CN115721724A

CN115721724A - Pharmaceutical composition containing secondary amine compound and preparation and application thereof

Info

Publication number: CN115721724A
Application number: CN202211034242.3A
Authority: CN
Inventors: 魏彦君; 巴萨瓦拉杰·希达贡纳瓦; 孙中亚; 杜文峰; 裴慧; 王建; 邢艳平; 刘艳; 胡青燕
Original assignee: Shandong Viwit Baike Pharmaceutical Co ltd; Weizhi Pharmaceutical Co ltd; Shandong Weizhi Zhongke Pharmaceutical Co ltd
Current assignee: Shandong Viwit Baike Pharmaceutical Co ltd; Weizhi Pharmaceutical Co ltd; Shandong Weizhi Zhongke Pharmaceutical Co ltd
Priority date: 2021-08-27
Filing date: 2022-08-26
Publication date: 2023-03-03
Also published as: CN115721625A

Abstract

The invention discloses a pharmaceutical composition containing a secondary amine compound, and preparation and application thereof. According to the pharmaceutical composition, the pharmaceutically acceptable acid is added into the secondary amine compound or the composition thereof, so that the generation of nitrosamine impurities can be effectively inhibited and reduced, the stability of the secondary amine compound or the composition thereof is improved, the content of the nitrosamine impurities is controlled at a low level, and the pharmaceutical composition meets the safety requirement.

Description

Pharmaceutical composition containing secondary amine compound and preparation and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition containing a secondary amine compound, and preparation and application thereof.

Background

Nitrosamine compounds, which contain nitroso (N (R1) (R2) -N = O) structures, are genotoxic substances in certain animals, some of which have been classified as possible or potential human carcinogens by the international agency for research on cancer (IARC). These nitrosamine compounds, referred to as "focus group" compounds in the International Conference on harmony (ICH) directive document M7 (R1) for human drug registration technology, evaluate and control DNA reactive (mutagenic) impurities in pharmaceutical products to limit potential carcinogenic risks (3 months 2018). ICH guidelines suggest that any known mutagenic/carcinogenic agent, including nitrosamine compounds, be controlled at levels of uptake where the risk of cancer in humans is negligible.

Currently, seven nitrosamine impurities have been identified by the U.S. Food and Drug Administration (FDA), which may theoretically be present in pharmaceutical products because of the use of manufacturing processes and materials that may lead to the formation of nitrosamines: n, N-dimethylnitrosamine (NDMA), N-Nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-Nitrosoisopropylamine (NIPEA), N-Nitrosodiisopropylamine (NDIPA), N-Nitrosodibutylamine (NDBA) and N-Nitrosomethylaniline (NMPA). Of these, five impurities (NDMA, NDEA, NMBA, NIPEA and NMPA) have been actually detected in bulk drugs or medicines.

For example, some preliminary results of FDA testing indicate that the NDMA content in certain ranitidine products has exceeded acceptable levels. In recent years, the FDA has also found that metformin products contain NDMA impurities, and in certain batches NDMA levels above the FDA recommended acceptable intake limits have been detected.

Currently, some studies have attempted to control and reduce the formation of these nitrosamine impurities by technical means, such as: CN 109748905A uses hydrogen peroxide to replace sodium nitrite, so as to reduce the content of NDMA and NDEA in sartan bulk drugs; CN 111686087A adopts the powder mixing and direct pressing process and the gastric-soluble film coating premix for coating, thereby avoiding excessive heat generated in the production process and reducing the risk of NDMA generation; CN 113081990A controls the content of N-Nitrosodimethylamine (NDMA), a genotoxic impurity, by controlling the content of dimethylamine, an impurity in metformin hydrochloride, and the content of nitrite, an impurity in hypromellose, as an auxiliary material.

For example, vancolan, an aryl fused azapolycyclic compound that modulates cholinergic energy, is sold as the tartrate salt under the trade name Vancolan

Or

Can bind to specific receptor sites of neuronal nicotinic acetylcholine and can be used for the following diseases:

treatment of inflammatory bowel diseases (including but not limited to:ulcerative colitis, pyoderma gangrenosum and Crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, diarrhea (celiac disease), cystitis (pouchitis), vasoconstriction, anxiety, panic disorder (panic disorder), depression, bipolar disorder (bipolar disorder), autism, sleep disorders, jet lag (jet lag), amyotrophic Lateral Sclerosis (ALS), cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., due to alcohol, barbiturates, vitamin deficiencies, recreational drugs (cognitive drug), lead, arsenic, mercury), disease-induced cognitive impairment (e.g., caused by Alzheimer's disease (Alzheimer's disease), vascular dementia (vascular dementia), parkinson's disease, multiple sclerosis, AIDS, (macro) encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, pick's disease, korsakoff's syndrome and prefrontal and subcortical dementia (subcortical dementia)), hypertension, bulimia, anorexia, obesity, arrhythmia, hyperacidity, ulcers, pheochromocytoma, progressive supranuclear palsy (progressive subaccular palsy), chemical dependence and addiction (e.g. to nicotine (and/or tobacco products), alcohol, benzodiazepines

Class(s), barbiturates, opiate or cocaine dependence and addiction), headache, migraine, stroke, traumatic Brain Injury (TBI), obsessive-compulsive disorder (OCD), psychosis, huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multiple sclerosis dementia, age-related cognitive decline, epilepsy, including seizure deficiency epilepsy (epilepsy), attention Deficit Hyperactivity Disorder (ADHD), tourette's Syndrome; in particular, nicotine dependence, addiction and withdrawal, including use in smoking cessation therapy (see: CN 1509174A).

In particular to the present invention in the sense that,

for secondary amine compounds, such as varenicline or pharmaceutically acceptable salts, crystal forms, solvates, compositions, formulations, and other pharmaceutical compounds thereof, there may also be a problem of excessive levels of nitrosamine impurities.

Therefore, there is also a need to detect and control nitrosamine impurities in secondary amine compounds, such as varenicline or pharmaceutically acceptable salts, crystal forms, solvates, compositions, formulations, and other pharmaceutical compounds.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

In view of the problems and/or disadvantages of the prior art, it is an object of the present invention to provide a pharmaceutical composition comprising a secondary amine compound. According to the pharmaceutical composition, the pharmaceutically acceptable acid is added into the secondary amine compound or the composition thereof, so that the generation of nitrosamine impurities can be effectively inhibited and reduced, the stability of the secondary amine compound or the composition thereof is improved, the content of the nitrosamine impurities is controlled at a low level, and the pharmaceutical composition meets the safety requirement.

The invention provides a pharmaceutical composition, which comprises the following components: a secondary amine compound and a pharmaceutically acceptable acid; wherein the secondary amine compound is the following compound or a pharmaceutically acceptable salt thereof, a crystal form of any one of the foregoing (referring to the foregoing compound or the pharmaceutically acceptable salt thereof), or a solvate of any one of the foregoing (referring to the foregoing compound or the pharmaceutically acceptable salt thereof):

further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the secondary amine compound is a salt, a crystal form or a solvate thereof formed by the following compound and a pharmaceutically acceptable acid:

serial number	Name of Chinese	Serial number	Name of Chinese
				1	Pabociclib	23	Imatinib
2	Salmeterol	24	Hydrochlorothiazide
				3	Pemetrexed	25	Sertraline
4	Dabigatran etexilate	26	Atenolol
				5	Mirabegron	27	Bupropion derivatives
6	Ticagrelor	28	Paroxetine
				7	Venetolara	29	Sulfamethoxazole
8	Simpinicline	30	Methylphenidate
				9	Duloxetine	31	Benzonatate and its preparation
10	Salbutamol	32	Diclofenac acid
				11	Rilpivirine	33	Enalapril
12	Aforana	34	Benazepril
				13	Metoprolol	35	Hydroxychloroquine
14	Vilanterol	36	Chloroquine
				15	Fluticasone furoate/vilanterol	37	Propranolol (Propranolol)
16	Vonoprazan	38	Nortriptyline
				17	Metformin	39	Nebivolol
18	Formoterol	40	Vancolan
				19	Pomalidomide	41	Ozarimod
20	Cinacalcet	42	Rapocillin
				21	Oxititinib	43	Nilaparib
22	Pazopanib

；

Preferably, the first and second liquid crystal display panels are,

the secondary amine compound is a salt formed by the following compounds and pharmaceutically acceptable acid, and a crystal form or a solvate thereof: palbociclib, salmeterol, dabigatran etexilate, ticagrelor, duloxetine, salbutamol, rilpivirine, metoprolol, vilanterol, fluticasone furoate/vilanterol, vorozan, metformin, formoterol, cinacalcet, oxictinib, pazopanib, imatinib, sertraline, bupropion, paroxetine, methylphenidate, enalapril, benazepril, hydroxychloroquine, chloroquine, propranolol, nortriptyline, nebivolol, valnemadectin, ozalimod, rapamimod, rilazarin or nilapanib;

more preferably still, the first and second liquid crystal compositions are,

the secondary amine compound is the following salifying compound or a crystal form and a solvate thereof: palbociclib hydrochloride, salmeterol xinafoate, dabigatran mesilate mesylate, ticagrelor hydrochloride, duloxetine hydrochloride, salbutamol sulfate, rilpivirine hydrochloride, metoprolol tartrate, metoprolol succinate, vilanterol tritoate triphenate, vilanterol triflate, vorazanoprazine fumarate, metformin hydrochloride, formoterol fumarate, formoterol tartrate, cinacalcet hydrochloride, oxiranine mesylate, pazopanib mesylate, imatinib mesylate, sertraline hydrochloride, bupropion hydrobromide, paroxetine hydrochloride, paroxetine maleate, methylphenidate hydrochloride, enalapril maleate, benazepril hydrochloride, hydroxychloroquine sulfate, chloroquine phosphate, pranopol hydrochloride, nortriptyline hydrochloride, nedocetalol hydrochloride, nebivolol hydrochloride, valonimod hydrochloride, pavalcanine hydrochloride, pravastatin hydrochloride, oxazelnib hydrochloride, oxacillin hydrochloride, nilaparine succinate, nilaparine hydrochloride, or toluene sulfonic acid; for example, the secondary amine compound is varenicline hydrochloride or varenicline tartrate.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the secondary amine compound is varenicline tartrate, or the secondary amine compound is varenicline hydrochloride.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the secondary amine compound is mirabegron.

