Pharmaceutical composition and quality control method thereof

Abstract

The present invention provides a pharmaceutical composition and a quality control method, the pharmaceutical composition comprises a compound of formula A or a salt thereof, and an antioxidant, the structure of the compound of formula A is that the pharmaceutical composition is mixed with one or more antioxidants, and the safety of a solid preparation is effectively solved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a kind of pharmaceutical composition and quality control method. BACKGROUND

[0002] The compound of formula A is a histamine H1 receptor agonist, and its chemical structure is as follows: The drug can reduce the symptoms such as inner ear vertigo, ear closing and tinnitus by increasing the blood flow of inner ear and vestibule, and is a first-line drug for treating ear vertigo in clinic. In addition, the drug can also dilate the heart and cerebral blood vessels, and the dilation effect on the basilar artery system is particularly obvious, which can increase the blood flow of the heart, cerebral blood vessels and peripheral circulation system, improve the blood circulation of the whole body, have a blood pressure lowering effect, and can also inhibit platelet aggregation to prevent thrombosis, and has a slight diuretic effect. The drug is mainly used in clinic to improve the dizziness, dizziness and other symptoms associated with Meniere's disease, Meniere's syndrome and vertigo. At present, the active ingredients of the drug on the market are in the form of hydrochloride and methanesulfonate, and the former has multiple dosage forms such as tablets, oral solutions, injection solutions and lyophilized products, and the latter only has tablets on the market.

[0003] Since N-nitrosodimethylamine (NDMA) was found and detected in valsartan bulk drug in July 2018, various regulatory agencies have detected various nitrosamine impurities in other bulk drugs. Nitrosamine is a high-strength carcinogen, and is classified according to different risk categories (1-5) by using the carcinogenic potency classification method (CPCA), in which the carcinogenic severity is determined based on the acceptable intake and the activation or inactivation properties defined based on the structural characteristics. Because of the presence of a secondary amine structure, nitrosamine impurities may be formed in the compound of formula A (BH), and according to the CPCA method, the substance is classified as a class 1 carcinogen. The chemical structure of the nitrosamine impurity in the compound of formula A is as follows:

[0004] There is no relevant literature reporting how to control the content of nitrosamine impurities in the compound of formula A drug, and solving this problem has become a difficult problem and urgent need in the pharmaceutical industry. SUMMARY

[0005] The pharmaceutical preparation of the compound of formula A will gradually generate nitrosamine impurities during storage, and the nitrosamine impurities will gradually increase as the storage time is prolonged.

[0006] The inventors found that the nitrosamine impurities in the existing hydrochloride tablets of the compound of formula A all exceed the acceptable limit (0.375 ppm).

[0007]

[0008] Test results of the methanesulfonic acid salt tablet of the compound of formula A

[0009] The methanesulfonic acid salt tablet of the compound of formula A was tested for the nitrosamine impurity, and the content of the nitrosamine impurity exceeded the allowable limit value within its shelf life.

[0010] An object of the present application is to overcome the problems of the prior art and provide a pharmaceutical composition containing a compound of formula A, which has excellent stability, and a method and use for quality control.

[0011] In a first aspect of the present application, there is provided a pharmaceutical composition comprising a compound of formula A or a salt thereof, and an antioxidant, the structure of the compound of formula A being: .

[0012] In a second aspect of the present application, there is provided an oral solid preparation, characterized by comprising a compound of formula A or a salt thereof, and a non-inorganic salt antioxidant, the structure of the compound of formula A being: .

[0013] In a third aspect of the present application, there is provided a method for controlling the content of a nitrosamine impurity in a pharmaceutical composition comprising a compound of formula A or a salt thereof, characterized by mixing the compound of formula A or a salt thereof with one or more antioxidants, the structure of the compound of formula A being , and the nitrosamine impurity being: .

[0014] In a fourth aspect of the present application, there is provided a use of a nitrosamine impurity in quality control of a pharmaceutical composition comprising a compound of formula A, characterized by the structure of the compound of formula A being , and the structure of the nitrosamine impurity being ; when the salt of the compound of formula A is hydrochloride, the content of the nitrosamine impurity in the pharmaceutical composition is less than 0.375 ppm; when the salt of the compound of formula A is methanesulfonic acid salt, the content of the nitrosamine impurity in the pharmaceutical composition is less than 0.500 ppm.

[0015] Additional aspects and advantages of the application will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following and the attached drawings. BRIEF DESCRIPTION OF DRAWINGS

[0016] The above and / or additional aspects and advantages of the application will become apparent and be readily understood by considering the following detailed description, from which the above-mentioned and other aspects and advantages of the application will become apparent, taken in conjunction with the accompanying drawings. Figure 1 To test the nitrosamine impurity growth trend in the hydrochloride salt formulation of the compound of Formula A in Test Example 2; Figure 2 To test the nitrosamine impurity growth trend in the methanesulfonic acid salt formulation of the compound of Formula A in Test Example 3; Figure 3 To test the nitrosamine impurity growth trend of Test Example 2-3, Test Example 2-4, Test Example 2-5, Test Example 2-6 and Test Example 2-7 of the present application under accelerated conditions of 40°C / 75% RH. DETAILED DESCRIPTION

[0017] The embodiments of the present application are described in detail below. The embodiments described below are exemplary only, and are not intended to be limiting of the present application.

[0018] It should be noted that the terms "first", "second" are used only for descriptive purposes, and are not to be construed as indicating or implying relative importance or an indicated number of technical features. Thus, features defined with "first", "second" can include one or more of the features explicitly or implicitly. Further, in the description of the present application, the meaning of "a plurality of" is two or more, unless otherwise specified.

[0019] In this document, the terms "comprising" or "including" are open-ended, that is, they mean including, but not limited to, the recited items.

[0020] In this document, the terms "optionally", "optional" or "optional" generally mean that the event or circumstance subsequently described can or can not occur, and that the description includes situations where the event or circumstance occurs, as well as situations where it does not.

[0021] In this document, the term "shelf life" generally refers to the shelf life of a drug in a form that is sold to consumers, during which the drug is suitable for use by patients. The term "shelf life" also refers to the period of time during which a drug can maintain its quality, safety and effectiveness under specified storage conditions. Within this period, the ingredients, content, properties, etc. of the drug meet the requirements of the national drug standards or drug registration standards, and can be used safely and effectively. The shelf life of a drug can be greater than 3 months, 6 months, 12 months, 18 months, 24 months, and preferably 36 months. The specified storage conditions for the drug are, for example, "in a cool, dry, light-protected place, with a temperature not exceeding 25°C" or "in a light-protected, airtight container". Specifically, the shelf life of the betamistine hydrochloride or methanesulfonate is 36 months.

