CN111635327A - Amorphous crystal form of methacholine chloride and preparation method thereof - Google Patents
Amorphous crystal form of methacholine chloride and preparation method thereof Download PDFInfo
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- CN111635327A CN111635327A CN202010566389.1A CN202010566389A CN111635327A CN 111635327 A CN111635327 A CN 111635327A CN 202010566389 A CN202010566389 A CN 202010566389A CN 111635327 A CN111635327 A CN 111635327A
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- methacholine chloride
- amorphous
- crystal form
- dissolving
- methacholine
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- 229960002931 methacholine chloride Drugs 0.000 title claims abstract description 61
- JHPHVAVFUYTVCL-UHFFFAOYSA-M methacholine chloride Chemical compound [Cl-].C[N+](C)(C)CC(C)OC(C)=O JHPHVAVFUYTVCL-UHFFFAOYSA-M 0.000 title claims abstract description 61
- 239000013078 crystal Substances 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 51
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 39
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims description 22
- 239000012065 filter cake Substances 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 18
- 238000005303 weighing Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960002329 methacholine Drugs 0.000 description 1
- NZWOPGCLSHLLPA-UHFFFAOYSA-N methacholine Chemical compound C[N+](C)(C)CC(C)OC(C)=O NZWOPGCLSHLLPA-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- OWUBJZCBVVZIEG-UHFFFAOYSA-M trimethyl-[2-(2-oxopropoxy)ethyl]azanium chloride Chemical compound [Cl-].CC(=O)COCC[N+](C)(C)C OWUBJZCBVVZIEG-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to the technical field of medicine crystal forms, in particular to an amorphous crystal form of methacholine chloride and a preparation method thereof. In an X-ray powder diffraction pattern of the methacholine chloride amorphous crystal form, 2 theta +/-0.2 degrees is used for representing, and an amorphous characteristic steamed bun peak exists at 2 theta = 20-35. The preparation method comprises the following steps: dissolving the crude product of the methacholine chloride in acetonitrile or n-butanol, and dropwise adding ethyl acetate, acetone or tetrahydrofuran to obtain the amorphous crystal form of the methacholine chloride. The amorphous crystal form has better stability to moisture, thereby being beneficial to the production and quality control of raw material medicaments.
Description
Technical Field
The invention relates to the technical field of medicine crystal forms, in particular to an amorphous crystal form of methacholine chloride and a preparation method thereof.
Background
Acetylmethylcholine chloride, also known as methacholine, is a white, very hygroscopic crystal with a light odor of dead fish and has the molecular formula C8H18ClNO2. Can excite M choline receptor, has strong selectivity to cardiovascular system and weak effect on gastrointestinal tract and bladder smooth muscle, and can also shrink bronchial smooth muscle to increase bronchial secretion.
Methacholine chloride is very sensitive to moisture, is easy to absorb moisture and agglomerate or is easy to deliquesce into liquid, and is not beneficial to storage. Due to the characteristics, the production of the raw material medicaments is greatly inconvenient, especially in the refining process. Meanwhile, in the new United states pharmacopoeia (USP-43), the water content of the raw material medicine is controlled to be below 0.5 percent, and higher requirements are provided for the production control and the wet stability of the methacholine chloride.
In the existing literature, CN 110950767 a discloses a preparation method of a new crystal form of methacholine chloride, which is characterized in that the stability is better in an acceleration test through ethanol-ethyl acetate mixed solvent crystallization or acetone, acetonitrile and ethyl acetate single solvent crystallization. But mainly aims at related substances of products, the crystal form is found to be still easy to absorb moisture into a liquid state in the actual production process, and operations such as centrifugation, mixing, packaging and the like are difficult to perform in the production process. The crystal form has poor wet stability, and even if a special packaging material such as an aluminum plastic package and the like is adopted, one item of moisture detection is still unqualified in long-term stability.
Disclosure of Invention
The invention aims to provide an amorphous crystal form of methacholine chloride and a preparation method thereof, and aims to solve the problems that methacholine chloride is easy to deliquesce and the moisture content is easy to exceed the standard in the prior art.
The technical scheme of the invention is as follows:
an amorphous form of methacholine chloride, wherein an X-ray powder diffraction pattern of the amorphous form of methacholine chloride is expressed by 2 theta +/-0.2 degrees, and an amorphous characteristic steamed bun peak exists at 2 theta 20-35.
Preferably, the amorphous form of methacholine chloride has an endothermic peak at 236.34 ± 2 ℃ in a DSC diagram.
