene dehydrated sorbitols, such as Tween 20 and Tween 80; polyoxyethylene fatty alcohols, such as Brij30, Brij35, and Cremophor; polyoxyethylene polyoxypropylene copolymers, such as Pluronic F-68; polyethylene glycol stearates, such as Solutol HS15; and phospholipids, such as one or more of soybean lecithin and phospholipid.

[0089] DPIs can be prepared by mixing the active ingredient with excipients, or without excipients, and then the drug or composition is loaded into a powder dispenser or into an inhalation cartridge or capsule for use with a DPI delivery device, which is commercially available. A DPI containing crystals of compound I, wherein the inert carrier comprises a diluent and a lubricant, wherein the diluent is one or a mixture of several selected from dextran, arabinose, lactose, mannitol, mannitol, xylitol, sucrose, fructose, sorbitol, maltose, amino acids, and glucose, and the lubricant is magnesium stearate or sodium benzoate.

[0090] Nasal sprays and drops are commercially available devices that dispense a composition containing crystals of compound I into nasal spray and drop containers. The inert carrier in nasal drops or metered-dose nasal sprays containing crystals of compound I is one or a mixture of several selected from benzalkonium chloride, benzalkonium bromide, benzyl alcohol, benzoic acid, chlorobutanol, parabens, sorbic acid, phenol, thymol, and volatile oils.

[0091] The present invention also provides the application of the pharmaceutical composition, which can be used to prepare drugs for the prevention and treatment of various acute and chronic airway obstructive diseases in mammals and humans, such as COPD, bronchial asthma, gastric ulcer, duodenal ulcer, acute and chronic rhinitis, and post-cold rhinitis.

[0092] In addition to the representative dosage forms mentioned above, other pharmaceutically acceptable excipients, carriers, and dosage forms are generally known to those skilled in the art and are included in this invention. It should be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the patient's age, weight, general health condition, sex, dietary status, timing of administration, rate of excretion, concomitant medications, the treating physician's judgment, and the severity of the specific disease being treated. The amount of the active ingredient also depends on the type and amount (if present) of other therapeutic agents in the composition. Attached Figure Description

[0093] Figure 1 XRPD spectrum of type A crystal

[0094] Figure 2 XRPD spectrum of type B crystal

[0095] Figure 3. TGA and DSC spectra of type A crystals (bottom line represents crystal A, top line represents crystal B).

[0096] Figure 4 TGA spectrum of type B crystal

[0097] Figure 5. DSC comparison spectra of type A and type B crystals (bottom solid line represents crystal A, top dashed line represents crystal B).

[0098] Figure 6 DVS adsorption curve of type A crystals

[0099] Figure 7 DVS adsorption curve of type B crystals Detailed Implementation

[0100] The following embodiments and test examples illustrate the present invention in more detail, but those skilled in the art will understand that the present invention is not limited to these embodiments and test examples.

[0101] [Example 1] Preparation of Compound I (active drug substance) of the present invention

[0102] Step 1: Preparation of 2-hydroxy-2-cyclopentyl-2-phenylethanol

[0103] Method 1: 124.0 g (0.500 mol) of cyclopentylmandelate and 1000 mL of anhydrous ethanol were added to a 2 L three-necked reaction flask. The mixture was then heated to below 5 °C using an ice-salt bath. 37.83 g (1.00 mol) of sodium borohydride was added in portions, maintaining the internal temperature below 5 °C. The temperature was then raised to approximately 45 °C and reacted for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure. The residue was neutralized to neutral with 0.5 M hydrochloric acid and extracted three times with dichloromethane (3 × 500 mL). The organic phases were combined and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was dried under reduced pressure to obtain 98.6 g of a yellow oily substance (95.60% yield). This oil was used directly in the next reaction.