In a further aspect of the present invention,

in any of the above technical solutions (pharmaceutical compositions), the molar ratio of the secondary amine compound to the pharmaceutically acceptable acid is 1 (0.01 to 50), for example, the molar ratio is 1; preferably, the molar ratio of secondary amine compound to pharmaceutically acceptable acid is 1 (1-20) (e.g., a molar ratio of 1:2-15, 1:3-15, 1:4-15, 1:5-10); more preferably, the molar ratio of the secondary amine compound to the pharmaceutically acceptable acid is 1 (2 to 10).

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant;

preferably, the first and second electrodes are formed of a metal,

the pharmaceutically acceptable auxiliary materials comprise one or more than two of the following auxiliary materials (1) to (7);

(1) and a diluent: the diluent is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, mannitol, copovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, starch, maltodextrin, agar and guar gum;

(2) and a disintegrating agent: the disintegrant is selected from one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, partially pregelatinized starch, pregelatinized hydroxypropyl starch, sodium carboxymethylcellulose and calcium carboxymethylcellulose;

(3) and a glidant: the glidant is one or more than two of colloidal silicon dioxide, fumed silica, colloidal silica, corn starch, talcum powder, calcium silicate, magnesium silicate, tricalcium phosphate and silicon hydrogel;

(4) and a lubricant: the lubricant is one or more than two of stearic acid, stearate, talcum powder, mineral oil, malt, glyceryl monostearate, glyceryl benzoate, glyceryl palmitostearate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate and sodium lauryl sulfate;

(5) a coating agent; preferably, the coating agent is an opadry coating agent, such as: white, blue, yellow, red, green or orange opadry coating agents;

(6) and polymer: the polymer is selected from one or more of polyoxyethylene (including low molecular polyoxyethylene and high molecular polyoxyethylene, wherein the low molecular polyoxyethylene is also called polyethylene glycol), polyvinylpyrrolidone, polyoxyethylene hardened castor oil and polyoxyethylene polyoxypropylene glycol, and preferably the polymer is PEO N60K and polyethylene glycol;

(7) and an antioxidant: the antioxidant is selected from one or more of butylated hydroxytoluene, propyl gallate and sodium ascorbate, and preferably the antioxidant is butylated hydroxytoluene;

more preferably, the pharmaceutically acceptable auxiliary material comprises one or more of the above auxiliary materials (1) to (5); it is still further preferred that the first and second substrates are,

the pharmaceutically acceptable auxiliary materials simultaneously comprise (1) to (4) or (1) to (5);

it is still further preferred that the first and second substrates are,

the pharmaceutically acceptable auxiliary materials meet one or more of the following conditions:

(1) Comprises (1), (4) and (6);

(2) Comprises (1), (4), (5) and (6);

(3) Comprises (1), (4), (5), (6) and (7);

further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the diluent is microcrystalline cellulose and anhydrous calcium hydrogen phosphate.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the disintegrant is partially pregelatinized starch.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the glidant is colloidal silicon dioxide.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the diluent is hydroxypropylcellulose.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the lubricant is stearate; magnesium stearate or sodium stearate is preferred.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the weight ratio of the secondary amine compound to the diluent is 1 (100-300); preferably 1 (150 to 250); more preferably 1 (184 to 195).

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the weight ratio of the secondary amine compound to the disintegrant is 1 (1-10); preferably 1 (2-6); more preferably 1 (3.5-4.5); for example 1:4.

Further, in the above-mentioned case,

in any technical scheme (pharmaceutical composition), the weight ratio of the secondary amine compound to the glidant is 1 (0.1-8); preferably 1 (0.2-5); more preferably 1 (0.5 to 2.5); most preferably 1 (0.8-2), for example 1.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the weight ratio of the secondary amine compound to the lubricant is 1 (0.1-8); preferably 1 (0.2-5); more preferably 1 (0.5 to 2.5); most preferably 1 (1-2), for example 1:1, 1.4 or 1:2.

In a further aspect of the present invention,

in any of the above technical solutions (pharmaceutical compositions), the pharmaceutical composition is a solid preparation or a liquid preparation; the solid preparation is preferably a tablet, for example, a plain tablet or a coated tablet.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the pharmaceutical composition is an oral formulation.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the pharmaceutically acceptable acid is a solid acid or a liquid acid.

Preferably, the first and second electrodes are formed of a metal,

in any of the above technical solutions (pharmaceutical compositions), when the pharmaceutical composition is a solid formulation, the pharmaceutically acceptable acid is a solid acid; when the pharmaceutical composition is a liquid formulation, the pharmaceutically acceptable acid is a solid acid or a liquid acid.

Preferably, the first and second electrodes are formed of a metal,

in any of the above technical solutions (pharmaceutical compositions), the solid acid is selected from one or more of tartaric acid, succinic acid, maleic acid, fumaric acid, citric acid, malic acid, ascorbic acid, benzenesulfonic acid, oxalic acid, triphenylacetic acid, 1-hydroxy-2-naphthoic acid and 3-hydroxy-2-naphthoic acid; the liquid acid is selected from one or more than two of hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid and trifluoromethanesulfonic acid;

more preferably still, the first and second liquid crystal compositions are,

in any of the above technical solutions (pharmaceutical compositions), the pharmaceutically acceptable acid is tartaric acid.

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the pharmaceutical composition has a nitrosamine impurity content of no greater than 7.5ppm; for example: not more than 7.4ppm, not more than 7.3ppm, not more than 7.2ppm, not more than 7.1ppm, not more than 7.0ppm; not more than 6.9ppm, not more than 6.8ppm, not more than 6.7ppm, not more than 6.6ppm, not more than 6.5ppm, not more than 6.4ppm, not more than 6.3ppm, not more than 6.2ppm, not more than 6.1ppm, not more than 6.0ppm; not more than 5.9ppm, not more than 5.8ppm, not more than 5.7ppm, not more than 5.6ppm, not more than 5.5ppm, not more than 5.4ppm, not more than 5.3ppm, not more than 5.2ppm, not more than 5.1ppm, not more than 5.0ppm; no greater than 4.9ppm, no greater than 4.8ppm, no greater than 4.7ppm, no greater than 4.6ppm, no greater than 4.5ppm, no greater than 4.4ppm, no greater than 4.3ppm, no greater than 4.2ppm, no greater than 4.1ppm, no greater than 4.0ppm, no greater than 3.9ppm, no greater than 3.8ppm, no greater than 3.7ppm, no greater than 3.6ppm, no greater than 3.5ppm, no greater than 3.4ppm, no greater than 3.3ppm, no greater than 3.2ppm, no greater than 3.1ppm, no greater than 3.0ppm; not greater than 2.9ppm, not greater than 2.8ppm, not greater than 2.7ppm, not greater than 2.6ppm, not greater than 2.5ppm, not greater than 2.4ppm, not greater than 2.3ppm, not greater than 2.2ppm, not greater than 2.1ppm, or not greater than 2.0ppm;

preferably, the nitrosamine impurity is a product of the conversion of a secondary amine group of the secondary amine compound to a nitrosamine group;

more preferably, when the secondary amine compound is mirabegron or a pharmaceutically acceptable salt thereof, the nitrosamine impurity is

More preferably, when the secondary amine compound is valnemulin tartrate, or,when the secondary amine compound is Vannikland hydrochloride, the nitrosamine impurity is

Further, in the above-mentioned case,

in any of the above technical solutions (pharmaceutical compositions), the pharmaceutical composition is a solution of formula a or formula B:

scheme A:

the pharmaceutical composition comprises the following components in parts by weight:

preferably, the pharmaceutical composition comprises the following components in parts by weight:

or scheme B:

1.71 parts of secondary amine compound;

100-250 parts of diluent;

2-10 parts of a disintegrating agent;

0-5 parts of a flow aid;

0-5 parts of a lubricant;

0.01 to 15 portions of pharmaceutically acceptable acid;

1.71 parts of secondary amine compound;

5363 parts of diluent 184.47;

4 parts of a disintegrating agent;

0.6 part of glidant;

5 parts of a lubricant;

1.71 to 3.42 portions of pharmaceutically acceptable acid;

more preferably still, the first and second liquid crystal compositions are,

the pharmaceutical composition is any one of the following formulas:

the first scheme is as follows:

1.71 parts of varenicline tartrate;

64 parts of anhydrous calcium bicarbonate;

5363 parts of microcrystalline cellulose 120.47;

4 parts of partial pregelatinized corn starch;

0.6 part of colloidal silicon dioxide;

5 parts of stearic acid;

3.42 parts of L- (+) -tartaric acid;

scheme two is as follows:

1.71 parts of varenicline tartrate;

64 parts of anhydrous calcium bicarbonate;

5363 parts of microcrystalline cellulose 120.47;

4 parts of partial pregelatinized corn starch;

0.6 part of colloidal silicon dioxide;

5 parts of stearic acid;

1.71 parts of L- (+) -tartaric acid;

the third scheme is as follows:

1.71 parts of varenicline tartrate;

64 parts of anhydrous calcium bicarbonate;

5363 parts of microcrystalline cellulose 120.47;

4 parts of partial pregelatinized corn starch;

0.6 part of colloidal silicon dioxide;

5 parts of stearic acid;

3.42 parts of L- (+) -tartaric acid;

6 parts of Opadry-white or Opadry-blue;

and the scheme is as follows:

1.71 parts of varenicline tartrate;

64 parts of anhydrous calcium bicarbonate;

5363 parts of microcrystalline cellulose 120.47;

4 parts of partial pregelatinized corn starch;

0.6 part of colloidal silicon dioxide;

5 parts of stearic acid;

1.71 portions of L- (+) -tartaric acid;

6 parts of opadry-white or opadry-blue.