A process for preparing an amorphous crystalline form of methacholine chloride, the process comprising the steps of:
1) dissolving methacholine chloride in a dissolving solvent;
2) dripping a crystallization solvent into the system obtained in the step 1), and cooling to precipitate crystals after solid is precipitated;
3) filtering, and drying the obtained filter cake;
the preparation of the amorphous crystal form of methacholine chloride is completed.
Preferably, the dissolving solvent of step 1) is acetonitrile or n-butanol or a combination thereof; the liquid-solid ratio of the dissolving solvent to the methacholine chloride is 1.8-3 mL/g.
Preferably, the temperature of the dissolution of step 1) is 45-55 ℃.
Preferably, the dissolving solvent in the step 1) is added in two parts, the dissolving solvent with the mass 1-1.2 times of that of the methacholine chloride is firstly added, the temperature is raised to 45-55 ℃, and then the rest dissolving solvent is dripped in.
Preferably, the temperature for dropping in the step 2) is 45-55 ℃.
Preferably, the crystallization solvent dropped in step 2) is ethyl acetate, or tetrahydrofuran, or acetone, or a combination thereof.
Preferably, the liquid-solid ratio of the crystallization solvent to the methacholine chloride in the step 2) is 2-8 mL/g.
Preferably, the temperature in the step 2) is reduced to 0-5 ℃, and the mixture is stirred for 2-4h to precipitate crystals.
The use of the amorphous crystalline form of methacholine chloride or the amorphous crystalline form of methacholine chloride prepared by the method of: the application of the compound in preparing the medicaments for treating cardiovascular diseases.
The invention has the following beneficial effects:
1. the present invention provides amorphous forms of methacholine chloride. Compared with CN 110950767A, it has stronger moisture stability, is convenient for the production and quality control of methacholine chloride, and is beneficial to the newly increased moisture control requirement of pharmacopoeia.
2. The good solvent of the crystal form is acetonitrile, absolute ethyl alcohol, and the crystallization solvent is ethyl acetate, tetrahydrofuran and acetone. The solvent combination has high yield, does not need seed crystal, can stably obtain amorphous crystal form in the production process, and has normal particle size distribution.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is an X-ray powder diffraction pattern of an amorphous form of methacholine chloride prepared according to an embodiment of the present invention;
FIG. 2 is a DSC diagram of amorphous form of methacholine chloride prepared in accordance with an example of the present invention;
FIG. 3 is a photomicrograph of an amorphous form of methacholine chloride prepared according to an example of the present invention;
FIG. 4 is an X-ray powder diffraction pattern of a crystalline form of methacholine chloride obtained by the method shown in the reference (CN 110950767A);
FIG. 5 is a photograph of a sample of methacholine chloride prepared in the reference (CN 110950767A) after being left for 1 hour at room temperature
FIG. 6 is a picture of a methacholine chloride sample prepared in an example of the present invention after being left at room temperature for 1 hour
Detailed Description
Example 1
The preparation method of the amorphous methacholine chloride crystal form comprises the following steps:
a first group:
(a) weighing 100g of crude methacholine chloride, placing the crude methacholine chloride in a container, adding 100mL of acetonitrile, stirring, slowly heating to 45-55 ℃, not completely dissolving the crude methacholine chloride, slowly dropwise adding the acetonitrile into the system, stopping dropwise adding the acetonitrile when the system is just clarified, and recording that the amount of the dropwise adding the acetonitrile is 96 mL.
(b) Keeping the solution system in the step (a) at 45-55 ℃, slowly dripping ethyl acetate into the system, stopping dripping the ethyl acetate when the system becomes turbid, recording that the dripping amount of the ethyl acetate is 352mL, and stopping heating.
(c) And (c) continuously stirring the turbid liquid in the step (b) to room temperature, cooling to 0-5 ℃, and stirring for 3 hours to precipitate crystals. The suspension is filtered off with suction, and the filter cake is washed with 30mL of ethyl acetate.
(d) And (c) drying the filter cake obtained in the step (c) for 24 hours under reduced pressure at room temperature to obtain uniform white powder with slow moisture absorption, weighing 87.98g and yield of 87.98%.
Second group:
(a) weighing 100g of crude methacholine chloride, placing the crude methacholine chloride in a container, adding 100mL of acetonitrile, stirring, slowly heating to 45-55 ℃, incompletely dissolving the crude methacholine chloride, slowly dropwise adding the acetonitrile into the system, stopping dropwise adding the acetonitrile when the system is just clarified, and recording that the amount of the dropwise adding acetonitrile is 89 mL.