[0104] Method 2: Add 200.00 g (0.908 mol) of cyclopentylmandelic acid and 3000 ml of ethylene glycol dimethyl ether to a 5 L three-necked reaction flask. Then, heat the flask to below 0 °C using an ice-salt bath. Add 363.20 g (2.724 mol) of aluminum trichloride, maintaining the internal temperature below 5 °C during the addition. After the addition is complete, stir the mixture at this temperature for half an hour. Then, add 137.40 g (3.632 mol) of sodium borohydride in portions, maintaining the internal temperature below 5 °C. Finally, raise the internal temperature to approximately 55 °C and react for 2 hours. Thin-layer chromatography indicates the reaction is complete. The reaction mixture was slowly poured into 1600 mL of ice-cold 1 mol / L hydrochloric acid while stirring continuously, controlling the solution temperature to not exceed 25°C. After the addition was complete, the mixture was extracted three times with ethyl acetate (3 × 1000 mL). The organic phases were combined and washed three times with 5% sodium carbonate aqueous solution (3 × 500 mL). The organic phase was then separated and washed three times with 5% sodium chloride aqueous solution (3 × 500 mL). The organic phase was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was removed under reduced pressure at 50°C. The residue was dissolved in isopropyl ether (1000 mL), and then washed with 2 mol / L sodium hydroxide aqueous solution (450 mL) with mechanical stirring for 10 min. The mixture was then placed in a separatory funnel, and the organic layer was separated and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was removed by rotary evaporation under reduced pressure using a water pump. Finally, 145.80 g of a pale yellow oil was obtained. Yield: 77.84%, which was used directly in the next reaction.

[0105] Step 2: Preparation of (R)-2-hydroxy-2-cyclopentyl-2-phenylethanolyl L-(-)-camphorsulfonyl

[0106] 112.50 g (545.38 mmol) of 2-hydroxy-2-cyclopentyl-2-phenylethanol was dissolved in 700 mL of dichloromethane and poured into a 5 L three-necked flask. The reaction solution was clear and transparent. 165.55 g (1636.03 mmol) of triethylamine was added at room temperature, and the mixture was then heated in an ice-water bath to below 10 °C. 500 mL of a dichloromethane solution containing 164.10 g (654.46 mmol) of L-(-)-camphorsulfonyl chloride was added dropwise. After the addition was complete, the mixture was heated to approximately 10 °C and reacted for 1 h. After the reaction was complete, 1 L of water was added, and the mixture was placed in a separatory funnel to separate the aqueous and organic phases. The organic phase was washed three times with water (3 × 1000 mL), 1 L each time. Finally, the organic phase was collected and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was removed by rotary evaporation under reduced pressure at 40°C. The residue was dissolved in 200 mL of ethyl acetate, and the solid was frozen to crystallize. The solid was collected by filtration and dried to give 70.03 g of white solid, with a yield of 61.0%.

[0107] Step 3: Preparation of (R)-2-cyclopentyl-2-phenylethylene oxide

[0108] Dimethyl sulfoxide (350 mL) and 2-hydroxy-2-cyclopentyl-2-phenylethanolyl L-(-)-camphorsulfonyl (69.23 g, 164.6 mmol) were added to a 1 L three-necked flask. After the solution became clear, potassium tert-butoxide (17.54 g, 156.31 mmol) was added at room temperature, and the mixture was heated in an oil bath to an internal temperature of 50 °C for 1 h. TLC detection: (developing solvent: petroleum ether: ethyl acetate = 3 mL: 1 mL) The mixture was heated in an ice-water bath to an internal temperature below 10 °C, 450 mL of water was added dropwise, and the mixture was placed in a separatory funnel and extracted three times with isopropyl ether (3 × 200 mL). The organic phases were combined and washed three times with 5% sodium chloride solution (3 × 200 mL). Anhydrous magnesium sulfate was added to the organic phase for drying, and the mixture was filtered. The filtrate was evaporated under reduced pressure in a water bath at 45 °C to remove the solvent, finally yielding 28.02 g of a pale yellow liquid, yield: 90.42%.