In a further aspect of the present invention,

in any of the above technical solutions (pharmaceutical compositions), the pH of the pharmaceutical composition is not more than 4 under the following test conditions: preferably, the pH is 1 to 4, e.g., 1, 1.5, 2, 2.5, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4, etc.;

when the pharmaceutical composition is a solid formulation, the test conditions are: mixing the pharmaceutical composition with water having a pH =6 ± 0.1 to form a dispersion having a concentration of 20% (i.e. 0.2 g/ml), and testing the resulting pH;

when the pharmaceutical composition is a liquid formulation, the test conditions are: the solvent of the liquid formulation is water at pH =6 ± 0.1, the concentration of the liquid formulation is 20% (g/ml), the pH value obtained by the test;

the above test conditions for pH are not intended to limit the pharmaceutical composition, and the pH obtained by the measurement under the above test conditions is the same as or within the error range described above, and falls within the scope of the present invention.

The invention also provides a preparation method of the pharmaceutical composition according to any one of the previous schemes, which comprises the following steps: mixing all the components, granulating, tabletting, and optionally coating;

preferably, the first and second electrodes are formed of a metal,

the granulation is dry granulation or wet granulation;

the tabletting is a direct tabletting method.

The invention also provides the use of a pharmaceutical composition according to any of the preceding aspects in the manufacture of a medicament;

preferably, the medicament is for the treatment and/or prevention of the following diseases: inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, diarrhea, capsulitis, vasoconstriction, anxiety, mania, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis, cognitive dysfunction, cognitive disorders caused by alcohol, barbiturates, vitamin deficiency, recreational drugs, lead, arsenic or mercury, alzheimer's disease, senile dementia, vascular dementia, parkinson's disease, multiple sclerosis, aids, encephalitis, trauma, hepatorenal encephalopathy, hypothyroidism, pick's disease, kefir syndrome, prefrontal dementia or subcortical dementia, hypertension, bulimia, anorexia, obesity, arrhythmia, hyperchlorhydria, ulcers, pheochromocytoma, progressive supranuclear palsy, nicotine, tobacco products, alcohol, benzodiazepines

Chemical dependencies and addictions to barbiturates, opioids or cocaine, headache, migraine, stroke, traumatic brain injury, obsessive-compulsive disorder, psychosis, huntington's chorea, tardive dyskinesia, hyperkinesia, reading disorders, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, attention deficit hyperactivity disorder or Tourette's syndrome.

The invention also provides the application of the pharmaceutically acceptable acid in inhibiting or slowing nitrosation of a secondary amine compound; wherein the secondary amine compound is the following compound or a pharmaceutically acceptable salt thereof, a crystal form or a solvate of any one of the foregoing compounds (the following compound or a pharmaceutically acceptable salt thereof):

preferably, said pharmaceutically acceptable acid and/or said secondary amine compound is as defined in any one of the preceding schemes.

The invention also provides a method for inhibiting or slowing nitrosation of a secondary amine compound, which comprises the following steps: mixing the secondary amine compound or the composition thereof with a pharmaceutically acceptable acid; wherein the secondary amine compound is the following compound or a pharmaceutically acceptable salt thereof, a crystal form or a solvate of any one of the foregoing compounds (the following compound or a pharmaceutically acceptable salt thereof):

serial number	Name of Chinese	Serial number	Name of Chinese
				1	Pabociclib	23	Imatinib
2	Salmeterol	24	Hydrochlorothiazide
				3	Pemetrexed	25	Sertraline
4	Dabigatran etexilate	26	Atenolol
				5	Mirabegron	27	Bupropion derivatives
6	Ticagrelor	28	Paroxetine
				7	Venetolara	29	Sulfamethoxazole
8	Simpinicline	30	Methylphenidate ester
				9	Duloxetine	31	Benzonatate and its preparation
10	Salbutamol	32	Diclofenac acid
				11	Rilpivirine	33	Enalapril
12	Aforana	34	Benazepril
				13	Metoprolol	35	Hydroxychloroquine
14	Vilanterol	36	Chloroquine
				15	Fluticasone furoate/vilanterol	37	Propranolol (Propranolol)
16	Vonoprazan	38	Nortriptyline
				17	Metformin	39	Nebivolol
18	Formoterol	40	Vannicallan
				19	Pomalidomide	41	Oazamod
20	Cinacalcet	42	Rapocillin
				21	Oxititinib	43	Nilaparib
22	Pazopanib

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The invention has the following beneficial effects: according to the pharmaceutical composition, the pharmaceutically acceptable acid is added into the secondary amine compound (such as Vannit, pharmaceutically acceptable salt thereof and the like) or the composition thereof, so that the generation of nitrosamine impurities can be effectively inhibited and reduced, the stability of the secondary amine compound or the composition thereof is improved, and the content of the nitrosamine impurities is controlled at a lower level, so that the pharmaceutical composition meets the safety requirement and the supervision regulation of pharmaceutical products, and the medication safety of patients is better guaranteed.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

Drawings

FIG. 1 shows the UHPLC-MS/MS detection result of nitrosamine impurity G06 in compound 5.

FIG. 2 shows the UHPLC-MS/MS detection result of nitrosamine impurity G02 in mirabegron bulk drug (API).

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The Chinese patent applications CN2021109612747, CN 202110997332.1 and International patent application WO 2021/259396 A2 are incorporated herein by reference in their entirety.

Example 1

Table 1, formulation A (specification 1 mg) components and their contents

Wherein the content of the first and second substances,

1.71 mg/tablet of valnemulin tartrate can be converted to 1 mg/tablet of valnemulin, namely: each tablet contains 1mg of active ingredient (varenicline), which can also be expressed as: 1mg of plain tablet (or 1mg of coated tablet, etc.). While 0.5mg tablets are a half-reduction in the amount of each component on the basis of 1mg tablets. In the above formulation, microcrystalline cellulose and anhydrous dibasic calcium phosphate are used as diluents, part of the pregelatinized corn starch is used as a disintegrant, colloidal silicon dioxide is used as a glidant, stearic acid is used as a lubricant, L- (+) -tartaric acid is used as an acidity regulator (otherwise known as a pH regulator), and purified water is used as a coating solvent.

The preparation method (13 ten thousand tablets per batch) comprises the following steps:

first, screening and mixing

a. Sieving colloidal silica (Part I) and anhydrous calcium hydrogen phosphate (Part I) with 40 mesh sieve, sieving with a discharger (diameter of 1.2mm, speed of 400 + -10 r/min), and stirring in a stirrer (rotation speed of 15 r/min) for 2min;

b. sieving Vanilla tartrate with 40 mesh sieve, sieving with a discharger (diameter of 1.2mm, speed of 800 + -15 r/min), and adding into the stirrer for stirring for 10min;

c. sieving colloidal silicon dioxide (Part II), anhydrous calcium hydrophosphate (Part II) and L- (+) -tartaric acid with a 40-mesh sieve, sieving with a discharger (diameter of 1.2mm, speed of 400 +/-15 r/min), and adding into the stirrer to continue stirring for 10min;

d. sieving microcrystalline cellulose, part of pregelatinized corn starch, and stearic acid (intragranular part) with a discharger (diameter of 1.2mm, speed of 100 + -5 r/min), and adding into the above stirrer and stirring for 10min.

Preparing grains by dry method

The mixture is granulated by using a dry granulator LGS120, and the specific parameters are as follows: screening: 1.0mm; feeding speed: 20-30 rpm; roller speed: 10 plus or minus 2rpm; roll gap: 0.5-3.0 mm; oil pressure: 60-70 bar; rotating speed: 100 to 140rpm.

Subjecting to the final mixing

Adding the granulated particles and stearic acid (the part outside the particles) into a stirrer (the rotating speed: 15 r/min) and stirring for 10min to obtain the final mixture.

Fourth, tabletting (prepared with 1mg plain tablet A)

The final blend was tabletted with the specific parameters given in table 2.

TABLE 2 Main Process parameters for tabletting

Fifthly, coating (prepared into 1mg white coated tablet A)

The Opadry White premix is added into purified water according to the proportion and mixed evenly to obtain the coating dispersion liquid. Coating the compressed tablets (plain tablets) by using a coating machine, wherein the specific parameters are as follows: pan speed (Pan speed): 3-12 r/min; air Inlet/outlet rotation speed (Inlet/outlet air rotating speed): 1200/1600rpm; intake air temperature (Inlet air temperature): 60 ℃; start spray gun pressure (Starting spray gun pressure): 2.5 +/-0.5 bar; atomization pressure (Atomization pressure): 2.0 plus or minus 0.5bar; latex tube diameter (Latex tube diameter): 4.00-5.00 mm; peristaltic pump speed (Peristtic pump rotating speed): 20-50 r/min.

The coating agent was replaced by Opadry-Blue (Opadry Blue premix) and the other conditions were unchanged, to obtain 1mg of Blue coated tablet a.

Sixthly, packaging the aluminum and plastic.

Example 2

Formulation B (specification 1 mg): the amount of L- (+) -tartaric acid was changed to 1.71 mg/tablet, and the other conditions were not changed. According to the same production method as in example 1, 1mg of the plain tablet B, 1mg of the white coated tablet B and 1mg of the blue coated tablet B were obtained.

Example 3

Formulation Y (Specification 1 mg): l- (+) -tartaric acid is not added into the tablet, and other conditions are not changed. According to the same production method as in example 1, 1mg of the plain tablet Y, 1mg of the white coated tablet Y and 1mg of the blue coated tablet Y were obtained.

Example 4

The prepared varenicline tartrate tablets were dispersed in purified water (pH =6.01 as detected) to form a 20% (g/ml) concentration dispersion (indicating that 100ml of the solution or dispersion contained 20g of the varenicline tartrate tablets), and the pH was measured after 5min of sonication. And detecting the content of nitrosamine impurity P08 in the Vanquish tartrate tablets by using HPLC Q-active-MS/MS (Vanquish HPLC Q-active-MS/MS).