[0022] In this document, the term "antioxidant" generally refers to a substance that controls nitrosamine-related impurities (NDSRIs) and other impurities in a pharmaceutical composition below an acceptable level.

[0023] The solution of the present application will be explained below in connection with examples. Those skilled in the art will understand that the following examples are only for illustrating the present application and should not be regarded as limiting the scope of the present application. If the specific technology or condition is not mentioned in the examples, it is carried out according to the technology or condition described in the literature in the art or according to the product instruction. If the manufacturer of the reagent or instrument is not mentioned, it is a conventional product that can be obtained by market purchase.

[0024] In a first aspect, the present application provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises a compound of formula A or a salt thereof, and an antioxidant, wherein the structure of the compound of formula A is: .

[0025] In a preferred embodiment of the present application, the antioxidant is selected from water-soluble antioxidants or non-water-soluble antioxidants; the water-soluble antioxidant is selected from cysteine and / or cysteine hydrochloride. Methionine, glutamic acid, acetylcysteine are water-soluble antioxidants equivalent to cysteine or cysteine hydrochloride; the non-water-soluble antioxidant is selected from one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tert-butylhydroquinone, tocopherol, ascorbyl palmitate, dilauryl thiodipropionate or distearyl thiodipropionate; preferably, the antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, ascorbyl palmitate, cysteine hydrochloride and cysteine; more preferably, the antioxidant is selected from cysteine hydrochloride and / or cysteine.

[0026] In a preferred embodiment of the present application, the pharmaceutical composition is an oral solid preparation of the compound of formula A or a liquid preparation of the compound of formula A; preferably, the oral solid preparation is a granule, a tablet or a capsule.

[0027] In a preferred embodiment of the present application, the salt of the compound of formula A is a hydrochloride salt or a methanesulfonate salt.

[0028] In a preferred embodiment of the present application, the weight content of the antioxidant in the pharmaceutical composition is not less than 0.2%.

[0029] In a preferred embodiment of the present application, the weight content of the antioxidant in the pharmaceutical composition is not more than 10% w / w; preferably, the content of the antioxidant in the pharmaceutical composition ranges from 0.5% to 6.4% w / w.

[0030] In a preferred embodiment of the present application, the pharmaceutical composition further comprises an excipient, which is selected from one or more of ① to ⑥:

[0031] In a preferred embodiment of the application, the pharmaceutical composition meets one or more of a) - c); a) the pharmaceutical composition comprising the compound of Formula A, after being exposed to 40°C / 75% RH for a period of 3 months, when the salt of the compound of Formula A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the appearance of the pharmaceutical composition is white or off-white; when the salt of the compound of Formula A is a mesylate salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the appearance of the pharmaceutical composition is white or off-white; b) the pharmaceutical composition comprising the compound of Formula A, after being exposed to 40°C / 75% RH for a period of 6 months, when the salt of the compound of Formula A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the appearance of the pharmaceutical composition is white or off-white; when the salt of the compound of Formula A is a mesylate salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the appearance of the pharmaceutical composition is white or off-white; c) the pharmaceutical composition comprising the compound of Formula A, within the shelf life of the drug product, ​​​​​​when the salt of the compound of Formula A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the appearance of the pharmaceutical composition is white or white-like; when the salt of the compound of Formula A is a mesylate salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm, and the appearance of the pharmaceutical composition is white or white-like.

[0032] In preferred embodiments of the present application, the antioxidant is present in the pharmaceutical composition in an amount of no more than 10% w / w; preferably, the antioxidant is present in the pharmaceutical composition in an amount ranging from 0.1% to 10% w / w. In some embodiments, the antioxidant is present in an amount of no less than 0.2% of the prescription weight (i.e., the weight of the oral solid preparation of the compound of Formula A), or in an amount ranging from 0.2% to 10%, 0.5% to 10%, or 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 6.4%, 7.0%, 7.2%, 8.0%, 9.0%, 10%.

[0033] In preferred embodiments of the present application, the salt of the compound of Formula A is a hydrochloride salt or a mesylate salt.

[0034] In preferred embodiments of the present application, the excipient comprises one or more of the following auxiliary materials ① to ⑥: ① filler: the filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose, mannitol, calcium hydrogen phosphate, starch, pregelatinized starch, and microcrystalline cellulose; ② binder: the binder is selected from one or more of hypromellose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, starch, carbomer, methyl cellulose, and gelatin; ③ pH adjuster: the pH adjuster is selected from one or more of tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate; ④ disintegrant: the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, carboxymethyl cellulose calcium, and starch; ⑤ glidant: the glidant is selected from one or more of silicon dioxide, talc, hydrogenated vegetable oil, calcium silicate, and magnesium silicate; ⑥ lubricant: the lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, and sodium docusate.

[0035] In some embodiments, the oral solid preparation of the compound of Formula A comprises 0.1 to 10 wt% of the antioxidant, 2 to 10 wt% of the compound of Formula A or a salt thereof, 70 to 90 wt% of the filler, 1 to 3 wt% of the pH adjuster, 1 to 3 wt% of the glidant, and 2 to 8 wt% of the lubricant.

[0036] In preferred embodiments of the present application, the pharmaceutical composition is a solid preparation or a liquid preparation; preferably, the solid preparation is a granule, a tablet or a capsule.

[0037] In a second aspect, the present application provides an oral solid preparation, characterized in that it comprises a compound of Formula A or a salt thereof and a non-mineral antioxidant, the structure of the compound of Formula A being as follows: .

[0038] In preferred embodiments of the present application, the salt of the compound of Formula A is a hydrochloride salt or a mesylate salt.

[0039] In preferred embodiments of the present application, the antioxidant accounts for not less than 0.1% of the prescription weight.

[0040] In preferred embodiments of the present application, the non-mineral antioxidant is selected from one or more of propyl gallate, dibutylhydroxytoluene, butylhydroxyanisole, vitamin C, ascorbyl palmitate, cysteine hydrochloride and cysteine.