(b) Keeping the solution system in the step (a) at 45-55 ℃, slowly dripping tetrahydrofuran into the system, stopping dripping the tetrahydrofuran when the system becomes turbid, recording that the dripping amount of the tetrahydrofuran is 467mL, and stopping heating.
(c) And (c) continuously stirring the turbid liquid in the step (b) to room temperature, cooling to 0-5 ℃, and stirring for 3 hours to precipitate crystals. The suspension is filtered off with suction, and the filter cake is washed with 30mL of tetrahydrofuran.
(d) And (c) drying the filter cake obtained in the step (c) for 24 hours under reduced pressure at room temperature to obtain uniform white powder with slow moisture absorption, weighing 87.98g and yield of 87.98%.
Third group:
(a) weighing 100g of crude methacholine chloride, placing the crude methacholine chloride in a container, adding 100mL of acetonitrile, stirring, slowly heating to 45-55 ℃, incompletely dissolving the crude methacholine chloride, slowly dropwise adding the acetonitrile into the system, stopping dropwise adding the acetonitrile when the system is just clarified, and recording that the amount of the dropwise adding the acetonitrile is 92 mL.
(b) Keeping the solution system in the step (a) at 45-55 ℃, slowly dripping acetone into the system, stopping dripping the acetone when the system becomes turbid, recording the quantity of the dripped acetone as 589mL, and stopping heating.
(c) And (c) continuously stirring the turbid liquid in the step (b) to room temperature, cooling to 0-5 ℃, and stirring for 3 hours to precipitate crystals. The suspension is filtered off with suction, and the filter cake is washed with 30mL of acetone.
(d) And (c) drying the filter cake obtained in the step (c) for 24 hours under reduced pressure at room temperature to obtain uniform white powder with slow moisture absorption, weighing 86.22g and yield of 86.22%.
Example 2
The preparation method of the amorphous methacholine chloride crystal form comprises the following steps:
a first group:
(a) weighing 100g of crude methacholine chloride, placing the crude methacholine chloride into a container, adding 200mL of n-butanol, stirring, slowly heating to 45-55 ℃, slowly dropwise adding the n-butanol into the system when the crude methacholine chloride is not completely dissolved, stopping dropwise adding the n-butanol when the system is just clarified, and recording the dropwise adding amount of the n-butanol to be 88 mL.
(b) Keeping the solution system in the step (a) at 45-55 ℃, slowly dripping ethyl acetate into the system, stopping dripping the ethyl acetate when the system becomes turbid, recording the dripping amount of the ethyl acetate to be 278mL, and stopping heating.
(c) And (c) continuously stirring the turbid liquid in the step (b) to room temperature, cooling to 0-5 ℃, and stirring for 3 hours to precipitate crystals. The suspension is filtered off with suction, and the filter cake is washed with 30mL of ethyl acetate.
(d) And (c) drying the filter cake obtained in the step (c) for 24 hours under reduced pressure at room temperature to obtain uniform white powder with slow moisture absorption, weighing 92.69g and yield of 92.69%.
Second group:
(a) weighing 100g of crude methacholine chloride, placing the crude methacholine chloride into a container, adding 200mL of n-butanol, stirring, slowly heating to 45-55 ℃, slowly dropwise adding the n-butanol into the system when the crude methacholine chloride is not completely dissolved, stopping dropwise adding the n-butanol when the system is just clarified, and recording the dropwise adding amount of the n-butanol to be 96 mL.
(b) Keeping the solution system in the step (a) at 45-55 ℃, slowly dripping tetrahydrofuran into the system, stopping dripping the tetrahydrofuran when the system becomes turbid, recording that the dripping amount of the tetrahydrofuran is 344mL, and stopping heating.
(c) And (c) continuously stirring the turbid liquid in the step (b) to room temperature, cooling to 0-5 ℃, and stirring for 3 hours to precipitate crystals. The suspension is filtered off with suction, and the filter cake is washed with 30mL of tetrahydrofuran.
(d) And (c) drying the filter cake obtained in the step (c) for 24 hours under reduced pressure at room temperature to obtain uniform white powder with slow moisture absorption, weighing 90.23g and yield of 90.23%.
Third group:
(a) weighing 100g of crude methacholine chloride, placing the crude methacholine chloride into a container, adding 200mL of n-butanol, stirring, slowly heating to 45-55 ℃, slowly dripping absolute ethyl alcohol into the system when the crude methacholine chloride is not completely dissolved, stopping dripping the absolute ethyl alcohol when the system is just clarified, and recording that the dripping amount of the absolute ethyl alcohol is 98 mL.