The results are shown in tables 3 to 5.

TABLE 3 test results for pH and nitrosamine impurity P08 content (plain sheet Core Tablet)

TABLE 4 detection results of pH value and nitrosamine impurity P08 content (White Coating tablet White Coating)

TABLE 5 test results for pH and nitrosamine impurity P08 content (Blue Coating of Blue Coating)

Wherein the content of the first and second substances,

API (Active Pharmaceutical Ingredient): refers to valnemulin tartrate bulk drug.

Initially: means that the test is carried out immediately after the preparation of the valnemulin tartrate tablets.

High-temperature test: the preparation method is characterized in that after the preparation of the valnemulin tartrate tablet, the valnemulin tartrate tablet is placed at the temperature of 60 ℃ for a period of time and then is detected (refer to Chinese pharmacopoeia).

Symbol: indicating the liquid sample after pH adjustment, which is subjected to detection.

Symbol #: which means a liquid sample after pH adjustment, is subjected to a high temperature test and then subjected to a test.

Example 5

The HPLC Q-active-MS/MS (Vanqish HPLC Q-active-MS/MS) method is used for the qualitative and/or quantitative detection of the nitrosamine impurity P08 in the valnemulin tartrate tablet, and the detection result is specifically shown in example 4 after the qualitative and/or quantitative detection is carried out and verified by methodology.

The chromatographic conditions and mass spectrum conditions of HPLC Q-active-MS/MS are shown in Table 6.

TABLE 6 chromatographic and Mass Spectroscopy conditions for HPLC Q-active-MS/MS

1. Solution preparation

Control stock solutions: weighing 7.5mg of nitrosamine compound P08 (the purity is more than or equal to 98 percent) and placing the nitrosamine compound P08 into a100 ml measuring flask, adding acetonitrile to dissolve the nitrosamine compound P08, and fixing the volume (fixing solution 1A). 1.0ml of the fixed solution 1A was put in a100 ml measuring flask, and acetonitrile was added to the solution to a constant volume (fixed solution 1B). And (3) putting 1.0ml of the fixed solution 1B into a 20ml measuring flask, and adding acetonitrile to fix the volume to obtain a reference substance stock solution.

Control solution: and (3) putting 1.0ml of reference substance stock solution into a10 ml measuring flask, and adding acetonitrile to a constant volume to obtain a reference substance solution.

Sample solution: putting 10 tablets of varenicline tartrate into a10 ml measuring flask, adding 3ml of purified water and 3ml of acetonitrile, carrying out ultrasonic treatment for 30s, diluting the mixture to the scale with the acetonitrile, and uniformly mixing.

Adding a standard solution to a sample: putting 10 tablets of varenicline tartrate into a10 ml measuring flask, adding 3ml of purified water and 3ml of acetonitrile, carrying out ultrasonic treatment for 30s, adding 1.0ml of reference substance stock solution, adding acetonitrile to a constant volume to scale, and uniformly mixing.

Placebo solution: weigh 1g of placebo (equivalent to a tablet with the active ingredient removed) into a10 ml volumetric flask, add 3ml of purified water and 3ml of acetonitrile, sonicate for 30s, dilute to the mark with acetonitrile and mix.

Placebo spiked solution: weighing 1g of placebo, placing the placebo in a10 ml measuring flask, adding 3ml of purified water and 3ml of acetonitrile, carrying out ultrasonic treatment for 30s, adding 1.0ml of control stock solution, adding acetonitrile, diluting to a constant volume to scale, and uniformly mixing.

Blank: and (3) acetonitrile.

2. Specificity

Blank, control solution, sample solution, placebo solution, sample plus standard solution and placebo plus standard solution are respectively injected for analysis.

The results show that the retention time of the target substances of the reference substance solution, the sample solution and the standard solution is about 7.80min, the peak position of the target substance has no obvious interference, the requirement of the separation degree is met, and the specificity is good.

3. Stability of solution

Taking the reference substance solution and the sample solution, standing at room temperature, and injecting samples at intervals for analysis: 0. the peak area ratio (i.e., peak area change rate) of each time point to the zero point was calculated for 2, 4, 6, 8, 10, and 12 hours.

The results show that the peak area change rate of the nitrosamine compound P08 in the control solution is less than 12% in 12 hours, and the peak area change rate of the nitrosamine compound P08 in the sample solution is less than 3.5% in 12 hours.

4. System applicability

And (4) sampling and analyzing the reference substance solution for 5 times, and calculating the RSD of the peak area of the target substance, wherein the result is 1.41%, and the system applicability is good.

5. Repeatability of

6 parts of sample solution are prepared in parallel and are respectively injected for analysis. The result shows that the RSD of the content of the impurity compound P08 in 6 sample solutions is 3.49 percent, the RSD meets the acceptance standard and the repeatability is good.

6. Intermediate precision

Two analysts weighed 6 sample solutions at different times, respectively, introduced samples for analysis, and calculated the average value and RSD. The results showed RSD =5.93%.

7. Linearity

Respectively preparing reference substance solutions of 0.015ng/ml, 0.38ng/ml, 1.88ng/ml, 3.77ng/ml, 5.65ng/ml, 18.83ng/ml, 37.66ng/ml and 753.2ng/ml, and carrying out sample injection analysis; taking the concentration (X) of the target object as a horizontal coordinate and the peak area (Y) as a vertical coordinate, performing linear regression, and calculating to obtain a linear equation and a linear correlation coefficient r;

the results show that the linear equation: y =462785X +1000000, linear correlation coefficient r =0.9999, good linearity, and good linearity in the concentration range of 0.015 ng/ml-753.2 ng/ml.

8. Accuracy of

The result shows that the recovery rate of the sample added with the standard solution is between 85 and 95 percent, the RSD is 2.03 percent, the standard is met, and the accuracy is good.

9. Detection Limit (LOD)

LOD =13.2ppb, the average S/N (signal-to-noise ratio) of the target peak is 75.94, the requirement of being more than 3 is met, and the method is sensitive.

10. Quantitative Limit (LOQ)

LOQ =17.6ppb, the average S/N of the target peak is 103.35, the requirement of being more than 10 is met, and the method is sensitive.

11. Durability

When the temperature change of the chromatographic column is +/-2 ℃, the result shows that the method has good durability.

Calculating the content of nitrosamine impurity compound P08 in the sample according to the following formula:

c (ppm) = concentration of P08 in sample solution (ng/ml)/concentration of varenicline tartrate in sample solution (mg/ml)

Example 6

Preparation of nitrosamine compounds P08

To a100 mL three-necked flask, 4.0g of Compound M02 (Vanilla) and 45mL of Tetrahydrofuran (THF) were added and stirred to dissolve; add 8.2mL of NaNO ₂ Adding 2.9g of acetic acid into an aqueous solution (the concentration is 0.4 g/mL), heating to 52 ℃, monitoring by TLC after the reaction is finished, separating out solids, filtering, and drying in vacuum to obtain the nitrosamine compound P08 with the purity of 98.87% (area normalization method).

Of nitrosamine compounds P08 ¹ H-NMR、 ¹³ C-NMR and IR spectra, shown in tables 7 to 9, respectively; m + H ⁺ =241.20; UV: the maximum absorption wavelength in acetonitrile solution was 204.40nm.

TABLE 7 preparation of nitrosamine Compound P08 ¹ H-NMR spectra

TABLE 8 preparation of nitrosamine Compound P08 ¹³ C-NMR spectra

TABLE 9 IR spectra of nitrosamine compound P08

Absorption wave number (cm) ^-1 )	Attribution
		3048.8	Ar-H
2961.4,2931.8	Saturated C-H stretching vibration
		1925.2	Benzene ring C = C stretching vibration
1575.2	N = O telescopic vibration
		885.2	C-H bending vibration of benzene ring

Example 7

The ultra performance liquid chromatography triple quadrupole mass spectrometry (UPLC-MS/MS) is used for qualitative and/or quantitative detection of nitrosamine impurities (compound P08) in bulk pharmaceutical chemicals of varenicline tartrate, and is performed and verified by methodology.

The chromatographic conditions and mass spectrum conditions of UPLC-MS/MS are shown in Table 10.

TABLE 10 chromatographic and mass spectral conditions for UPLC-MS/MS

1. Solution preparation

Diluent agent: purified water

Control stock solutions: 19.970mg nitrosamine compound P08 (purity is more than or equal to 98%) is weighed and placed in a10 ml measuring flask, 8ml acetonitrile is added, then diluent is added to dissolve and dilute to scale, and the mixture is mixed evenly.

Mother liquor of a reference product: measuring 37.5 μ l of the control stock solution in a10 ml measuring flask, diluting with diluent to scale, and mixing.

2. System applicability

System applicability solution (100% limit level control solution): measuring 100.0 μ l of the control mother liquor in a10 ml measuring flask, diluting with diluent to scale, and mixing.

The 6-pin system suitability solution was continuously fed, and RSD of the peak area of the target in the 6-pin system suitability solution was calculated, and the result was 4%, and the system suitability was good.

3. Linearity

Standard curve solution: respectively weighing control mother liquor 50.0 μ L, 100.0 μ L, 150.0 μ L and 200.0 μ L, placing in 4 10ml measuring bottles, diluting with diluent to scale, mixing, and sequentially making into linear solutions L-3, L-4, L-5 and L-6. Measuring the L-3 solution in a measuring flask of 800 mu 1 to 10ml, diluting the solution to the scale with a diluent, and uniformly mixing to obtain the L-2. Measuring the L-2 solution into a measuring flask with the volume of 1000 mu 1 to 10ml, diluting the solution to the scale with a diluent, and uniformly mixing to obtain the L-1.