[0109] Step 4: Preparation of (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2]octane

[0110] R-(-)-3-quinol (16.46 g, 129.45 mmol) and 250 mL of dry tetrahydrofuran were added to a 1 L three-necked flask. After the solid dissolved, Z04 (24.38 g, 129.45 mmol dissolved in 50 mL of tetrahydrofuran) was added at room temperature. The mixture was heated to an internal temperature of 85 °C in an oil bath, and then NaH (60%, 3.45 g, 86.3 mmol) was added. The reaction was maintained at 85 °C for 2 h. TLC was used for detection (developing solvent: petroleum ether: ethyl acetate = 51:0.1). After the reaction was completed, the solvent was removed under reduced pressure. 500 mL of ice water was added dropwise to the residue, and then the mixture was extracted three times with ethyl acetate (3 × 500 mL). The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was removed under reduced pressure to obtain a light yellow-brown solid. The solid was dissolved in isopropyl ether by heating and reflux, and then frozen to crystallize. The solid was collected by filtration and dried to constant weight, finally yielding 36.28 g of an off-white solid, which was the target compound, with a yield of 88.85%.

[0111] Step 5: (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-bromo-1-azabicyclo[2,2,2]octium salt

[0112] 98.46 g (0.312 mol) of (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2]octane and 490 mL of anhydrous ethanol were placed in a 5 L reactor and dissolved by stirring at room temperature. After complete dissolution, approximately 100 mL of anhydrous ethanol solution containing 82.93 g (0.386 mol) of 3-phenoxybromopropane was added, and the mixture was heated under reflux for 2 h. After the reaction was complete, the solvent was removed under reduced pressure to obtain a white solid. 149.28 g of a white solid of compound I was obtained, with a yield of 90.2%.

[0113] [Example 2] Preparation of Type A crystal of the present invention

[0114] Weigh 43.3 g of compound I (prepared according to Example 1, hereinafter the same, also referred to as the active pharmaceutical ingredient) and 86.7 ml of anhydrous ethanol, place them in a 200 mL round-bottom flask, and dissolve by reflux and stirring. Add 0.87 g of activated carbon, and decolorize by reflux and stirring for 0.5 h. Remove the activated carbon by vacuum filtration while hot, obtaining a light yellow transparent filtrate. Transfer the filtrate to a 1.0 L round-bottom flask, add 1.0 L of ethyl acetate under reflux, cool to 25 ± 5 °C, and stir to crystallize for 2 h. Filter by vacuum filtration, and dry the solid at 80 °C with forced air for 4 h to obtain type A crystals of the present invention (39.2 g, yield 90.5%). The powder X-ray diffraction pattern of type A crystals of the present invention is shown in Figure 1. Figure 1 .

[0115] Elemental analysis C 29 H 40BrNO3, calculated values: C 65.65, H 7.60, Br 15.06, N 2.64; measured values: C 65.60, H 7.58, Br 15.0, N 2.62. Elemental analysis results show that this product does not contain water of crystallization or other crystallization solvents and has the same molecular formula as compound I.

[0116] [Example 3] Preparation of Type A crystal of the present invention

[0117] Weigh 35.1g of the active pharmaceutical ingredient and 300ml of dichloromethane, place them in a 500mL round-bottom flask, and dissolve them under reflux with stirring. Add 0.7g of activated carbon, and decolorize by reflux with stirring for 2 hours. Remove the activated carbon by vacuum filtration while hot, obtaining a light yellow transparent filtrate. Transfer the filtrate to a 2.0L round-bottom flask, and under reflux conditions, first add 3g of crystal A, then add 900L of isopropyl ether. Cool to 5±5℃ and stir to crystallize for 48 hours. Filter by vacuum filtration, and dry the solid at 40℃ and below 10mmHg for 24 hours to obtain type A crystals of this invention (27.6g, yield 72.3%).

[0118] Elemental analysis C 29 H 40 BrNO3, calculated values: C 65.65, H 7.60, Br 15.06, N 2.64; measured values: C 65.45, H 7.42, Br 15.11, N 2.50. Elemental analysis results show that this product does not contain water of crystallization or other crystalline solvents and has the same molecular formula as compound I.