[0041] In preferred embodiments of the present application, the oral solid preparation comprises 0.1 to 10 wt% of the non-mineral antioxidant, 2 to 10 wt% of the compound of Formula A or a salt thereof, 70 to 90 wt% of the filler, 1 to 3 wt% of the pH adjuster, 1 to 3 wt% of the glidant, and 2 to 8 wt% of the lubricant; Optionally, wherein the filler is selected from one or more of starch, dextrin, malt dextrin, sucrose, lactose (anhydrous or hydrate), mannitol, calcium hydrogen phosphate, starch, pregelatinized starch and microcrystalline cellulose; preferably, microcrystalline cellulose and mannitol; and / or The pH adjuster is selected from one or more of tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate; preferably, citric acid; and / or The glidant is selected from one or more of silicon dioxide, talc, hydrogenated vegetable oil; preferably, silicon dioxide and talc; and / or The lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, sodium docusate; preferably talc.

[0042] In a preferred embodiment of the present application, the oral solid formulation is prepared using a dry process or a wet process.

[0043] In a third aspect, the present application provides a method of controlling the content of nitrosamine impurities in a pharmaceutical composition comprising a compound of Formula A or a salt thereof, characterized in that the method comprises mixing the compound of Formula A or a salt thereof with one or more antioxidants, the compound of Formula A having the structure: , the nitrosamine impurities being: .

[0044] In a preferred embodiment of the present application, the nitrosamine impurities are when the salt of the compound of Formula A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; when the salt of the compound of Formula A is a mesylate salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm.

[0045] In a preferred embodiment of the present application, the pharmaceutical composition of the compound of Formula A meets one or more of a) - c); a) the pharmaceutical composition comprising the compound of Formula A, after being exposed to 40°C / 75% RH for a period of 3 months, when the salt of the compound of Formula A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the appearance of the pharmaceutical composition is white or off-white; when the salt of the compound of Formula A is a mesylate salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the appearance of the pharmaceutical composition is white or off-white; b) the pharmaceutical composition comprising the compound of Formula A, after being exposed to 40°C / 75% RH for a period of 6 months, when the salt of the compound of Formula A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the appearance of the pharmaceutical composition is white or off-white; when the salt of the compound of Formula A is a mesylate salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the appearance of the pharmaceutical composition is white or off-white; c) the pharmaceutical composition comprising the compound of Formula A, within the shelf life of the drug product, when the salt of the compound of Formula A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the appearance of the pharmaceutical composition is white or off-white; When the salt of the compound of Formula A is a mesylate salt, the content of the nitrosamine impurity in the pharmaceutical composition is less than 0.500 ppm, and the appearance of the pharmaceutical composition is white or white-like.

[0046] In a preferred embodiment of the present application, the pharmaceutical composition is an oral solid preparation or a liquid preparation of the compound of Formula A; preferably, the oral solid preparation is a granule, a tablet or a capsule.

[0047] In a preferred embodiment of the present application, the antioxidant is selected from a water-soluble antioxidant and / or a non-water-soluble antioxidant; the water-soluble antioxidant is selected from cysteine and / or cysteine hydrochloride. Methionine, glutamic acid, acetylcysteine are water-soluble antioxidants equivalent to cysteine or cysteine hydrochloride; the non-water-soluble antioxidant is selected from one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tert-butylhydroquinone, tocopherol, ascorbyl palmitate, dilauryl thiodipropionate or distearyl thiodipropionate; preferably, the antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, ascorbyl palmitate, cysteine hydrochloride and cysteine. Further preferably, the antioxidant is selected from one or both of cysteine hydrochloride and cysteine.

[0048] In a preferred embodiment of the present application, the content of the antioxidant in the pharmaceutical composition is not higher than 10% w / w; preferably, the content of the antioxidant in the pharmaceutical composition ranges from 0.1% to 10% w / w. In some embodiments, the antioxidant is not less than 0.2% or ranges from 0.2% to 10%, from 0.5% to 10%, or 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 6.4%, 7.0%, 7.2%, 8.0%, 9.0%, 10% of the prescription weight (i.e. the weight of the oral solid preparation of the compound of Formula A).

[0049] In a preferred embodiment of the present application, the salt of the compound of Formula A is a hydrochloride salt or a mesylate salt.

[0050] In a preferred embodiment of the present application, the method comprises mixing the compound of Formula A or a salt thereof with one or more antioxidants and excipients, wherein the excipients comprise one or more of the following auxiliary materials ①-⑥: ①. Filler: the filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose, mannitol, calcium hydrogen phosphate, starch, pregelatinized starch and microcrystalline cellulose; (ii) Binder: the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, starch, carbomer, methyl cellulose and gelatin; (iii) pH adjuster: the pH adjuster is selected from one or more of tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate; (iv) Disintegrant: the disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, carboxymethyl cellulose calcium and starch; (v) Glidant: the glidant is selected from one or more of silicon dioxide, talc, hydrogenated vegetable oil, calcium silicate and magnesium silicate; (vi) Lubricant: the lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, sodium docusate.

[0051] In some embodiments, the composition of the oral solid preparation of the compound of Formula A comprises 0.1% to 10% by weight of an antioxidant, 2% to 10% by weight of the compound of Formula A or a salt thereof, 70% to 90% by weight of a filler, 1% to 3% by weight of a pH adjuster, 1% to 3% by weight of a glidant and 2% to 8% by weight of a lubricant.

[0052] In preferred embodiments of the present application, the pharmaceutical composition is a solid preparation or a liquid preparation; preferably, the solid preparation is a granule, a tablet or a capsule.

[0053] In a fourth aspect, the present application provides a use of a nitrosamine impurity in the quality control of a pharmaceutical composition comprising a compound of Formula A, characterized in that the compound of Formula A has the structure , and the nitrosamine impurity has the structure ; When the salt of the compound of Formula A is hydrochloride, the content of the nitrosamine impurity in the pharmaceutical composition is less than 0.375 ppm; When the salt of the compound of Formula A is mesylate, the content of the nitrosamine impurity in the pharmaceutical composition is less than 0.500 ppm.