Respectively sampling and analyzing the standard curve solution, performing linear regression by taking the concentration (X) of the target object as a horizontal coordinate (unit: ng/ml) and the peak area (Y) as a vertical coordinate, and calculating to obtain a linear equation and a linear correlation coefficient r; the results show that the linear equation: y =7370X-12900, linear correlation coefficient r =0.999, good linearity, in the concentration range of 0.2951ng/ml to 147.6ng/ml (i.e., 0.02951ppm to 14.76 ppm).

4. Detection Limit (LOD)

LOD solution: measuring the L-1 solution into a measuring flask with 5000 mu 1 to 10ml, diluting the solution to the scale with a diluent, and uniformly mixing the solution to obtain an LOD solution.

2 needles of LOD solution are continuously injected, S/N (signal to noise ratio) of a target peak is respectively 11 and 8, the requirement of not less than 3 is met, and the method is sensitive; LOD =0.01476ppm.

5. Limit of quantitation (LOQ)

Taking a quantitative limiting solution (L-1 solution) for continuous sampling 6 needles, wherein S/N of a target peak is 23, 24, 17, 12, 24 and 14 respectively, the requirement of not less than 10 is met, and the method is sensitive; LOQ =0.02951ppm.

6. Accuracy of

Sample solution: weighing about 100mg of sample (such as purchased or synthesized valnemulin tartrate bulk drug) and placing in a10 ml measuring flask, adding diluent to dilute to the scale, and mixing well. 2 parts are prepared in parallel.

Accuracy solution: weighing about 100mg of sample, placing in a10 ml measuring flask, adding control mother liquor 50.0 μ l (50% limit level), 100.0 μ l (100% limit level), and 150.0 μ l (150% limit level), diluting with diluent to scale, and mixing. Each level of accuracy was formulated in 3 parts in parallel.

The results show that the recovery of the solution at the 50% limit level accuracy is between 95% and 102%, the RSD is 4%; the recovery rate of the solution at the 100% limit level accuracy is between 90% and 103%, and the RSD is 7%; the recovery rate of the solution at the accuracy of 150% limit level is between 98% and 100%, the RSD is 1%, the solution meets the acceptance standard, and the accuracy is good.

7. Repeatability

Weighing about 100mg of sample, placing in a10 ml measuring flask, adding 100.0 μ l of control mother liquor, diluting with diluent to scale, and mixing. 6 parts are prepared in parallel.

The result shows that the RSD of the content of the nitrosamine compound P08 in 6 parts of repetitive solution is 6 percent, the receiving standard is met, and the repeatability is good.

8. Specificity

Blank solution (diluent), 100% limit level control solution, sample solution (same as "repetitive" sample solution), 100% limit level accuracy solution were injected separately for analysis.

The results show that the retention time of the target in the sample solution, the 100% limit level control solution and the 100% limit level accuracy solution is 3.47min, the peak position of the target is not obviously interfered, the requirement of the separation degree is met, and the specificity is good.

9. Intermediate precision

Intermediate precision solution: weighing about 100mg of sample, placing in a10 ml measuring flask, adding 100.0 μ l of control mother liquor, diluting with diluent to scale, and mixing. 6 parts are prepared in parallel. Plus 6 portions of "7, duplicate" solution.

The concentration RSD of 12 parts of solution in total of 6 parts of intermediate precision solution and 6 parts of repetitive solution is calculated to be 9 percent, the requirement of not more than 15 percent is met, the receiving standard is met, and the intermediate precision is good.

10. Stability of solution

And (3) placing the solution with the 100% limit horizontal accuracy at 15 ℃, carrying out sample injection analysis at intervals, and calculating the concentration ratio of each time point to a zero point, wherein the ratio is 96-113% in 21 h.

11. Durability

The method has the advantages that when the temperature change of a chromatographic column is +/-2 ℃, the initial proportion of an organic phase is +/-1%, and the flow rate is +/-0.01 ml/min, the concentration value of a target object in a solution with 100% limit horizontal accuracy is respectively inspected, 2 needles are respectively injected under each condition, and in the calculation of the same parameter fluctuation, the RSD of the concentration value of the target object in 6 parts of solution is 4% -6%, and the method has good durability.

Calculating the content of nitrosamine compound P08 in the sample according to the following formula, detecting for 2 times, and taking an average value:

the content of P08: c (ppm) = P08 concentration in sample solution (ng/ml)/[ m (mg)/V (ml) ]

m: sample mass, mg;

v: sample dilution volume, ml.

Example 8

The nitrosamine impurity compound P08 was tested for genotoxicity (capable of mutagenizing or carcinogenic).

1 materials and methods

1.1 Experimental strains

Salmonella typhimurium TA97a, TA98, TA100, TA102, TA1535, source: MOLT OX, USA, available from Shanghai Bao Bingshi Co. The identified Salmonella typhimurium strain meeting the requirements is adopted for the test.

1.2 Metabolic activation System

Rat liver S ₉ And (3) source: shanghai Bao Bian Biotech Co., ltd.

1.3 test substances

The name is as follows: nitrosamine impurity compound P08, property: white powder.

1.4 Main instruments and reagents

X SR-204 electronic balance (Mettler, switzerland); an autoclave (SANYO, japan); a water-insulated constant temperature incubator (Shanghai-constant technology Co., ltd.); stuart temperature controlled shaker incubators (Stuart, uk); BHC-1300II A2 biological safety cabinet (Sujing group Suzhou Antai air technology, inc.).

Glucose-6-phosphate, source: beijing Bailingwei Tech Co., ltd; coenzyme II, source: chemical agents of the national drug group, ltd; nutrient broth, source: beijing Luqiao technology GmbH; technical agar powder, source: kyoto Tokay microbial science and technology Co., ltd; sterilized water for injection, source: chenxin pharmaceutical industry, gmbh; dexrazoxane, source: CHEMSERVICE; methyl methanesulfonate, source: beijing Bailingwei science and technology Co., ltd; 2-aminofluorene, source: shanghai pure reagents, inc.; 1,8-dihydroxyanthraquinone, source: SIGMA-ALDRICH, USA; cyclophosphamide, source: SIGMA-ALDRICH, USA; sodium azide, source: RIEDEL-seeleie.

1.5 test methods (Ames test plate incorporation method)

The experiment used the plate incorporation method.

1.5.l dose selection and test formulation

Dose design: the tests were carried out at 5mg, 2.5mg, 1.25mg, 0.625mg, 0.3125mg, 0.15625mg per dish.

Preparing a test substance: taking the product, preparing the product into 50mg/ml solution by using dimethyl sulfoxide, and sequentially diluting the solution into 25mg/ml, 12.5mg/ml, 6.25mg/ml, 3.125mg/ml and 1.5625mg/ml by using the dimethyl sulfoxide.

1.5.2 test methods.

The frozen and preserved bacterial solutions TA97a, TA98, TA100, TA102 and TA 1535.1 ml were inoculated into 10ml nutrient broth medium, and cultured at 37 ℃ for 10 hours with shaking (100 times/min). 2.0ml of top layer culture medium containing 0.5mmol/L histidine to 0.5mmol/L biotin is subpackaged in test tubes, sterilized at 0.103MPa for 20min, and kept warm in 50 ℃ water bath. Then, 0.1ml of the test solution and S are added into each tube in turn ₉ Mixing the mixed solution 0.5ml (when needing metabolism activation) and the bacterial solution 0.1ml, mixing well, pouring onto the bottom agar plate quickly, rotating the plate to make it distribute uniformly. Horizontally placing for condensation and solidification, inversely placing in an incubator at 37 ℃ for incubation for 48h, and counting the number of bacterial colonies changed per dish. Three parallel plates were made for each dose, with a self-priming regression group, a solvent control group, and a positive control group.

1.6 statistics of test data

Data are averaged. + -. Standard deviation

Data analysis calculations are shown using SPSS 19.0.

1.7 determination of results

If the number of the test object retrogradation colonies is two or more times of the number of the solvent control retrogradation colonies and shows a dose-response relationship, the test object is judged to be mutagenic positive; and if the test object has positive reaction under any dosage condition and has repeatability, judging the test object as mutagenic positive. If the test substance is tested by the test strain, no matter whether S is added ₉ And without addition of S ₉ If all conditions are negative, the test substance is mutagenic negative.

2 results of the test

The results are shown in Table 11.

TABLE 11 Ames test results

Table of Ames test results

As can be seen from the Ames test results, the S is not added ₉ At a nitrosamine impurity compound P08 dose of 625 μ g/dish, the number of TA1535 colonies exceeded twice that of the solvent control. Adding S ₉ Under the condition, the TA98 colony count exceeds twice of the solvent control group when the dosage is 2500 mu g/dish, and the TA1535 colony count exceeds twice of the solvent control group when the dosage is 5000, 2500, 1250 and 625 mu g/dish, and the dosage-response relationship is formed. This indicates that the nitrosamine impurity compound P08 is mutagenically positive for salmonella typhimurium with and without the addition of a metabolic activation system.

Example 9

Secondary amine compounds having a secondary amine structure (NH) (meaning compounds containing a secondary amine structure) are specifically shown in table 12.

TABLE 12 List of Secondary amine Compounds

These secondary amine compounds, or pharmaceutically acceptable salts, crystalline forms, solvates, compositions, formulations, etc., thereof, may undergo nitrosation during preparation and/or storage (meaning nitrosation of the secondary amine structure (NH) to form a nitrosamine structure (N-N = O)), resulting in small, trace, or trace amounts of nitrosamine impurity compounds.

As mentioned above, vanilla tartrate is taken as a representative of secondary amine compounds to illustrate that acid is used as an acidity regulator to effectively inhibit or slow the nitrosation of the secondary amine structure of a secondary amine compound (e.g., vanilla tartrate, etc.). Through multi-party research and analysis, the reasonable theoretical explanation is as follows:

the above reaction can be regarded as beingAnd the reverse is carried out. When present in the form of varenicline tartrate, the secondary amine groups (NH) of varenicline are protected by the acid (tartaric acid) and are relatively less susceptible to nitrosation; but when Vanillan tartrate degrades Cheng Fani gram (reversible process, ppm scale), the secondary amine groups (NH) of Vanillan become exposed and are relatively easy to react with N, O, NO in air _x Nitrosamine reaction occurs to generate nitrosamine impurity P08, which results in increase of nitrosamine impurity in the product. And the acid (tartaric acid) is added, so that the degradation of the tartaric acid varenicline can be effectively inhibited, the nitrosamine content of the varenicline is reduced, and the impurity content of the nitrosamine is reduced.