[0119] [Example 4] Preparation of type B crystal of the present invention

[0120] Weigh 30.3 g of compound I (prepared according to Example 1, hereinafter the same, also referred to as the active pharmaceutical ingredient) and 100 ml of 95% ethanol, place them in a 200 mL round-bottom flask, and dissolve them under reflux with stirring. Add 0.6 g of activated carbon, and decolorize by reflux with stirring for 2 h. Remove the activated carbon by vacuum filtration while hot, obtaining a light yellow transparent filtrate. Transfer the filtrate to a 2.0 L round-bottom flask, add 1000 mL of tetrahydrofuran under reflux, cool to 20 ± 5 °C, and stir to crystallize for 2 h. Filter by vacuum filtration, and dry the solid at 60 °C with forced air for 8 h to constant weight, obtaining type B crystals of the present invention (26.5 g, yield 83.3%). The powder X-ray diffraction pattern of type B crystals of the present invention is shown in Figure 1. Figure 2 .

[0121] Elemental analysis showed that the B-type crystal of compound I contained 1.5 molecules of water, and its molecular formula was C. 29 H 40 BrNO 3. 1.5H2O, calculated values: C 62.47, H 7.77, Br 14.33, N 2.51, measured values: C 62.60, H 7.82, Br 14.25, N 2.48.

[0122] [Example 5] Preparation of type B crystal of the present invention

[0123] Weigh 32.8 g of the active pharmaceutical ingredient and 200 ml of 98% ethanol, place them in a 500 mL round-bottom flask, and dissolve them under reflux with stirring. Add 0.7 g of activated carbon, and decolorize by reflux with stirring for 4 h. Remove the activated carbon by hot filtration, obtaining a light yellow transparent filtrate. Transfer the filtrate to a 5.0 L reactor, add 1000 mL of acetone under reflux, cool to 10 ± 5 °C, and stir to crystallize for 24 h. Filter, and dry the solid at 80 °C with forced air for 4 h to constant weight, obtaining type B crystals of this invention (25.5 g, yield 74.9%).

[0124] Elemental analysis showed that the B-type crystal of compound I contained 1.5 molecules of water, and its molecular formula was C. 29 H 40 BrNO 3. 1.5H2O, calculated values: C 62.47, H 7.77, Br 14.33, N 2.51, measured values: C 62.36, H 7.79, Br 14.21, N 2.68.

[0125] [Example 6] Preparation of type B crystals by crystal transformation method

[0126] 40.3 g of compound I crystal A was weighed and added to a 1 L reactor. 400 mL of purified water was added, and the mixture was stirred and slurried at 250-270 r / min and 25 ± 5 °C for 5 h. The mixture was then filtered, and the solid was dried in a forced-air oven at 60 °C for 12 h. After the moisture content was measured and the weight was constant, type B crystal of the present invention was obtained (35.7 g, yield 84.3%). The powder X-ray diffraction pattern of type B crystal of the present invention is shown in [Figure / Image]. Figure 2 .

[0127] Elemental analysis showed that the B-type crystal of compound I contained 1.5 molecules of water, and its molecular formula was C. 29 H 40 BrNO 3. 1.5H2O, calculated values: C 62.47, H 7.77, Br 14.33, N 2.51; measured values: C 62.41, H 7.84, Br 14.16, N 2.63.

[0128] [Formulation Example 7] Preparation of a dry powder inhaler composition for maintenance treatment of asthma and COPD.

[0129] Components and their dosage in the composition

[0130] Crystal A 100mg

[0131] Lactose 25000mg

[0132] The crystal A of this invention is micronized to achieve an average particle size D. 50The drug is smaller than 5 μm and thoroughly mixed with lactose with a particle size of 1–100 μm. The mixture is then encapsulated, with each capsule containing 25.1 mg of the drug / lactose mixture, and administered via a powder inhaler.

[0133] Test case

[0134] The type A crystal of the present invention is prepared by using the method of Example 2 or a method with the same mechanism as Example 2; the type B crystal of the present invention is prepared by using the methods of Examples 4 and 6 or a method with the same mechanism as Examples 4 and 6.

[0135] [Experimental Example 1] X-ray powder diffraction (XRPD) test of the crystal of the present invention

[0136] All solid samples obtained in the experiment were analyzed using a powder X-ray diffractometer (Bruker D8 advance) equipped with a LynxEye detector. The 2θ scan angle of the samples ranged from 3° to 40°, the scan step size was 0.02°, and the tube voltage and tube current were 40 kV and 40 mA, respectively. A zero-background sample disk was used for sample measurements.