[0054] In a fifth aspect, the present application provides a preparation method of the pharmaceutical composition of the first or second aspect of the present application, which is a dry preparation process, specifically, a process of directly mixing powders or mixing powders after dry granulation, and then adding excipients to mix and directly package into a powder / granule, or directly filling into a capsule, or compressing into a tablet. Specifically, the preparation method comprises the following steps: a) sieving the compound of formula A or its salt, antioxidant and other individual excipients separately; b) mixing the drug substance with the excipients in a mixer, or after mixing, dry granulation; c) adding additional excipients to the powder or granules obtained in step b) to obtain total powder or total granules; d) directly packaging the total powder or total granules to obtain a powder / granule, or directly filling a capsule, or compressing to obtain a tablet; In some embodiments, the preparation process comprises the following steps: a) excipient treatment: sieving the glidant through an 80 mesh sieve, and grinding the pH adjuster and sieving the fine powder through an 80 mesh sieve for later use; b) premixing: mixing the pH adjuster and the filler in equal increments in a stirring mixer to obtain powder 1; mixing the antioxidant and the glidant, then adding the compound of formula A or its salt, and then adding the filler in a stirring mixer to obtain powder 2; mixing powder 1 and powder 2 in a stirring mixer, and then adding the glidant and the lubricant to obtain powder 3; c) total mixing: adding the powder 3 to a mixer, and then adding the glidant and the lubricant to obtain total powder; d) product preparation: packaging the total powder to obtain a powder, or filling a capsule, or directly compressing to obtain a tablet.

[0055] In the above preparation process, the antioxidant used is a non-water-soluble stabilizer selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, and ascorbyl palmitate. Preferably, the antioxidant is ascorbyl palmitate.

[0056] In some embodiments, the preparation process comprises the following steps: a) excipient treatment: sieving the glidant through an 80 mesh sieve, and grinding the pH adjuster and sieving the fine powder through an 80 mesh sieve for later use; b) premixing: mixing the pH adjuster and the filler in equal increments in a stirring mixer to obtain powder 1; mixing the antioxidant and the glidant, then adding the compound of formula A or its salt, and then adding the filler in a stirring mixer to obtain powder 2; mixing powder 1 and powder 2 in a stirring mixer, and then adding the glidant and the lubricant to obtain powder 3; c) granulation: granulating the powder 3 in a dry granulator to obtain drug-containing granules; d) total mixing: adding silicon dioxide and talc to the drug-containing granules, and then compressing to obtain a tablet of the compound of formula A.

[0057] In some embodiments, the present application provides a method for preparing the pharmaceutical composition of the first or second aspect of the present application, and the method is a wet process.

[0058] The inventors found during the research that when the compound of formula A is prepared by a dry process, the compound of formula A is very hygroscopic, and the uneven distribution of the compound of formula A in the preparation process is prone to cause yellow spots on the surface of the tablet.

[0059] In the large-scale production process, the compound of formula A can be dissolved by using a wet process, which greatly improves the uniformity of the distribution of the compound of formula A in the preparation, and avoids the uneven distribution of the API caused by the hygroscopicity of the compound of formula A in the dry process, and the yellow spot phenomenon. In the wet process, the nitrosamine impurity is gradually generated when the hydrochloride salt and the mesylate salt of the compound of formula A exist in the solution state in water, and the nitrosamine impurity gradually increases with the extension of the storage time. In order to avoid the increase of the nitrosamine impurity, a water-soluble antioxidant is preferably selected from one or more of cysteine, hydrochloric acid cysteine, methionine, glutamic acid, acetylcysteine, ascorbic acid, oxalic acid, tartaric acid, propionic acid, malonic acid, thiopropionic acid, glucuronic acid, galacturonic acid or sorbitol; specifically, hydrochloric acid cysteine or cysteine is preferably used.

[0060] Specifically, in the preferred embodiments of the present application, the wet process comprises the following steps: (1) Pre-mixing Mixing the raw material drug of the compound of formula A with the antioxidant and part of the pharmaceutical excipients; (2) Granulation Granulating by using a wet granulation method to obtain granules, and then drying and granulating; (3) Total mixing Adding the granules prepared in step (2) to the glidant or lubricant and mixing uniformly; (4) Tabletting or capsule filling Tabletting or directly filling the mixture prepared in step (3).

[0061] In some specific embodiments, the preparation process comprises the following steps: (1) Dissolution of the raw material drug: Dissolving the hydrochloride salt of the compound of formula A, the antioxidant and the pH adjuster in water to obtain a liquid; (2) Granulation Mixing the filler in a wet granulator, adding the liquid in step (1) for wet granulation, and then drying and granulating; (3) Total mixing Adding the dry granules obtained in step (2) to the glidant or lubricant and mixing uniformly; (4) tabletting or potting capsule The mixture prepared in step (3) is tabletted or directly potted.

[0062] In the above wet preparation process, the antioxidant used is preferably a water-soluble antioxidant selected from one or more of vitamin C, cysteine hydrochloride, cysteine; preferably, the water-soluble antioxidant is selected from one or both of cysteine hydrochloride and cysteine.

[0063] Detection of genotoxic impurities, nitrosamine impurities Instrument: Agilent 6470 QQQ liquid chromatograph-mass spectrometer.

[0064] Determination by high performance liquid chromatography, mass spectrometry (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0512, 0431).

[0065] Solvent: water-acetonitrile (10:90).

[0066] The test solution is freshly prepared. An appropriate amount of the product is accurately weighed, dissolved in solvent and quantitatively diluted to prepare a solution containing about 0.2 mg per 1 ml.

[0067] The control solution is prepared by accurately weighing an appropriate amount of nitrosamine impurity control, dissolving in solvent and quantitatively diluting to prepare a solution containing about 0.075 ng of nitrosamine impurity per 1 ml.

[0068] Chromatographic conditions: HILIC C as the filler (such as: ACQUITY UPLC BEH HILIC 1.7 μm, 2.1 x 50 mm or a chromatographic column with equivalent performance), water-acetonitrile-formic acid (10:90:0.1) containing 5 mmol / L ammonium formate as the mobile phase; flow rate is 0.2 ml per minute; column temperature is 35°C; injection volume is 5 μl; sample tray temperature is 4°C.

[0069] Mass spectrometry conditions (reference instrument model: Agilent 6470 QQQ liquid chromatograph-mass spectrometer, parameters can be adjusted according to the specific instrument to meet the detection requirements): ESI+, MRM mode, ion pair 166→93, Dwell 200, Fragmentor 60 (V), CCollision Energy 10 (V), CellAccelerator Voltage 5 (V), carrier gas temperature 300°C, carrier gas flow rate 10 L per minute, atomizer pressure 45 psi, sheath gas temperature 250°C, sheath gas flow rate 11 L per minute, capillary voltage 3500 V, nozzle voltage 500 V.

[0070] Switching valve:

[0071] The test solution and the control solution are precisely measured and injected into the liquid chromatograph, respectively, and the mass spectrum is recorded.