Similarly, the above technical means or technical solutions are also applicable to other secondary amine compounds listed in table 12, and the addition of an acid (tartaric acid, succinic acid, toluenesulfonic acid, etc.) to these secondary amine compounds or pharmaceutically acceptable salts, crystal forms, solvates, compositions, and formulations thereof can also effectively inhibit and reduce nitrosation of these secondary amine compounds.

Example 10

1. Preparation of nitrosamine impurity compound G05

Adding 10g of compound 4, 100ml of tetrahydrofuran, 5.5g of sodium nitrite, 20ml of water and 75ml of acetic acid into a three-neck flask, heating to 50 ℃, stirring for 1h, concentrating after the reaction is finished, adding 50ml of water, pulping, filtering and drying to obtain 9.5g of crude product; dissolving the crude product in 150ml ethyl acetate, adding 150ml water, stirring, separating, washing an organic phase with 100ml water and 100ml saturated brine respectively, adding anhydrous sodium sulfate into the organic phase, filtering, concentrating to 50ml, adding 300ml petroleum ether, filtering and drying to obtain 8.4G of nitrosamine impurity compound G05 with the chromatographic purity of 99.4%.

Of nitrosamine impurity compound G05 ¹ H-NMR、 ¹³ C-NMR and IR spectra, shown in tables 13 to 15, respectively; m + H ⁺ =316.00; UV: the maximum ultraviolet absorption wavelength in the acetonitrile solution is 193.60nm.

TABLE 13 nitrosamine impurity Compound G05 ¹ H-NMR spectral data

TABLE 14 production of nitrosamine impurity Compound G05 ¹³ C-NMR spectral data

TABLE 15 IR spectra of nitrosamine impurity compound G05

Absorption wave number (cm) ^-1 )	Attribution
		1253、847、761	C-H bending vibration of benzene ring
3062	C-H stretching vibration of benzene ring
		1452、1426	Vibration of C = C skeleton of benzene ring
717	Hydroxyl O-H bending vibration
		3433	OH-O-H stretching vibration
1055	Hydroxy C-O stretching vibration
		2941、2885	Methylene C-H stretching vibration
1317	Methylene C-H bending vibration
		1143	C-C stretching vibration
1605	Nitroso vibration
		1520、1346	Nitro expansion vibration

2. Preparation of nitrosamine impurity compound G06

Adding 5G of compound G05, 25ml of methanol and 0.18G of palladium carbon catalyst (Pd/C, pd content is 5 wt%) into a three-neck flask, replacing with nitrogen for three times, introducing hydrogen, stirring at 25 ℃ for 18 hours to react, filtering, concentrating to about 17G, adding 60ml of methyl tert-butyl ether, and concentrating to obtain 3.3G of nitrosamine impurity compound G06 with the chromatographic purity of 99.4%.

Of nitrosamine impurity compound G06 ¹ H-NMR、 ¹³ C-NMR and IR spectra, shown in tables 16 to 18, respectively; m + H ⁺ =286.00; UV: the maximum ultraviolet absorption wavelength in the acetonitrile solution is 194.20nm.

TABLE 16 production of nitrosamine impurity Compound G06 ¹ H-NMR spectral data

TABLE 17 production of nitrosamine impurity Compound G06 ¹³ C-NMR spectral data

TABLE 18 IR spectra of nitrosamine impurity Compound G06

3. Preparation of nitrosamine impurity compound G02

Adding 30.0g of mirabegron and 310ml of methanol into a three-neck bottle, uniformly stirring, adding a solution of 13.05g of sodium nitrite and 60ml of water and 11.56g of glacial acetic acid, heating to 50-60 ℃, and reacting for 3 hours; after the reaction is finished, methanol is evaporated, 300ml of ethyl acetate is added for extraction, liquid separation is carried out, the water phase is extracted for 1 time by 300ml of ethyl acetate, the organic phase is combined, dried by anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography, 4.1G of nitrosamine impurity compound G02 is obtained, and the chromatographic purity is 93.2%.

Of nitrosamine impurity compound G02 ¹ H-NMR、 ¹³ C-NMR and IR spectra, shown in tables 19 to 21, respectively; m + H ⁺ =426.04; UV: the maximum ultraviolet absorption wavelength in the acetonitrile solution is 193.60nm.

TABLE 19 production of nitrosamine impurity Compound G02 ¹ H-NMR spectral data

TABLE 20 production of nitrosamine impurity Compound G02 ¹³ C-NMR spectral data

TABLE 21 IR spectra of nitrosamine impurity compound G02

Absorption wave number (cm) ^-1 )	Attribution
		1259、824、755	C-H bending vibration of benzene ring
3120	C-H stretching vibration of benzene ring
		1515、1452、1412	Vibration of C = C skeleton of benzene ring
700	Hydroxyl O-H bending vibration
		3191	OH-O-H stretching vibration
1058	Hydroxy C-O stretching vibration
		2926	Methylene C-H stretching vibration
1340	Methylene C-H bending vibration
		1135	C-C stretching vibration
1605	Nitroso vibration
		1668	Acyl C = O stretching vibration
3312	Amino group N-H bending vibration

Example 11

Chinese patent applications CN 202011327825.6 (title of the invention: crystal transformation solvent and application thereof, and preparation method of mirabegron alpha crystal form; application date: 2020/11/24) and CN202011327875.4 (title of the invention: preparation method of mirabegron and intermediate thereof; application date: 2020/11/24) are incorporated herein by reference in their entirety.

1. Preparation of Compound 3

2. Preparation of Compound 4

3. Preparation of Compound 5

4. Preparation of mirabegron

Example 12

The UHPLC-MS/MS method is adopted for the qualitative and/or quantitative detection of the nitrosamine impurity G06 in the compound 5, and the chromatographic conditions and the mass spectrum conditions are shown in Table 22.

TABLE 22 chromatographic and mass spectrometric conditions for detection of nitrosamine impurity G06 in Compound 5

External standard method:

(1) Preparing reference substance (standard) solutions with different concentrations, detecting to obtain corresponding peak area data, and performing linear regression on the concentrations and the peak areas to obtain a linear equation;

(2) The compound 5 to be detected is prepared into a sample solution (solvent: water), the content (ppm) of the nitrosamine impurity G06 in the compound 5 is finally obtained through detection and calculation according to a linear equation, and the figure 1 shows that the capture time (acquisition time) or the Retention time (Retention time) of the nitrosamine impurity G06 is 11.289 min.

Example 13

Preparation of mirabegron

(1) Under the protection of inert gas (such as nitrogen), adding 1170G of purified water, 35G of concentrated hydrochloric acid (the mass fraction is 36-38 wt%, the content of HCl is about 0.35 mol) and 9.37G (about 0.6 mol) of 2-aminothiazole-4-acetic acid into a three-necked bottle, uniformly stirring, adding 100G (0.34 mol) of a compound 5 (the content of nitrosamine impurity G06 is 0.011 ppm) and a water (143.6G) solution of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDC; 75.3G, about 0.39 mol), controlling the temperature to be 2-10 ℃ in the adding process, heating to 20-30 ℃ after the adding is finished, carrying out heat preservation reaction for 1h, and obtaining a reaction liquid after the point plate shows that the reaction is finished;

(2) Adding 1012g of purified water into the reaction solution, uniformly stirring, then adding a purified water (500 g) solution of sodium hydroxide (32.8 g), controlling the temperature to be 20-35 ℃ in the adding process, stirring for 1h, performing suction filtration, pulping for 2 times (3121 g multiplied by 2, each time for 30 min) by using the purified water, and performing suction filtration again to obtain a wet product B (which is detected by X-ray powder diffraction (XRD) and identified as a mirabegron beta crystal form);

(3) Adding the wet product B (containing about 150g of water) into a mixed solvent of isopropyl acetate (2248.5 g) and purified water (75 g), heating to 68-78 ℃ while stirring, cooling to 15-25 ℃ (the cooling rate is 5 ℃/10 min) after complete dissolution, stirring for 40min, and performing suction filtration to obtain a wet product A (which is detected by X-ray powder diffraction (XRD) and identified as a mirabegron alpha crystal form);

(4) Adding the wet product A (about 290G) into 422G of ethanol, heating to 50-60 ℃, stirring and dissolving, then performing suction filtration by a Buchner funnel (a pad of activated carbon), adding 108G of ethanol and 840G of purified water into the filtrate, heating to 65-75 ℃, then slowly cooling to 5-10 ℃ (the cooling rate is 5 ℃/10 min), performing heat preservation and stirring for 1h, performing suction filtration, controlling the temperature to be 20-30 ℃ and performing vacuum drying (the vacuum degree is less than or equal to-0.09 MPa) to obtain the white mirabegron raw material drug (identified as mirabegron alpha crystal form), wherein the yield is 75.6%, the HPLC purity is greater than or equal to 99.8%, and the content of nitrosamine impurities G02 is 0.27ppm.

Example 14

The UHPLC-MS/MS method is adopted for the qualitative and/or quantitative detection of the nitrosamine impurity G02 in the mirabegron raw material medicine (API), and the chromatographic conditions and the mass spectrum conditions are shown in a table 23.

TABLE 23 chromatographic conditions and mass spectrometric conditions for detection of nitrosamine impurity G02 in mirabegron crude drug

An external standard method:

(2) The mirabegron raw material medicine to be detected is prepared into a test solution (the solvent is water: methanol =3:7, volume ratio), detection is carried out, the content (ppm) of nitrosamine impurities G02 in the mirabegron raw material medicine is finally obtained through calculation according to a linear equation, and the figure 2 shows that the acquisition time (acquisition time) of the nitrosamine impurities G02 is 4.641 min.