[0137] result:

[0138] (1) Type A crystals are shown in the appendix. Figure 1 Taking into account factors such as D-value, low-angle data, intensity characteristic lines, and peak shape integrity, the characteristic peaks are selected from the following 2θ values: 5.7±0.2 degrees, 12.9±0.2 degrees, 16.7±0.2 degrees, 18.0±0.2 degrees, 19.5±0.2 degrees, 21.1±0.2 degrees, 22.3±0.2 degrees, and 23.3±0.2 degrees. The X-ray powder diffraction data of crystal A of this invention are shown in Table 1.

[0139] Table 1. X-ray powder diffraction data of crystal A in Example 2

[0140]

[0141]

[0142] Approximately 10 mg of crystal A was weighed into an 8 ml sample vial, sealed with filter paper, and placed in a 40℃ / 75%RH stability test chamber. After 3 days, samples were taken for XRPD analysis. The results showed that crystal A had partially transformed into crystal B. This indicates that type A crystals are unstable under high humidity conditions.

[0143] (2) Type B crystals are shown in the appendix. Figure 2Taking into account factors such as D-value, low-angle data, intensity characteristic lines, and peak shape integrity, its characteristic peaks are selected from the following 2θ values: 5.2±0.2 degrees, 15.8±0.2 degrees, 16.9±0.2 degrees, 17.7±0.2 degrees, 19.5±0.2 degrees, 20.2±0.2 degrees, and 22.1±0.2 degrees. The X-ray powder diffraction data of crystal B of this invention are shown in Table 2.

[0144] Table 2. Characteristic X-ray powder diffraction data of crystal B in Example 6

[0145]

[0146] Approximately 10 mg of crystal B was weighed into an 8 ml sample vial, sealed with filter paper, and placed in a 40℃ / 75%RH stability test chamber. After 3 days, samples were taken for XRPD testing, and the results showed that crystal B did not change.

[0147] Experimental Example 1 demonstrates that in high humidity environments, type B crystals are more stable than type A crystals.

[0148] [Experimental Example 2] Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) Experiments

[0149] TGA: Solid samples were subjected to thermogravimetric analysis using a TA TGA Q500. 2–3 mg of sample was placed in a pre-equilibrated aluminum sample pan, and the sample mass was automatically weighed within the TGA furnace. The sample was heated to 200–300 °C at a rate of 10 °C / min. During the test, the nitrogen flow rates to the balance chamber and sample chamber were 40 mL / min and 60 mL / min, respectively.

[0150] DSC: Solid samples were subjected to differential scanning calorimetry (DSC) using a TA DSC Q200, with indium as the standard sample for calibration. 2–3 mg of sample was accurately weighed and placed in the TA DSC sample pan, and the exact mass of the sample was recorded. The sample was heated to 200–250 °C at a heating rate of 10 °C / min in a nitrogen flow of 50 mL / min.

[0151] Results: The TGA results are shown in Figures 3 and 4. Figure 3 shows that crystal A did not lose significant weight before decomposition, indicating that crystal A molecules do not contain water of crystallization. Figure 4The results show that crystal B underwent two weight losses before decomposition, at 3.163% and 1.131% respectively, consistent with the characteristics of crystal B as a 1.5-molecule hydrate of compound I. The DSC results are shown in Figures 3 and 5. Figure 3 shows that crystal A has only one endothermic peak, with an initial temperature of 157.44℃ and a peak temperature of 161.03℃, which is the melting point peak. Figure 5 shows that crystal B has three endothermic peaks, with peak values ​​of 90.52℃, 113.26℃, and 160.65℃. After heating to 105℃ by DSC, XRPD analysis revealed that the hydrate transformed into a mixed crystal of hydrate and type A crystals. This indicates that the first two endothermic peaks were caused by the loss of water of crystallization, and the third endothermic peak was the melting peak of the anhydrous form after losing water of crystallization.

[0152] [Experimental Example 3] Dynamic Moisture Adsorption (DVS)

[0153] Dynamic moisture adsorption-desorption analysis was performed on an IGA SORP (Hiden Isochema) instrument. The samples were tested in gradient mode, with a humidity range of 0% to 90%. The humidity increment for each gradient was 10%. The shortest test time for each gradient was 30 min, and the longest test time was 120 min. The system collected data at 3-minute intervals.