[0072] Limit If there are impurity peaks in the test solution mass spectrum, the nitrosamine impurities in the hydrochloride formulation of the compound of formula A should not be more than 0.0000375% and the nitrosamine impurities in the methanesulfonate compound of formula A should not be more than 0.00005% by peak area calculation according to the external standard method.

[0073] Test Example 1 Test Example 1-1 Prepare 1000 tablets according to the following table.

[0074] Table 1-1

[0075] Preparation process of Test Example 1-1: (1) Dissolve the compound of formula A hydrochloride and citric acid in water as a granulation wetting agent; (2) Mix microcrystalline cellulose, mannitol, and ascorbic palmitate in a wet granulator, and add the wetting agent for wet granulation; (3) Dry the wet granules obtained in step (2) in a fluidized bed dryer at an inlet temperature of 60°C until the moisture content is not more than 1.5%, and then size the granules; (4) Add silicon dioxide and talc to the dry granules obtained in step (3) and mix; (5) Tablet, and prepare the compound of formula A hydrochloride tablets.

[0076] Test Examples 1-2 to 1-4 Prepare 1000 tablets according to the following table.

[0077] Table 1-2

[0078] Preparation process of Test Examples 1-2 to 1-4: (1) Grind citric acid through an 80-mesh screen, treat silicon dioxide through an 80-mesh screen, and treat the compound of formula A hydrochloride and other excipients through a 60-mesh screen for use; (2) Mix all the components treated by sieving, tablet, and prepare the compound of formula A hydrochloride tablets.

[0079] Test Examples 1-5 to 1-6 Prepare 1000 tablets according to the following table.

[0080] Table 1-3

[0081] Test Example 1-5 to 1-6 Preparation Process: (1) Citric acid was ground to pass through an 80 mesh sieve, and the silicon dioxide was passed through an 80 mesh sieve. The hydrochloride salt of the compound of Formula A and other excipients were passed through a 60 mesh sieve and were ready for use; (2) The components for dry granulation after sieving were mixed and put into a dry granulator to obtain granules; (3) The granules were mixed with additional silicon dioxide and talc and then tableted.

[0082] Test Example 1-7 to 1-8 Tablets were prepared in a batch size of 1000 tablets according to the following table.

[0083] Table 1-4

[0084] Test Example 1-7 Preparation Process: (1) The compound of Formula A methanesulfonate, microcrystalline cellulose, mannitol, and crospovidone were mixed in a wet granulator, and a wetting agent was added to obtain wet granules; (2) The wet granules obtained in step (2) were dried in a fluidized bed dryer at an inlet temperature of 60°C until the moisture content was less than 1.5%, and then the granules were sized; (3) The dry granules obtained in step (3) were mixed with silicon dioxide, calcium stearate, and lemon flavor; (4) The mixture was tableted to obtain tablets of the compound of Formula A methanesulfonate.

[0085] Test Example 1-8 Preparation Process: (1) The compound of Formula A methanesulfonate, microcrystalline cellulose, mannitol, crospovidone, and ascorbyl palmitate were mixed in a wet granulator, and a wetting agent was added to obtain wet granules; (2) The wet granules obtained in step (2) were dried in a fluidized bed dryer at an inlet temperature of 60°C until the moisture content was less than 1.5%, and then the granules were sized; (3) The dry granules obtained in step (3) were mixed with silicon dioxide, calcium stearate, and lemon flavor; (4) The mixture was tableted to obtain tablets of the compound of Formula A methanesulfonate.

[0086] Test Example 1-9 to 1-10 Tablets were prepared in a batch size of 1000 tablets according to the following table.

[0087] Table 1-5

[0088] Test Example 1-9 to 1-10 Preparation Process: (1) The silica was passed through an 80-mesh sieve, the compound of Formula A mesylate salt and other excipients were passed through a 60-mesh sieve, and were reserved; (2) The above components were mixed uniformly, and the compound of Formula A mesylate salt tablets were prepared.

[0089] Stability Study (1) Accelerated stability study and influence factor condition study The compound of Formula A hydrochloride salt tablets and the compound of Formula A mesylate salt tablets obtained in Test Example 1-1 to 1-10 were placed in the influence factor study at 40°C and 60°C, respectively, to investigate the change in nitrosamine impurities, as shown in Table 1-6, and the change in nitrosamine impurities of Test Example 1-5, Test Example 1-9 and the compound of Formula A tablet reference preparation under accelerated conditions at 40°C / 75% RH, as shown in Table 1-7.

[0090] Table 1-6 Change in nitrosamine impurities of the compound of Formula A tablet under high temperature conditions

[0091] Table 1-7 Change in nitrosamine impurities of some test examples and reference preparations under accelerated conditions

[0092] From the above table of nitrosamine impurity detection results, it can be seen that: After adding an antioxidant to the prescription composition of the compound of Formula A tablet, the tablet was placed at 40°C and 60°C for 30 days, which could significantly inhibit the increase of nitrosamine impurities, and even had no increasing trend.

[0093] Test Example 2 The compound of Formula A hydrochloride salt tablets were prepared in a batch of 1000 tablets according to the following table.

[0094] Table 2-1

[0095] Comparative Example 2-1 (1) Dissolution of the raw material drug: the compound of Formula A hydrochloride salt and citric acid were dissolved in water as a wetting agent for granulation; (2) The microcrystalline cellulose and mannitol were mixed uniformly in a wet granulator, and the wetting agent was added for wet granulation; (3) The wet granules obtained in step (2) were dried in a fluidized bed, and the inlet air temperature was 60°C, and the moisture content was less than 1.5%, and then the granules were sized; (4) The dry granules obtained in step (3) were mixed with silica and talc; (5) The tablets were compressed to prepare the compound of Formula A hydrochloride salt tablets.

[0096] Test Example 2-1 (1) Dissolution of raw material: Dissolve the compound of Formula A hydrochloride and citric acid in water, and use as a wetting agent for granulation; (2) Mix microcrystalline cellulose, mannitol, and ascorbic palmitate in a wet granulator, and add a wetting agent to perform wet granulation; (3) Dry the wet granules obtained in step (2) using a fluidized bed dryer at an inlet temperature of 60°C until the moisture content is not more than 1.5%, and then perform size adjustment; (4) Add silicon dioxide and talc to the dry granules obtained in step (3), and mix; (5) Tablet, and produce tablets of the compound of Formula A hydrochloride.

[0097] Test Example 2-2 (1) Dissolution of raw material: Dissolve the compound of Formula A hydrochloride, citric acid, and vitamin C in water, and use as a wetting agent for granulation; (2) Mix microcrystalline cellulose and mannitol in a wet granulator, and add a wetting agent to perform wet granulation; (3) Dry the wet granules obtained in step (2) using a fluidized bed dryer at an inlet temperature of 60°C until the moisture content is not more than 1.5%, and then perform size adjustment; (4) Add silicon dioxide and talc to the dry granules obtained in step (3), and mix; (5) Tablet, and produce tablets of the compound of Formula A hydrochloride.

[0098] Test Examples 2-3 to 2-8 The procedure of Test Example 2-2 was followed, except that the amount of vitamin C was replaced with the amount of cysteine hydrochloride.

[0099] Test Example 2-9 The procedure of Test Example 2-2 was followed, except that the amount of vitamin C was replaced with the amount of cysteine.

[0100] Stability Study (1) Accelerated stability study and influence factor condition study The compound of Formula A hydrochloride tablets obtained in Test Example 2 were placed in the influence factor study at 40°C and 60°C, respectively, to investigate the change in nitrosamine impurities, as shown in Table 2-2, and the change in nitrosamine impurities of Test Example 2-3, Test Example 2-4, and Test Example 2-5 under accelerated conditions at 40°C / 75% RH, as shown in Table 2-2 and Table 2-3 and Figure 1 and Figure 3 .

[0101] Table 2-2 Change in nitrosamine impurities of Test Example 2 under high temperature conditions

[0102] Table 2-3 Accelerated 40°C / 75%RH condition nitrosamine impurity stability

[0103] Both vitamin C and ascorbyl palmitate can inhibit the growth of nitrosamine impurities in the tablets, but vitamin C and ascorbyl palmitate prepared tablets, the appearance of the tablet color obvious change.

[0104] Cysteine hydrochloride and cysteine can inhibit the growth of nitrosamine impurities at the same time, can keep the appearance of the tablet no obvious change.

[0105] The tablets were placed under accelerated 40°C / 75%RH conditions for 6 months, when the amount of cysteine hydrochloride was too low, the nitrosamine impurities had a risk of exceeding 0.375 ppm; if the amount of cysteine hydrochloride was too high, the tablets had a tendency to become light yellow.

[0106] Cysteine hydrochloride in the range of 0.5-16 mg / tablet (0.5%-6.4% w / w relative to the total tablet weight) can effectively inhibit the growth of nitrosamine impurities.

[0107] From Figure 3 It can be seen that the results show that the nitrosamine impurities of the compound of formula A hydrochloride tablets placed under accelerated test conditions (40°C / 75%RH) for 6 months have no significant change, and meet the quality control limit requirements.

[0108] The nitrosamine impurities of the compound of formula A are greatly affected by temperature and humidity, and grow rapidly under high temperature and high humidity conditions. The nitrosamine impurities of test examples 2-3, 2-4 and 2-5 have no significant change compared with those of 0 months, and are less than the limit value after being placed under high temperature and humidity conditions for 6 months. As can be seen from Table 1-7, the nitrosamine impurities of the reference formulation grow many times under accelerated conditions. According to the growth trend of the nitrosamine impurities of the product, it can be known that the amount of nitrosamine impurities is less than 0.375 ppm after the pharmaceutical composition is exposed to 40°C / 75%RH for 6 months and throughout the 36-month effective period. The content of nitrosamine impurities still meets the requirements.

[0109] The results prove that the formulations of test examples 2-3, 2-4, 2-5 and 2-7 can effectively control the growth of nitrosamine impurities, and the formulations of test examples are superior to the reference formulation, especially under accelerated conditions.

[0110] Test Example 3 A batch of 1000 tablets of the compound of formula A mesylate was prepared according to the following table.

[0111] Table 3-1

[0112] Comparative Example 3-1 (1) The compound of formula A methanesulfonate, microcrystalline cellulose and hydroxypropyl methyl cellulose were mixed in a wet granulator, and a wetting agent was added for wet granulation; (2) The wet granules prepared in step (2) were dried in a fluidized bed dryer at an inlet temperature of 60°C until the moisture content was less than 1.5%, and then the granules were sized; (3) The dry granules prepared in step (3) were mixed with silicon dioxide, talc and calcium stearate; (4) The mixture was tabletted to produce the compound of formula A methanesulfonate tablets.

[0113] Test Example 3-1 (1) The compound of formula A methanesulfonate, microcrystalline cellulose, hydroxypropyl methyl cellulose and ascorbyl palmitate were mixed in a wet granulator, and a wetting agent was added for wet granulation; (2) The wet granules prepared in step (2) were dried in a fluidized bed dryer at an inlet temperature of 60°C until the moisture content was less than 1.5%, and then the granules were sized; (3) The dry granules prepared in step (3) were mixed with silicon dioxide, talc and calcium stearate; (4) The mixture was tabletted to produce the compound of formula A methanesulfonate tablets.

[0114] Test Example 3-2 (1) The compound of formula A methanesulfonate and cysteine hydrochloride were dissolved in water as a wetting agent for granulation; (2) The microcrystalline cellulose and hydroxypropyl methyl cellulose were mixed in a wet granulator, and a wetting agent was added for wet granulation; (3) The wet granules prepared in step (2) were dried in a fluidized bed dryer at an inlet temperature of 60°C until the moisture content was less than 1.5%, and then the granules were sized; (4) The dry granules prepared in step (3) were mixed with silicon dioxide, talc and calcium stearate; (5) The mixture was tabletted to produce the compound of formula A methanesulfonate tablets.

[0115] Test Examples 3-3 to 3-4 The procedure of Test Example 3-2 was followed, except that the amount of cysteine hydrochloride was varied.

[0116] Table 3-2 Results of the influence factor test

[0117] The results of the stability test of Test Example 3 are shown in Table 3-2 and Figure 2Similar to the results of the study of the hydrochloride salt tablets of the compound of Formula A, ascorbyl palmitate can inhibit the growth of nitrosamine impurities in the methanesulfonate salt tablets of the compound of Formula A, but it is not stable at high temperatures and is easily oxidized to yellow, and the appearance of the tablets changes significantly. Hydrochloric cysteine and cysteine can inhibit the growth of nitrosamine impurities while maintaining the appearance of the tablets.

[0118] Hydrochloric cysteine in the range of 2-6 mg / tablet (1.0% to 3.0% w / w relative to the total tablet weight) can effectively inhibit the growth of nitrosamine impurities.