(b) Keeping the solution system in the step (a) at 45-55 ℃, slowly dripping acetone into the system, stopping dripping the acetone when the system becomes turbid, recording that the quantity of the dripped acetone is 471mL, and stopping heating.
(c) And (c) continuously stirring the turbid liquid in the step (b) to room temperature, cooling to 0-5 ℃, and stirring for 3 hours to precipitate crystals. The suspension is filtered off with suction, and the filter cake is washed with 30mL of acetone.
(d) And (c) drying the filter cake obtained in the step (c) for 24 hours under reduced pressure at room temperature to obtain uniform white powder with slow moisture absorption, weighing 88.04g and yield of 88.04%.
Synthesis of Compound (III)
Table 1 examples and comparative literature comparison of yields to impurities
The above-described embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and features in the embodiments and examples in the present application may be arbitrarily combined with each other without conflict. The protection scope of the present invention is defined by the claims, and includes equivalents of technical features of the claims. I.e., equivalent alterations and modifications within the scope hereof, are also intended to be within the scope of the invention.
Claims (9)
1. An amorphous crystalline form of methacholine chloride characterized by: in an X-ray powder diffraction pattern of the methacholine chloride amorphous crystal form, 2 theta +/-0.2 degrees is used for representing, and an amorphous characteristic steamed bun peak exists at 2 theta = 20-35.
2. The amorphous form of methacholine chloride according to claim 1, characterized in that: in a DSC picture of the amorphous crystal form of the methacholine chloride, an endothermic peak is shown at 236.34 +/-2 ℃.
3. A process for the preparation of an amorphous crystalline form of methacholine chloride, said process comprising the steps of:
1) dissolving methacholine chloride in a dissolving solvent;
2) dripping a crystallization solvent into the system obtained in the step 1), and cooling to precipitate crystals after solid is precipitated;
3) filtering, and drying the obtained filter cake;
the preparation of the amorphous crystal form of methacholine chloride is completed.
4. The method of claim 3, wherein: the dissolving solvent in the step 1) is acetonitrile or n-butanol or the combination thereof; the liquid-solid ratio of the dissolving solvent to the methacholine chloride is 1.8-3 mL/g.
5. The method of claim 3, wherein: the dissolving temperature of the step 1) is 45-55 ℃.
6. The method of claim 3, wherein: adding the dissolving solvent in the step 1) in two parts, firstly adding the dissolving solvent with the mass 1-1.2 times of that of the methacholine chloride, heating to 45-55 ℃, and then dropwise adding the rest dissolving solvent.
7. The method of claim 3, wherein: the dropping temperature in the step 2) is 45-55 ℃.
8. The method of claim 3, wherein: the crystallization solvent dropped in the step 2) is ethyl acetate, tetrahydrofuran, acetone or a combination thereof.
9. The method of claim 3, wherein: the liquid-solid ratio of the crystallization solvent in the step 2) to the methacholine chloride is 2-8 mL/g.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010566389.1A CN111635327A (en) | 2020-06-19 | 2020-06-19 | Amorphous crystal form of methacholine chloride and preparation method thereof |
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| CN202010566389.1A CN111635327A (en) | 2020-06-19 | 2020-06-19 | Amorphous crystal form of methacholine chloride and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113368065A (en) * | 2021-06-29 | 2021-09-10 | 上海轩耘生物医药科技有限公司 | Formulation of freeze-dried powder of methacholine chloride for inhalation and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2040145A (en) * | 1932-08-12 | 1936-05-12 | Merck & Co Inc | Beta-methylcholine derivatives and salts and processes for their production |
| EP1584334A2 (en) * | 2004-04-01 | 2005-10-12 | Methapharm Inc. | Solution based methacholine formulations |
| CN110950767A (en) * | 2018-09-26 | 2020-04-03 | 北京泰德制药股份有限公司 | Novel crystal form of methacholine chloride and preparation method thereof |
-
2020
- 2020-06-19 CN CN202010566389.1A patent/CN111635327A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2040145A (en) * | 1932-08-12 | 1936-05-12 | Merck & Co Inc | Beta-methylcholine derivatives and salts and processes for their production |
| EP1584334A2 (en) * | 2004-04-01 | 2005-10-12 | Methapharm Inc. | Solution based methacholine formulations |
| CN110950767A (en) * | 2018-09-26 | 2020-04-03 | 北京泰德制药股份有限公司 | Novel crystal form of methacholine chloride and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113368065A (en) * | 2021-06-29 | 2021-09-10 | 上海轩耘生物医药科技有限公司 | Formulation of freeze-dried powder of methacholine chloride for inhalation and preparation method thereof |
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