[0154] Results: See DVS results. Figure 6 and Figure 7 The results show that crystal A has strong hygroscopicity, with a moisture absorption weight gain of 52.4% at 80% RH. Crystal B has much lower hygroscopicity than crystal A, with a moisture absorption weight gain of only 2.58% at 80% RH.

[0155] [Experimental Example 4] Determination of the concentration of residual solvent contained in the crystal of the present invention

[0156] The concentration of residual solvent in the crystals of this invention was determined under the following conditions. The results are shown in Table 3.

[0157] Measurement conditions:

[0158] Gas chromatography equipped with an FID detector

[0159] Column: OPTIMA-624 (30m × 0.32mm × 1.8μm)

[0160] Column temperature: 60℃ (3 min) 20℃ / min 200℃ (5 min)

[0161] Inlet temperature: 200℃

[0162] Detector temperature: 250℃

[0163] Carrier gas: Nitrogen

[0164] Column flow rate: 2 ml / min

[0165] Headspace parameters: Headspace equilibrium temperature 80℃, headspace equilibrium time 30min

[0166] Flow split ratio: 10:1

[0167] Table 3: Residual Solvents in the Active Pharmaceutical Ingredient and the Invented Crystal

[0168]

[0169] The recrystallization processes of this invention remove residual solvents. Both the type A crystals and type B crystals of this invention have very little residual solvent. No residual solvent was detected in the crystals in Example 6.

[0170] [Experimental Example 5] Impurity Removal Effect of Recrystallization

[0171] The impurity removal effect of the recrystallization process of the crystals of this invention was determined using the following high-performance phase chromatography conditions.

[0172] Instrument: High-performance liquid chromatograph equipped with ultraviolet detector

[0173] Column: AgelaPromosil C18 4.6×250mm, 5μm

[0174] Mobile phases: Phase A: 0.01 mol / L potassium dihydrogen phosphate solution (with 0.04 mol / L ammonium chloride added, pH adjusted to 3.0 with phosphoric acid) - methanol (38:62); Phase B: acetonitrile.

[0175] Gradient elution table:

[0176] Time (min) Phase A (%) Phase B (%) 0 100 0 30 75 25 60 40 60 65 40 60 68 100 0 80 100 0

[0177] Detection wavelength: 210nm

[0178] Flow rate: 1.0 ml / min

[0179] Injection volume: 20 μl

[0180] Column temperature: 30℃

[0181] Solvent: Mobile phase A

[0182] First, the purity (%) of compound I in each crystal is calculated using the following formula based on HPLC chromatography: Purity (%) of compound I in each crystal = (Peak area of ​​compound I in each crystal) / (Sum of all peak areas) × 100; Next, the impurity removal rate (%) in each crystal is calculated using the following formula: Impurity removal rate (%) in each crystal = [{(Purity of compound I in each crystal) - (Purity of compound I in the raw material)} / {100 - (Purity of compound I in the raw material)}] × 100

[0183] The results are shown in Table 4.

[0184] [Table 4] Results of Recrystallization Removal of Impurities from Drug Substance

[0185] Serial Number Crystal form Purity (%) of compound I in each crystal form Impurity removal rate (%) in each crystal form 1 raw materials 98.15 - 2 Type A crystal of this invention 99.78 88.1 3 The present invention is a type B crystal. 99.82 90.3

[0186] The results show that the recrystallization process of both the Type A crystal and the Type B crystal of the present invention can remove most of the impurities in the active pharmaceutical ingredient.

[0187] [Experimental Example 6] Study on Crystallization Solvents

[0188] According to "2. Preparation of Type A Crystals and Type B Crystals of the Invention (hereinafter collectively referred to as the Crystals of the Invention)" in the "Best Method for Realizing the Invention," the recrystallization method of Type A and Type B crystals of the Invention sometimes fails to crystallize under certain conditions. Even after removing the solvent, the active pharmaceutical ingredient eventually becomes an oily substance. The good solvents for this phenomenon in the preparation of Type A crystals are alcohol and acetonitrile at 2℃~4℃, and the antisolvents are tetrahydrofuran and methyl tert-butyl ether. The good solvents for this phenomenon in the preparation of Type B crystals are alcohol / water solution and acetonitrile at 2℃-4℃, and the antisolvents are tetrahydrofuran and methyl tert-butyl ether. Twelve good solvents (including good solvents containing a certain amount of water) and eight antisolvents were used, resulting in 192 crystallization combinations. It was found that nine cases in the table below did not yield crystals, and the active pharmaceutical ingredient became an oily substance after solvent evaporation.