Example 15

The mirabegron drug substance was prepared into mirabegron tablets according to the formulation of table 24 below.

TABLE 24 formulation AM of mirabegron tablets

The preparation method (500-2500 tablets/batch) comprises the following steps:

(1) Premixing

Respectively sieving mirabegron, polyoxyethylene, polyethylene glycol, hydroxypropyl cellulose and tartaric acid with 40 mesh sieve, adding into a stirrer (rotation speed: 15 rpm), stirring for 20min, adding magnesium stearate (in granules) sieved with 60 mesh sieve, and continuously stirring for 10min to obtain premix;

(2) Dry granulation

Granulating the premix, wherein the specific parameters are as follows:

mesh (Mesh): 1.0mm;

feed rate (fed speed): 22rpm;

roller speed (Press roll speed): 10rpm;

roll gap (Clearance): 0.8mm;

oil pressure (Oil pressure): 40bar;

rotational speed (Breaking speed): 120rpm;

(3) Final mixing

Adding the granulated granules and magnesium stearate (outside granules) sieved by a 60-mesh sieve into a stirrer (rotating speed: 15 r/min) and stirring for 10min to obtain a final mixture;

(4) Tabletting (plain tablet)

Tabletting the final mixture, wherein the specific parameters are as follows:

mold size/shape (Tooling size/shape): 12X 6mm (oval);

turntable speed (Turret speed): 30rpm;

feed rate (fed speed): 30rpm;

average main pressure (Average main pressure): 20-25N;

(5) Coating (coated tablet)

Adding the opadry-yellow into purified water according to the proportion, uniformly mixing to obtain a coating dispersion, and coating tablets (plain tablets) by using a coating machine, wherein the specific parameters are as follows:

pan speed (Pan speed): 2rpm;

feed pan speed (Feed pan speed): 900rpm;

blower speed (Blower speed): 2100rpm;

intake air temperature (Inlet air temperature): 55 plus or minus 2 ℃;

outlet temperature (Outlet air temperature): 45 to 50 ℃;

bed temperature (Bed temperature): 40 to 45 ℃;

peristaltic pump speed (Peristtic pump rotating speed): 1rpm;

atomization pressure (Atomization pressure): 0.08MPa;

lance pressure (Spray gun pressure): 0.2MPa;

flat press (a flat press): 0.1MPa;

latex tube diameter (Latex tube diameter): 25mm;

drying temperature (Drying temperature): 40 ℃;

drying time (Drying time): 10min;

(6) Package (I)

HDPE bottles (high density polyethylene bottles) were used for packaging (30 tablets per bottle, 2g desiccant in).

Example 16

TABLE 25 formulation BM of mirabegron tablets

A mirabegron drug substance was prepared into mirabegron tablets according to substantially the same preparation method and formulation of table 25 as those of the previous example 15.

Example 17

TABLE 26 formulation CM of mirabegron tablets

A mirabegron drug substance was prepared into mirabegron tablets following essentially the same manufacturing method and recipe in table 26 as described in example 15 above.

Example 18

TABLE 27 formulation DM of Mirabegron tablets

Mirabegron drug substance is prepared into mirabegron tablets according to the substantially same preparation method as that of the previous example 15 (premixing: after mirabegron, polyoxyethylene, polyethylene glycol, hydroxypropylcellulose, tartaric acid and butylated hydroxytoluene are mixed, magnesium stearate (intragranular) is added) and the formulation of table 27.

Example 19

TABLE 28 formulation EM of Mirabegron tablets

A mirabegron drug substance was prepared into mirabegron tablets according to substantially the same preparation method and formulation of table 28 as those of the previous example 18.

Example 20

TABLE 29 formulation FM of mirabegron tablets

A mirabegron drug substance was prepared into mirabegron tablets according to substantially the same preparation method as in example 18 and the formulation of table 29.

Example 21

Accelerated testing of mirabegron tablets:

the mirabegron coated tablets packaged by HDPE bottles obtained in examples 15 to 20 were placed at 40 ℃. + -. 2 ℃ and 75%. + -. 5% relative humidity, and were sampled once at the end of 1 month (1M), 2 months (2M) and 3 months (3M) of the test period, and then the qualitative and/or quantitative detection of nitrosamine impurity G02 in the mirabegron tablets was carried out by UHPLC-MS/MS method (the chromatographic conditions and mass spectrometric conditions were the same as those in the mirabegron bulk drug detection method of example 14), and the detection results are shown in Table 30.

Quantitative determination (external standard method):

(2) Preparing a mirabegron tablet to be detected into a test solution (the solvent is water: methanol =3:7, volume ratio), detecting, calculating the concentration (ng/ml) of nitrosamine impurities G02 in the test solution according to a linear equation, and calculating the content of the nitrosamine impurities G02 in the mirabegron tablet according to the following formula;

c (ppm) = G02 concentration in sample solution (ng/ml)/mirabegron concentration in sample solution (mg/ml)

Wherein the concentration of mirabegron (mg/ml) = mirabegron content per tablet (mg/tablet) × number of tablets/dilution volume (ml) in the sample solution.

TABLE 30 results of nitrosamine impurity G02 in mirabegron tablets during accelerated testing

According to the common knowledge in the art, an Ames test (contaminant mutagenicity test) or the like can be used to identify whether the nitrosamine impurity compound is genotoxic, for example, the impurity compound G02 is genotoxic (mutagenicity positive).

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof, and it is therefore intended that all such changes and/or modifications be considered within the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising the following components: a secondary amine compound and a pharmaceutically acceptable acid; wherein the secondary amine compound is the following compound or a pharmaceutically acceptable salt thereof, a crystalline form of any of the foregoing, or a solvate of any of the foregoing: the pharmaceutical composition has a nitrosamine impurity content of no greater than 7.5ppm;

serial number Name of Chinese Serial number Name of Chinese 1 Pabociclib 23 Imatinib 2 Salmeterol 24 Hydrochlorothiazide 3 Pemetrexed 25 Sertraline 4 Dabigatran etexilate 26 Atenolol 5 Mirabegron 27 Bupropion derivatives 6 Ticagrelor 28 Paroxetine 7 Venetolara 29 Sulfamethoxazole 8 Simpinicline 30 Methylphenidate 9 Duloxetine 31 Benzonatate and its preparation 10 Salbutamol 32 Diclofenac acid 11 Rilpivirine 33 Enalapril 12 Aforana (r.) Africa 34 Benazepril 13 Metoprolol 35 Hydroxychloroquine 14 Vilanterol 36 Chloroquine 15 Fluticasone furoate/vilanterol 37 Propranolol (Propranolol) 16 Vonoprazan 38 Nortriptyline 17 Metformin 39 Nebivolol 18 Formoterol 40 Vannicallan 19 Pomalidomide 41 Oazamod 20 Cinacalcet 42 Ribocillin 21 Oxitinib 43 Nilaparib 22 Pazopanib

。

2. The pharmaceutical composition of claim 1, wherein the secondary amine compound is a salt, a crystalline form or a solvate of the following compound with a pharmaceutically acceptable acid:

preferably, the first and second electrodes are formed of a metal,

more preferably, the amount of the organic solvent is,

the secondary amine compound is the following salifying compound or a crystal form and a solvate thereof: palbociclib hydrochloride, salmeterol xinafoate, dabigatran etexilate mesylate, ticagrelor hydrochloride, duloxetine hydrochloride, salbutamol sulfate, rilpivirine hydrochloride, metoprolol tartrate, metoprolol succinate, vilanterol triphenate, vilanterol triflate, vorexanoprazine fumarate, metformin hydrochloride, formoterol fumarate, formoterol tartrate, cinacalcet hydrochloride, oxirtinib mesylate, pazopanib hydrochloride, imatinib mesylate, sertraline hydrochloride, bupropion hydrobromide, paroxetine hydrochloride, paroxetine maleate, methylphenidate hydrochloride, enalapril maleate, benazepril hydrochloride, hydroxychloroquine sulfate, chloroquine phosphate, propranolol hydrochloride, nortriptyline hydrochloride, nebivolol hydrochloride, imitanid tartrate, pavafloxacin hydrochloride, oxacillin hydrochloride, nilapanib succinate, or toluenesulfonic acid.

3. The pharmaceutical composition of claim 1, wherein the secondary amine compound is mirabegron;

or, the secondary amine compound is varenicline tartrate; or the secondary amine compound is Vanillan hydrochloride.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the molar ratio of the secondary amine compound to the pharmaceutically acceptable acid is 1 (0.01 to 50), for example, a molar ratio of 1; preferably, the molar ratio of secondary amine compound to pharmaceutically acceptable acid is 1 (1-20) (e.g., a molar ratio of 1:2-15, 1:3-15, 1:4-15, 1:5-10); more preferably, the molar ratio of the secondary amine compound to the pharmaceutically acceptable acid is 1 (2 to 10).