[0119] The reference formulation was placed under accelerated research conditions (40°C / 75% RH) and long-term research conditions (30°C / 65% RH) in the drug stability study, and the content of nitrosamine impurities in the tablets increased further with time. The results are shown in Table 4-1.

[0120] Table 4-1 Growth of nitrosamine impurities in the reference formulation of the compound of Formula A in the stability study

[0121] When the hydrochloride salt and the methanesulfonate salt of the compound of Formula A exist in the form of a solution in water, nitrosamine impurities will gradually be generated, and the content of nitrosamine impurities will gradually increase with the extension of the storage time. The growth rate of the nitrosamine impurities is shown in Table 4-2.

[0122] Table 4-2 Stability of API test solution at room temperature

[0123] Comparative Example 1: The hydrochloride salt tablets of the compound of Formula A were prepared according to Example 1 of the patent CN111249237A. The preparation process is as follows: (1) Dissolution of the raw material drug: dissolve the hydrochloride salt of the compound of Formula A and citric acid in water as a wetting agent for granulation; (2) Mix microcrystalline cellulose and mannitol in a wet granulator, and add a wetting agent for wet granulation; (3) Dry the wet granules obtained in step (2) in a fluidized bed dryer at an inlet temperature of 55°C until the moisture content is not more than 3.0%, and then perform size reduction; (4) Mix the dry granules obtained in step (3) with silicon dioxide and talc; (5) Tablet compression to prepare the hydrochloride salt tablets of the compound of Formula A.

[0124] The weights of the raw and auxiliary materials used to prepare the above-mentioned 1000 tablets of the compound of Formula A are shown in the following table: Table 5

[0125] Comparative Example 2: The compound of formula A methanesulfonate salt orally disintegrating tablet was prepared according to the patent CN101797237A example 1, and the preparation process was as follows: (1) The compound of formula A methanesulfonate salt and other all auxiliary materials were crushed into fine powder with fineness above 80 mesh; (2) All the components after crushing were mixed uniformly, and then tabletting was carried out to prepare the compound of formula A methanesulfonate salt orally disintegrating tablet.

[0126] The weights of the raw and auxiliary materials used for preparing the above 1000 tablets of the compound of formula A were shown in the following table: Table 6

[0127] The changes of nitrosamine impurities of the compound of formula A hydrochloride tablet and the compound of formula A methanesulfonate salt tablet obtained in the above comparative examples 1-2 were investigated under the conditions of 40℃ and 60℃ in the influence factor study, and the results were shown in the following table.

[0128] Table 7

[0129] Comparative examples 3-5 The tablets with a batch size of 1000 tablets were prepared according to the following table.

[0130] Table 8

[0131] Preparation process of comparative examples 3-5: (1) The compound of formula A hydrochloride, microcrystalline cellulose, mannitol, citric acid and optional antioxidants (sodium pyrosulfite or dibutyl hydroxytoluene) were mixed uniformly in a wet granulator, and a wetting agent was added for wet granulation; (2) The wet granules prepared in step (2) were dried in a fluidized bed dryer with an inlet temperature of 60℃, and the moisture content was less than 1.5% after drying, and then the granules were sized; (3) The dry granules obtained in step (3) were mixed with silicon dioxide and talc; (4) Tabletting was carried out to prepare the compound of formula A hydrochloride tablet.

[0132] The results of the influence factor test of each comparative example were shown in the following table.

[0133] Table 9

[0134] After the preparations prepared with sodium pyrosulfite or dibutyl hydroxytoluene were placed at high temperature of 60℃ for 30 days, the nitrosamine impurities increased significantly, which exceeded the quality control requirements. The use of pH adjuster could not inhibit the increase of nitrosamine impurities in the preparation.

[0135] Comparative Example 6-9: The weight of the raw and auxiliary materials for preparing 1000 tablets of the hydrochloride salt of the compound of Formula A is shown in the following table using glycerin and linoleic acid as antioxidants: Table 10

[0136] Preparation process of Comparative Example 6: (1) The microcrystalline cellulose and mannitol were premixed after being treated with a 50-mesh sieve and reserved; (2) Preparation of the wetting agent: the raw drug of the hydrochloride salt of the compound of Formula A and citric acid were weighed and dissolved by stirring after being added to purified water; (3) Preparation of the glycerin solution: the prescribed amount of glycerin was weighed and dissolved by stirring after being added to anhydrous ethanol; (4) Hand wet granulation: the wetting agent was first added for wet granulation, and then the glycerin ethanol solution was added. After granulation, the soft material was sieved with a 20-mesh steel wire to make the granules, which were then dried in an oven at 60°C.

[0137] (5) The dried granules were sieved, and talc and silicon dioxide were added in proportion to mix uniformly to obtain the total mixed powder.

[0138] (6) Tabletting.

[0139] Preparation process of Comparative Example 7: (1) The microcrystalline cellulose and mannitol were premixed after being treated with a 50-mesh sieve and reserved; (2) Preparation of the wetting agent: the raw drug of the hydrochloride salt of the compound of Formula A and citric acid were weighed and dissolved by stirring after being added to purified water; (3) Preparation of the conjugated linoleic acid solution: the prescribed amount of conjugated linoleic acid was weighed and dissolved by stirring after being added to anhydrous ethanol; (4) Hand wet granulation: the wetting agent was first added for wet granulation, and then the conjugated linoleic acid ethanol solution was added. After granulation, the soft material was sieved with a 20-mesh steel wire to make the granules, which were then dried in an oven at 60°C.

[0140] (5) The dried granules were sieved, and talc and silicon dioxide were added in proportion to mix uniformly to obtain the total mixed powder.

[0141] (6) Tabletting.

[0142] Preparation process of Comparative Examples 8-9: (1) The microcrystalline cellulose and mannitol were premixed after being treated with a 50-mesh sieve and reserved; (2) Preparation of the wetting agent: the raw drug of the hydrochloride salt of the compound of Formula A and citric acid were weighed and dissolved by stirring after being added to purified water; (3) Preparation of the conjugated linoleic acid and glycerin solution: the prescribed amount of conjugated linoleic acid and glycerin was weighed and dissolved by stirring after being added to anhydrous ethanol; (4) Hand wet granulation: first add wetting agent to wet granulation, then add conjugated linoleic acid and glycerol ethanol solution, after granulation, soft material is passed through 20 mesh steel screen to make whole grain, and then dried in 60 °C oven.

[0143] (5) The dried granules are made into whole grain, and talc and silicon dioxide are added in proportion to make total mixed powder.

[0144] (6) Tabletting.

[0145] The results of the influence factor test of Comparative Examples 6-9 are shown in the following table.

[0146] Table 11

[0147] The solid particles prepared using conjugated linoleic acid have poor flowability, small bulk density, and poor compressibility, and are not suitable for preparing solid tablets.

[0148] The results show that the addition of conjugated linoleic acid has no significant inhibitory effect on the nitrosamine impurity content in the hydrochloride salt tablet of the compound of Formula A. The nitrosamine impurity in the 0-day sample exceeds the limit, and there is a significant growth trend after 5 days of storage at high temperature of 60 °C. Moreover, the appearance of the tablet changes from white to white to light yellow.

[0149] At the same time, conjugated linoleic acid is not soluble in water, and if a solution is to be prepared, a concentration of more than 70% ethanol solution needs to be added to achieve better dispersion or dissolution. It is not possible to prepare a clear solution using 10% ethanol.

[0150] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. In addition, different embodiments or examples described in the present specification and the features of different embodiments or examples can be combined and combined by those skilled in the art without contradiction.

[0151] Although the embodiments of the present application have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above embodiments within the scope of the present application.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound of formula A or a salt thereof, and an antioxidant, wherein the structure of the compound of formula A is as follows: The antioxidant is selected from water-soluble antioxidants or non-water-soluble antioxidants; the water-soluble antioxidant is selected from cysteine ​​and / or cysteine ​​hydrochloride; the non-water-soluble antioxidant is selected from one or more of butylated hydroxyanisole, propyl gallate, and ascorbyl palmitate.

2. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is an oral solid dosage form of compound A or a liquid dosage form of compound A; the oral solid dosage form is granules, tablets or capsules.

3. The pharmaceutical composition according to claim 1, characterized in that, The salt of compound A is a hydrochloride or methanesulfonate.

4. The pharmaceutical composition according to claim 1, characterized in that, The antioxidant is present in the pharmaceutical composition at a weight content of not less than 0.2% w / w.

5. The pharmaceutical composition according to claim 1, characterized in that, The antioxidant is present in the pharmaceutical composition at a concentration ranging from 0.2% to 6.4% w / w.

6. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further comprises other excipients selected from one or more of ① to ⑥: ① Filler: The filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose, mannitol, dicalcium phosphate, starch, pregelatinized starch and microcrystalline cellulose; ② Adhesive: The adhesive is selected from one or more of hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, starch, carbomer, methylcellulose and gelatin; ③ pH adjuster: The pH adjuster is selected from one or more of the following: tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate. ④ Disintegrant: The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, calcium carboxymethyl cellulose and starch; ⑤ Glide aid: The glide aid is selected from one or more of silica, talc, hydrogenated vegetable oil, calcium silicate and magnesium silicate; ⑥ Lubricant: The lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearate fumarate, glyceryl behenate, and sodium docusate.

7. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition satisfies one or more of a)-c); a) After the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 3 months, When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance; When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance; b) After the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 6 months, When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance; When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance; c) The pharmaceutical composition containing compound A is within its shelf life. When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance; When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm, and the pharmaceutical composition has a white or off-white appearance.

8. An oral solid dosage form, characterized in that, It includes a compound of formula A or its salt and a non-inorganic salt antioxidant, wherein the structure of the compound of formula A is as follows: The non-inorganic salt antioxidant is selected from one or more of propyl gallate, butylated hydroxyanisole, vitamin C, ascorbyl palmitate, cysteine ​​hydrochloride, and cysteine.

9. The oral solid dosage form according to claim 8, characterized in that, The salt of compound A is a hydrochloride or a methanesulfonate.

10. The oral solid dosage form according to any one of claims 8 or 9, characterized in that, The antioxidant constitutes no less than 0.1% w / w of the prescription weight.

11. The oral solid dosage form according to any one of claims 8 or 9, characterized in that, The oral solid dosage form comprises 0.1% to 10% by weight of a non-inorganic salt antioxidant, 2% to 10% by weight of a compound of formula A or a salt thereof, 70% to 90% by weight of a filler, 1% to 3% by weight of a pH adjuster, 1% to 3% by weight of a flow aid, and 2% to 8% by weight of a lubricant. The filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose, mannitol, dicalcium phosphate, starch, pregelatinized starch, and microcrystalline cellulose; and / or The pH adjuster is selected from one or more of the following: tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate; and / or The flow aid is selected from one or more of silica, talc, and hydrogenated vegetable oil; and / or The lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearate fumarate, glyceryl behenate, and sodium docusate.

12. The oral solid dosage form according to any one of claims 8 or 9, characterized in that, The oral solid dosage form is prepared using either a dry process or a wet process.

13. A method for controlling the content of nitrosamine impurities in a pharmaceutical composition comprising a compound of formula A or a salt thereof, characterized in that, The method includes mixing a compound of formula A or a salt thereof with one or more antioxidants, wherein the compound of formula A has the following structure: The nitrosamine impurity is: The antioxidant is selected from water-soluble antioxidants and / or non-water-soluble antioxidants; the water-soluble antioxidant is selected from cysteine ​​and / or cysteine ​​hydrochloride; the non-water-soluble antioxidant is selected from one or more of butylated hydroxyanisole, propyl gallate, and ascorbyl palmitate.

14. The method according to claim 13, characterized in that, When the salt of compound A is a hydrochloride salt, the content of nitrosamine in the pharmaceutical composition is less than 0.375 ppm; When the salt of compound A is a methanesulfonate, the content of nitrosamine in the pharmaceutical composition is less than 0.500 ppm.

15. The method according to claim 13, characterized in that, The pharmaceutical composition of formula A satisfies one or more of a)-c); a) After the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 3 months, When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance; When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance; b) After the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 6 months, When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition is white or off-white in appearance; When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance; c) The pharmaceutical composition containing compound A is within its shelf life. When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition is white or off-white in appearance. When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm, and the pharmaceutical composition has a white or off-white appearance.

16. The method according to claim 13, characterized in that, The antioxidant is present in the pharmaceutical composition at a weight content of not less than 0.5% w / w.

17. The method according to claim 13, characterized in that, The antioxidant is present in the pharmaceutical composition at a weight range of 0.2%-6.4% w / w.

18. The use of a nitrosamine impurity in the quality control of a pharmaceutical composition containing compound A, characterized in that, The structure of compound A is as follows: The structure of the nitrosamine impurity is as follows: ; When the salt of compound A is hydrochloric acid, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm.

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