[0189] [Table 5] Cases where recrystallization fails to yield crystals

[0190]

[0191] * Ratio 1: Good solvent / active drug ratio (ml / g)

[0192] Ratio 2: Antisolvent / Good Solvent Ratio (ml / ml)

[0193] Studies have found that increasing the antisolvent / good solvent ratio to ≥8 can effectively prevent the inability to recrystallize.

Claims

1. Type B crystals of (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane salt, wherein the type B crystals are (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane salts. [2] A hydrate of octium salt and 1.5 molecules of H2O, the powder X-ray diffraction pattern of the crystal shows diffraction peaks at the following diffraction angles 2θ: 5.2±0.2 degrees, 15.8±0.2 degrees, 16.9±0.2 degrees, 17.7±0.2 degrees, 19.5±0.2 degrees, 20.2±0.2 degrees, and 22.1±0.2 degrees, the powder X-ray diffraction pattern being obtained using Cu Kα rays.

2. The method for manufacturing type B crystals of brominated (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane salt according to claim 1, characterized in that, Heating is performed to dissolve (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane salt in an alcohol or a mixture of acetonitrile and water; an antisolvent is added to the solution, the antisolvent being selected from esters, water, ethers, ketones, liquid cycloalkanes, or aromatics; the resulting solution is slowly cooled to crystallize it; or (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane salt is dissolved under heating conditions in a solvent selected from alcohols, acetonitrile, dichloromethane, or trichloromethane, water is added to the solution, and the resulting solution is slowly cooled to crystallize it to obtain type B crystals.

3. The manufacturing method according to claim 2, characterized in that, The alcohol in question is ethanol.

4. The manufacturing method according to claim 2, characterized in that, The antisolvent is ethyl acetate.

5. The method for manufacturing type B crystals of brominated (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane salt according to claim 1, characterized in that, Type A crystals of (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane salt were added to a reaction vessel, purified water was added, the mixture was stirred and slurried, filtered, and the solid was dried in a forced-air environment at 40°C–80°C until constant weight was achieved, yielding type B crystals. The type A crystals were prepared using the following method: Heating is performed to dissolve (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octium salt in a good solvent selected from alcohols, acetonitrile, dichloromethane, or trichloromethane. An antisolvent, selected from esters, ethers, ketones, liquid cycloalkanes, or aromatics, is added to the solution. The resulting solution is slowly cooled to crystallize, yielding type A crystals. Contact with water must be avoided throughout the process. The powder X-ray diffraction pattern of crystal A shows diffraction peaks at the following diffraction angles 2θ: 5.7±0.2 degrees, 12.9±0.2 degrees, 16.7±0.2 degrees, 18.0±0.2 degrees, 19.5±0.2 degrees, 21.1±0.2 degrees, 22.3±0.2 degrees, and 23.3±0.2 degrees. The powder X-ray diffraction pattern is a spectrum obtained using Cu Kα rays.

6. A pharmaceutical composition comprising the crystals of claim 1 as an active ingredient.

7. The use of the crystal according to claim 1 in the preparation of M receptor subtype selective antagonists.

8. The use of the crystal of claim 1 in the preparation of preventive or therapeutic agents for rhinitis, chronic bronchitis, airway obstruction, asthma, COPD, cough, urinary incontinence, urinary frequency, unstable bladder syndrome, bladder spasm, cystitis, and gastrointestinal diseases.

9. The application according to claim 8, wherein the rhinitis is post-cold rhinitis.

10. The application according to claim 8, characterized in that... The gastrointestinal diseases mentioned are selected from stress-induced colitis, spastic colitis, duodenal ulcers, or gastric ulcers.

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