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition further comprises pharmaceutically acceptable excipients;

preferably, the first and second liquid crystal display panels are,

(6) and polymer: the polymer is selected from one or more of polyoxyethylene (including low molecular polyoxyethylene and high molecular polyoxyethylene, wherein the low molecular polyoxyethylene is also called polyethylene glycol), polyvinylpyrrolidone, polyoxyethylene hardened castor oil and polyoxyethylene polyoxypropylene glycol, preferably the polymer is PEO N60K and polyethylene glycol;

more preferably, the pharmaceutically acceptable auxiliary material comprises one or more of the above auxiliary materials (1) to (5);

it is still further preferred that the first and second liquid,

still more preferably, the pharmaceutically acceptable excipients meet one or more of the following conditions:

(1) Comprises (1), (4) and (6);

(2) Comprises (1), (4), (5) and (6);

(3) Comprises (1), (4), (5), (6) and (7);

more preferably, the pharmaceutical composition meets one or more of the following conditions:

(1) The weight ratio of the secondary amine compound to the diluent is 1 (100-300); preferably 1 (150-250); more preferably 1 (184-195);

(2) The weight ratio of the secondary amine compound to the disintegrant is 1 (1-10); preferably 1 (2-6); more preferably 1 (3.5-4.5); for example 1:4;

(3) The weight ratio of the secondary amine compound to the glidant is 1 (0.1-8); preferably 1 (0.2-5); more preferably 1 (0.5 to 2.5); most preferably 1 (0.8-2), for example 1;

(4) The weight ratio of the secondary amine compound to the lubricant is 1 (0.1-8); preferably 1 (0.2-5); more preferably 1 (0.5 to 2.5); most preferably 1 (1-2), such as 1:1, 1.4 or 1:2;

(5) The diluent is microcrystalline cellulose and anhydrous calcium hydrogen phosphate; or, hydroxypropyl cellulose;

(6) The disintegrant is partially pregelatinized starch;

(7) The glidant is colloidal silicon dioxide; and

(8) The lubricant is stearate; magnesium stearate or sodium stearate is preferred.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is a solid preparation or a liquid preparation; the solid preparation is preferably a tablet, for example, a plain tablet or a coated tablet.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is an oral formulation.

8. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutically acceptable acid is a solid acid or a liquid acid;

preferably, when the pharmaceutical composition is a solid formulation, the pharmaceutically acceptable acid is a solid acid; when the pharmaceutical composition is a liquid formulation, the pharmaceutically acceptable acid is a solid acid or a liquid acid;

preferably, the solid acid is selected from one or more of tartaric acid, succinic acid, maleic acid, fumaric acid, citric acid, malic acid, ascorbic acid, benzenesulfonic acid, oxalic acid, triphenylacetic acid, 1-hydroxy-2-naphthoic acid and 3-hydroxy-2-naphthoic acid; the liquid acid is selected from one or more than two of hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid and trifluoromethanesulfonic acid;

more preferably, the pharmaceutically acceptable acid is tartaric acid.

9. The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutical composition has a nitrosamine impurity level of no greater than 7.4ppm, no greater than 7.3ppm, no greater than 7.2ppm, no greater than 7.1ppm, no greater than 7.0ppm; not more than 6.9ppm, not more than 6.8ppm, not more than 6.7ppm, not more than 6.6ppm, not more than 6.5ppm, not more than 6.4ppm, not more than 6.3ppm, not more than 6.2ppm, not more than 6.1ppm, not more than 6.0ppm; not more than 5.9ppm, not more than 5.8ppm, not more than 5.7ppm, not more than 5.6ppm, not more than 5.5ppm, not more than 5.4ppm, not more than 5.3ppm, not more than 5.2ppm, not more than 5.1ppm, not more than 5.0ppm; no greater than 4.9ppm, no greater than 4.8ppm, no greater than 4.7ppm, no greater than 4.6ppm, no greater than 4.5ppm, no greater than 4.4ppm, no greater than 4.3ppm, no greater than 4.2ppm, no greater than 4.1ppm, no greater than 4.0ppm, no greater than 3.9ppm, no greater than 3.8ppm, no greater than 3.7ppm, no greater than 3.6ppm, no greater than 3.5ppm, no greater than 3.4ppm, no greater than 3.3ppm, no greater than 3.2ppm, no greater than 3.1ppm, no greater than 3.0ppm; no greater than 2.9ppm, no greater than 2.8ppm, no greater than 2.7ppm, no greater than 2.6ppm, no greater than 2.5ppm, no greater than 2.4ppm, no greater than 2.3ppm, no greater than 2.2ppm, no greater than 2.1ppm, or no greater than 2.0ppm;

more preferably, when the secondary amine compound is mirabegron or a drug thereofWhen the salt is acceptable in chemistry, the nitrosamine impurity is

More preferably, when the secondary amine compound is varenicline tartrate or the secondary amine compound is varenicline hydrochloride, the nitrosamine impurity is valenicline hydrochloride

10. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition is a regimen A or a regimen B:

scheme a:

or, scheme B:

1.71 parts of secondary amine compound;

100-250 parts of diluent;

2-10 parts of a disintegrating agent;

0-5 parts of a flow aid;

0-5 parts of a lubricant;

0.01 to 15 portions of pharmaceutically acceptable acid;

1.71 parts of secondary amine compound;

5363 parts of diluent 184.47;

4 parts of a disintegrating agent;

0.6 part of a flow aid;

5 parts of a lubricant;

1.71 to 3.42 portions of pharmaceutically acceptable acid;

more preferably still, the first and second liquid crystal compositions are,

the pharmaceutical composition is any one of the following formulas:

the first scheme is as follows:

1.71 parts of varenicline tartrate;

64 parts of anhydrous calcium bicarbonate;

5363 parts of microcrystalline cellulose 120.47;

4 parts of partial pregelatinized corn starch;

0.6 part of colloidal silicon dioxide;

5 parts of stearic acid;

3.42 parts of L- (+) -tartaric acid;

scheme II:

1.71 parts of varenicline tartrate;

64 parts of anhydrous calcium bicarbonate;

5363 parts of microcrystalline cellulose 120.47;

4 parts of partial pregelatinized corn starch;

0.6 part of colloidal silicon dioxide;

5 parts of stearic acid;

1.71 parts of L- (+) -tartaric acid;

the third scheme is as follows:

1.71 parts of varenicline tartrate;

64 parts of anhydrous calcium bicarbonate;

5363 parts of microcrystalline cellulose 120.47;

4 parts of partial pregelatinized corn starch;

0.6 part of colloidal silicon dioxide;

5 parts of stearic acid;

3.42 parts of L- (+) -tartaric acid;

6 parts of Opadry-white or Opadry-blue;

and the scheme is as follows:

1.71 parts of varenicline tartrate;

64 parts of anhydrous calcium bicarbonate;

5363 parts of microcrystalline cellulose 120.47;

4 parts of partial pregelatinized corn starch;

0.6 part of colloidal silicon dioxide;

5 parts of stearic acid;

1.71 parts of L- (+) -tartaric acid;

6 parts of opadry-white or opadry-blue.

11. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition has a pH value of 4 or less under the following test conditions: preferably, the pH is 1 to 4, e.g., 1, 1.5, 2, 2.5, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4, etc.;

when the pharmaceutical composition is a solid formulation, the test conditions are: mixing the pharmaceutical composition with water having a pH =6 ± 0.1 to form a 20% concentration dispersion, and testing the resulting pH;

when the pharmaceutical composition is a liquid formulation, the test conditions are: the solvent of the liquid formulation was water at pH =6 ± 0.1, the concentration of the liquid formulation was 20%, and the resulting pH value was tested.

12. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 11, characterized in that it comprises the following steps: mixing all the components, granulating, tabletting, and optionally coating;

preferably, the first and second electrodes are formed of a metal,

the granulation is dry granulation or wet granulation;

the tabletting is a direct tabletting method.

13. Use of a pharmaceutical composition according to any one of claims 1 to 11 for the manufacture of a medicament;

preferably, the medicament is used for the treatment and/or prevention of the following diseases: inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, diarrhea, capsulitis, vasoconstriction, anxiety, mania, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis, cognitive dysfunction, cognitive disorders caused by alcohol, barbiturates, vitamin deficiency, recreational drugs, lead, arsenic or mercury, alzheimer's disease, senile dementia, vascular dementia, parkinson's disease, multiple sclerosis, aids, encephalitis, trauma, hepatorenal encephalopathy, hypothyroidism, pick's disease, kefir syndrome, prefrontal dementia or subcortical dementia, hypertension, bulimia, anorexia, obesity, arrhythmia, hyperchlorhydria, ulcers, pheochromocytoma, progressive supranuclear palsy, nicotine, tobacco products, alcohol, benzodiazepines

Chemical dependencies and addictions to barbiturates, opioids or cocaine, headache, migraine, stroke, traumatic brain injury, obsessive-compulsive disorder, psychosis, huntington's chorea, tardive dyskinesia, hyperkinesia, reading disorder, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, attention deficit hyperactivity disorder or Tourette's syndrome.

14. Use of a pharmaceutically acceptable acid to inhibit or slow nitrosation of a secondary amine compound; wherein the secondary amine compound is the following compound or a pharmaceutically acceptable salt thereof, a crystalline form of any of the foregoing, or a solvate of any of the foregoing:

serial number Name of Chinese Serial number Name of Chinese 1 Pabociclib 23 Imatinib 2 Salmeterol 24 Hydrochlorothiazide 3 Pemetrexed 25 Sertraline 4 Dabigatran etexilate 26 Atenolol 5 Mirabegron 27 Bupropion derivatives 6 Ticagrelor 28 Paroxetine 7 Venetolara 29 Sulfamethoxazole 8 Simpinicline 30 Methylphenidate 9 Duloxetine 31 Benzonatate 10 Salbutamol 32 Diclofenac acid 11 Rilpivirine 33 Enalapril 12 Aforana 34 Benazepril 13 Metoprolol 35 Hydroxychloroquine 14 Vilanterol 36 Chloroquine 15 Fluticasone furoate/vilanterol 37 Propranolol (Propranolol) 16 Vonoprazan 38 Nortriptyline 17 Metformin 39 Nebivolol 18 Formoterol 40 Vancolan 19 Pomalidomide 41 Oazamod 20 Cinacalcet 42 Rapocillin 21 Oxititinib 43 Nilaparib 22 Pazopanib

Preferably, said pharmaceutically acceptable acid and/or said secondary amine compound is as defined in any one of claims 1 to 4.

15. A method for inhibiting or slowing nitrosation of a secondary amine compound, comprising contacting the secondary amine compound or a combination thereof with a pharmaceutical

Mixing with acceptable acid; wherein the secondary amine compound is the following compound or a pharmaceutically acceptable salt thereof, a crystalline form of any of the foregoing, or a solvate of any of the foregoing: