CN112979639A - Novel crystal form of Maropitan and preparation method thereof - Google Patents

Novel crystal form of Maropitan and preparation method thereof Download PDF

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CN112979639A
CN112979639A CN201911299978.1A CN201911299978A CN112979639A CN 112979639 A CN112979639 A CN 112979639A CN 201911299978 A CN201911299978 A CN 201911299978A CN 112979639 A CN112979639 A CN 112979639A
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citric acid
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marantan
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宿磊
李峰
陈真贵
傅霖
陈刚
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Kemus medical technology (Shanghai) Co.,Ltd.
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Abstract

A novel crystal form of Marupitan and a preparation method thereof. The invention provides an amorphous malopiptan citrate compound and a preparation method thereof, a pharmaceutical composition and application thereof. The amorphous malopiptan citrate compound has stable property, good water solubility and high bioavailability, and provides an effective solution for improving the safety and effectiveness of medicaments; meanwhile, the preparation method of the amorphous malopitan citrate compound disclosed by the invention is simple in process, high in yield and high in purity, and is suitable for industrial mass production.

Description

Novel crystal form of Maropitan and preparation method thereof
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation method and application of a novel crystal form of malpigram.
Background
The chemical name of the malopiptan is (2S, 3S) -2-benzhydryl-N- (5-tert-butyl-2-methoxy benzyl alcohol) quinuclidine-3-amine, belongs to one of alternative quinine drugs, is a receptor antagonist of neurokinin type 1 (NK1), and can act on the central nervous system by inhibiting substance P (a key neurotransmitter causing emesis), so that the malopiptan can inhibit peripheral and central emesis. Malopiptan was also developed as citrate monohydrate under the trade name Cerenia (antiemetic), developed by the pioneer research of the company pfeiri, and was approved by the FDA in 2007 for the prevention and treatment of acute emesis in dogs, and subsequently approved for the prescription of cats. The chemical structural formula of the marketed macriptan citrate monohydrate is as follows:
Figure BDA0002319166180000011
patent CN1353711A of the Feverre company discloses a crystal form of malpigram citrate monohydrate and a preparation method thereof. However, the water solubility and physicochemical stability of the crystalline form are poor. Patent CN106977512A discloses a preparation method of a crystalline form of macriptan free base, but the solubility of the crystalline form of macriptan free base is poor. In addition, the prior art reports very little about other crystal forms of the marapidem.
It is well known that different salified forms or different crystal forms of a drug may have different colors, melting points, stabilities, apparent solubilities, dissolution rates, etc., which directly affect the stability, solubility, hygroscopicity, bioavailability, etc. of the drug formulation and thus lead to differences in the quality and clinical efficacy of the drug. The preparation and research of other novel crystal forms of the marafortine hopefully further improve the in vitro dissolution and in vivo absorption properties after the drug is prepared, bring higher clinical value of the drug and are very significant.
Disclosure of Invention
The invention aims to provide amorphous malopiptan citric acid with stable property and good water solubility, and a preparation method, a pharmaceutical composition and application thereof.
The invention provides an amorphous malopiptan citrate compound, which is subjected to X-ray powder diffraction by adopting a Cu Ka radiation source, wherein an X-ray powder diffraction pattern of the compound has no characteristic peak; preferably, the compound has an X-ray powder diffraction pattern characteristic substantially as shown in figure 1, figure 4 or figure 5.
The invention provides a preparation method of amorphous malopiptan citric acid, which comprises the following operation steps:
A. heating and dissolving a crude product of the marantan citric acid hydrate by using a solvent;
B. filtering, concentrating the filtrate under reduced pressure to dryness, and drying the obtained product under reduced pressure to obtain the amorphous malupitan citric acid.
In the step A, the solvent is acetone, and the temperature range of heating and dissolving is 25-60 ℃; the volume mass ratio of the solvent acetone to the crude product of the marantan citric acid is 12: 1-2: 1mL/g, preferably 4: 1-6: 1 mL/g; in the step B, the temperature range of the reduced pressure concentration is 35-50 ℃; the temperature range of reduced pressure drying is 60-75 ℃.
In step a, the crude maropiptan citric acid can be subjected to citrate formation treatment with a free base of maropiptan in any conventional salt formation method, but considering the yield of the reaction itself and the reasons of impurities, the preferred preparation method is as follows:
C. dissolving free hippeasant alkali and citric acid monohydrate in acetone;
D. refluxing for dissolution, hot filtering, adding dropwise methyl tert-butyl ether into the filtrate, standing at room temperature for crystallization, filtering, and washing the filter cake with methyl tert-butyl ether.
In the step C, the mass ratio of citric acid monohydrate to free alkali of malapidem is 0.45: 1-0.5: 1; the volume-mass ratio of the acetone to the free alkali of the malpigtan is 5: 1-10: 1 mL/g.
In the step D, the volume mass ratio of the methyl tert-butyl ether to the free matriptan is 5: 1-10: 1.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the amorphous malopiptan citric acid as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients. Preferably, it is in the form of solution, injection, mixture, lotion, aerosol, spray, powder, pill, tablet, membrane, ointment, suppository, or paste.
The invention also provides application of the amorphous malopiptan citric acid in preparing a medicament for treating and preventing emesis.
The pharmaceutically acceptable auxiliary materials or auxiliary components are common excipients or auxiliary materials which are well known in the field and used for preparing the preparation. Common excipients or auxiliary materials for oral preparations or injections include, but are not limited to, fillers (diluents), lubricants (glidants or antiadherents), dispersants, wetting agents, binders, regulators, solubilizers, antioxidants, bacteriostats, disintegrants, and the like. Binders such as syrup, acacia, gelatin, starch slurry, povidone, cellulose derivatives, etc.; fillers such as lactose, dextrin, starch and its derivatives, cellulose derivatives, inorganic calcium salts, mannitol, agar powder, etc.; lubricants such as aerosil, stearic acid and its salts, talc, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants such as starch and its derivatives, crospovidone, cellulose derivatives, etc.; wetting agents such as water, alcohols or other organic solvents, and the like. Common excipients or adjuvants for such injections include, but are not limited to: antioxidants such as sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, and the like; bacteriostatic agents such as phenol, benzyl alcohol, chlorobutanol, etc.; regulators such as hydrochloric acid, citric acid, potassium (sodium) hydroxide, buffers, etc.; emulsifiers such as polysorbate 80, lecithin, soybean lecithin, etc.; solubilizers such as tween 80 and the like. In addition, the active ingredient can be mixed with pharmaceutically acceptable sustained or controlled release carrier to make sustained or controlled release preparation according to the preparation method of sustained or controlled release preparation known in the art.
The preparation form of the composition of the invention can be liquid preparation, solid preparation and semisolid preparation, and common dosage forms such as oral solution, injection, tablet and the like are preferred.
Compared with the existing crystalline form of the maratanian citric acid monohydrate and the maratanian free alkali, the amorphous maratanian citric acid provided by the invention has the advantages of more stable property, better water solubility and high bioavailability, and provides an effective solution for improving the safety and effectiveness of medicaments; in addition, the amorphous malopiptan citric acid disclosed by the invention is simple in preparation process, high in yield and suitable for industrial production.
Drawings
Figure 1X-ray powder diffraction pattern of amorphous marantan citric acid prepared in example 1.
Figure 2 TGA profile of amorphous marapitan citric acid prepared in example 1.
Figure 3 DSC profile of amorphous maratanan citric acid prepared in example 1.
Figure 4X-ray powder diffraction pattern of amorphous marantan citric acid prepared in example 2.
Figure 5X-ray powder diffraction pattern of amorphous marantan citric acid prepared in example 3.
Detailed Description
All the raw materials and equipment of the invention are known products and are obtained by purchasing commercial products.
Wherein, the raw material of the marariptan free base (chemical name is (2S, 3S) -2-benzhydryl-N- (5-tert-butyl-2-methoxy benzyl alcohol) quinuclidine-3-amine) is a known compound and is prepared according to the method reported in the prior literature.
Example 1 preparation of amorphous Maropritan citric acid
Dissolving 500.0g of marantan free base (with HPLC content of 98.0%) and 224.0g of citric acid monohydrate in 3.5L of acetone, heating to reflux and dissolve, performing heat filtration, dropwise adding 3.5L of methyl tert-butyl ether into the filtrate, standing at room temperature for crystallization overnight, filtering, and washing a filter cake with methyl tert-butyl ether to obtain 688.0g of crude marantan citric acid monohydrate, wherein the yield is 95.0%.
688.0g of crude malopiptan citric acid monohydrate is added into 2.8L of acetone and heated to 50 ℃ for dissolution, the mixture is filtered, the filtrate is concentrated to be dry at 40 ℃ under reduced pressure, and the obtained sample is dried for 72 hours at 70 ℃ under reduced pressure to obtain 685.7g of white powdery amorphous malopiptan citric acid with the yield of 100 percent, the HPLC content of 100.10 percent and the HPLC purity of 99.91 percent.
The Karl Fischer water content detection method comprises the following steps:
0.2g of the product is precisely weighed, and the moisture content is 1.28 percent according to the moisture content determination method (2015 edition of the four parts of Chinese pharmacopoeia).
Drying weight loss test:
1.0g of the product is precisely weighed, and the result of the loss on drying is 2.29 percent according to the loss on drying determination method (2015 edition in the four parts of Chinese pharmacopoeia).
Figure 2 provides a TGA profile of amorphous marariptan citric acid prepared under the preparation method of this example; FIG. 3 provides a DSC spectrum of amorphous malopiptan citric acid prepared under the preparation method of the example; meanwhile, the residual solvent detection shows that the acetone residue result is 0.87%, the methyl tertiary butyl ether residue result is 0.16%, and the comprehensive water and solvent residue measurement result is consistent with the result of the loss on drying and the TGA result.
Example 2 preparation of amorphous Maropritan citric acid
Dissolving 500.0g of marantan free base (with HPLC content of 98.0%) and 250.0g of citric acid monohydrate in 2.5L of acetone, heating to reflux for reaction for 1 hour, carrying out hot filtration, dropwise adding 5.0L of methyl tert-butyl ether into the filtrate, standing at room temperature for crystallization overnight, filtering, and washing a filter cake with methyl tert-butyl ether to obtain 673.5g of crude marantan citric acid monohydrate, wherein the yield is 93.0%.
673.5g of crude malopiptan citrate monohydrate is added into 4.0L of acetone and heated to 40 ℃ for dissolution, the mixture is filtered, the filtrate is concentrated to be dry at 50 ℃ under reduced pressure, and the obtained sample is dried for 65 hours at 75 ℃ under reduced pressure to obtain 671.2g of white powdery amorphous malopiptan citrate with the yield of 100 percent, the HPLC content of 99.95 percent and the HPLC purity of 99.92 percent.
The Karl Fischer water content detection method comprises the following steps:
0.2g of the product is precisely weighed, and the moisture content is 1.29 percent according to the moisture content determination method (2015 edition of the four parts of Chinese pharmacopoeia).
Drying weight loss test:
1.0g of the product is precisely weighed, and the result of the loss on drying is 2.30 percent according to the loss on drying determination method (2015 edition in the four parts of Chinese pharmacopoeia).
Figure 4 provides an X-ray powder diffraction pattern of the amorphous marapitan citric acid.
Example 3 preparation of amorphous Maropritan citric acid
Dissolving 500.0g of marantan free base (with HPLC content of 98.0%) and 225.0g of citric acid monohydrate in 5L of acetone, heating to reflux for reaction for 1 hour, carrying out hot filtration, dropwise adding 5L of methyl tert-butyl ether into the filtrate, standing at room temperature for crystallization overnight, filtering, and washing a filter cake with methyl tert-butyl ether to obtain 681.0g of crude marantan citric acid monohydrate with the yield of 94.0%.
681.0g of crude malopiptan citrate monohydrate is added into 8.3L of acetone and heated to 25 ℃ for dissolution, the mixture is filtered, the filtrate is concentrated to be dry at 35 ℃ under reduced pressure, and the obtained sample is dried for 80 hours at 60 ℃ under reduced pressure to obtain 678.7g of white powdery amorphous malopiptan citrate with the yield of 100 percent, the HPLC content of 99.92 percent and the HPLC purity of 99.85 percent.
The Karl Fischer water content detection method comprises the following steps:
0.2g of the product is precisely weighed, and the moisture content is 1.30 percent according to the moisture content determination method (2015 edition of the four parts of Chinese pharmacopoeia).
Drying weight loss test:
1.0g of the product is precisely weighed, and the result of the loss on drying is 2.31 percent according to the loss on drying determination method (2015 edition in the four parts of Chinese pharmacopoeia).
Figure 5 provides an X-ray powder diffraction pattern of the amorphous marapitan citric acid.
Example 4 preparation of amorphous Maropritan citric acid
688.0g of crude malopiptan citrate monohydrate is added into 1.4L of acetone and heated to 60 ℃ for dissolution, the mixture is filtered, the filtrate is concentrated to dryness at 40 ℃ under reduced pressure, and the obtained sample is dried for 72 hours at 70 ℃ under reduced pressure to obtain 685.7g of amorphous malopiptan citrate, wherein the yield is 100%, the HPLC content is 99.97%, and the HPLC purity is 99.84%.
The Karl Fischer water content detection method comprises the following steps:
0.2g of the product is precisely weighed, and the moisture content is 1.28 percent according to the moisture content determination method (2015 edition of the four parts of Chinese pharmacopoeia).
Drying weight loss test:
1.0g of the product is precisely weighed, and the result of the loss on drying is 2.29 percent according to the loss on drying determination method (2015 edition in the four parts of Chinese pharmacopoeia).
Example 5 sustained release tablets prepared from amorphous Maropritan citric acid of the invention
Figure BDA0002319166180000051
Uniformly mixing amorphous marantan citric acid, hydroxypropyl methylcellulose and lactose to be prepared, sieving, adding 75% ethanol solution to prepare soft material, sieving with a 20-mesh sieve to prepare wet granules, drying at about 50 ℃, grading with a 20-mesh sieve, adding magnesium stearate and talcum powder, uniformly mixing, and tabletting.
Example 6 capsules of amorphous Maropritan citric acid of the invention
Figure BDA0002319166180000052
Uniformly mixing amorphous marantan citric acid and starch to be prepared by equivalent incremental method, uniformly mixing with microcrystalline cellulose, granulating, and making into capsule.
Example 7 Sublingual tablets prepared with amorphous Maropritan citric acid of the invention
Figure BDA0002319166180000061
The raw and auxiliary materials are respectively sieved by a 100-mesh sieve. Uniformly mixing amorphous maratanan citric acid and low-substituted hydroxypropyl methylcellulose in a to-be-prepared amount by an equivalent incremental method, sequentially adding mannitol and lactose starch, finally adding sweet orange essence and magnesium stearate, uniformly mixing, and tabletting.
Comparative example:
the citric acid malopiptan is prepared by the following method, and the types and the processing conditions of different solvents and the types and the quality of the obtained crystal forms are shown in the following table 1:
A. heating and dissolving a crude product of the marantan citric acid hydrate prepared by the prior art by using a solvent;
B. drying or filtering after recrystallization, concentrating the filtrate under reduced pressure to dryness, and drying the obtained product under reduced pressure.
TABLE 1 solvent type, treatment conditions and resulting crystalline forms
Figure BDA0002319166180000062
Figure BDA0002319166180000071
The applicant of the present invention has screened a large amount of solvents, only acetone can obtain the amorphous form of the marantan citric acid under the condition of reduced pressure concentration, and the volume-to-mass ratio of the solvent acetone to the crude marantan citric acid monohydrate is 20: 1-2: 1mL/g, wherein the temperature range of reduced pressure concentration is 35-50 ℃; the temperature range of reduced pressure drying is required to be 60-75 ℃, and if the solvent volume proportion, the concentration temperature or the drying temperature are not in the range, the obtained mixed crystal composed of amorphous form of the malpigram citric acid and the citric acid monohydrate crystal form, or the solvent residue, the impurity content and the like of the obtained amorphous form of the malpigram citric acid are too large.
The beneficial effects of the present invention are demonstrated by the following experimental examples.
Experimental example 1 solubility test of Crystal form
Test group 1 amorphous malopitan citric acid prepared in example i of the present invention;
control group 1, marantan citric acid monohydrate prepared by the method disclosed in the prior art (example 1 of CN 1353711A);
control group 2: the prepared free matriptan base is disclosed in the prior art (example 5 of CN 106977512A).
Weighing 0.5g of test sample, placing in water of 25 + -2 deg.C, shaking strongly every 1min for 10s, observing dissolution condition within 3min, if no visible dissolved particles exist, determining as complete dissolution; if there are visually-dissolved particles, 10 times the weight of the test article of water (i.e., 5ml of water) is added and the above procedure is repeated until complete dissolution occurs. The total water usage was recorded and the results are shown in table 2.
TABLE 2 solubility of different crystal modifications
Figure BDA0002319166180000081
The solubility test results in table 1 show that the solubility of free alkali of malpigtan is very poor, and almost insoluble in water, and the amount of water required for dissolving and the time required for completely dissolving the amorphous malpigtan citric acid prepared by the invention are both significantly less than those of the crystalline form of malpigtan citric acid monohydrate disclosed by the prior art, i.e. the solubility of the amorphous malpigtan citric acid disclosed by the invention is significantly better than that of the crystalline form of malpigtan citric acid monohydrate disclosed by the prior art. In general, good water solubility may improve the bioavailability and in vivo absorption of the drug, and may be developed into more dosage forms to improve the therapeutic effect of clinical medication.
Experimental example 2 test of Crystal form stability Effect
1. Experimental methods
(1) Preparation of test article
Test group 1 amorphous malopitan citric acid prepared in example i of the present invention;
control group 1, marantan citric acid monohydrate prepared by the method disclosed in the prior art (example 1 of CN 1353711A);
control group 2: the prepared free matriptan base is disclosed in the prior art (example 5 of CN 106977512A).
(2) The stability test conditions included: (1) thermal degradation: taking about 200mg of a test sample, and placing the test sample in a drying oven at 60 ℃; (2) photo-degradation: taking about 200mg of a test sample, and placing the test sample in an environment with the illumination of 4500 +/-5001 x; (3) high-humidity degradation: about 200mg of the sample was taken and placed in a desiccator containing a saturated solution of KNO3 at room temperature. The stability test results are shown in table 3.
2. Results of the experiment
TABLE 3 stability test results
Figure BDA0002319166180000082
Figure BDA0002319166180000091
The test results in table 2 show that the purity of the amorphous malopitan citric acid prepared by the invention has no obvious change under the conditions of high heat, high humidity and illumination. The purity of the control group 1, the marariptan citric acid monohydrate and the marariptan free alkali of the control group 2 are reduced under the conditions of high heat, high humidity and illumination.
Therefore, compared with the amorphous malopiptan citric acid monohydrate and the free alkali of the malopiptan disclosed by the prior art, the amorphous malopiptan citric acid prepared by the invention has more stable and controllable quality, and is suitable for manufacturing and storing medicinal preparations for a long time.
Test example 3 bioavailability test
Test group 1 amorphous malopitan citric acid prepared in example i of the present invention;
control group 1, marantan citric acid monohydrate prepared by the method disclosed in the prior art (example 1 of CN 1353711A);
8 healthy male beagle dogs were randomly divided into 2 groups of 4, each group being orally administered with an equivalent dose of 8mg/kg (as marariptan free base) of amorphous marariptan citric acid, marariptan citric acid monohydrate, respectively. The test sample was prepared as an aqueous solution at a concentration of lmg/mL before administration. Beagle dogs were fasted for 12 hours prior to dosing and returned to food 4 hours after dosing. Blank blood was taken before administration, 4ml of blood was taken from the forelimb vein at preset time intervals of 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 24 hours after administration, placed in a centrifuge tube containing heparin, plasma was separated by centrifugation at 4000 rpm for l0min, supernatant was taken, concentration of malopiptan in plasma was measured, pharmacokinetic parameters were calculated, and the results are shown in table 4. Comparison of pharmacokinetic parameters for each group was considered to be significantly different using One-way analysis of variance (AVOVA) with P <0.05 or P < 0.01.
TABLE 4 comparison of pharmacokinetic parameters
Test subject AUC(ng·h/mL) T1/2(h) Tmax(h) Cmax(ng/mL)
Test group 1 9450±72.4## 5.2±0.1 1.6±0.1# 978±18.6##
Control group 1 7760±63.2 5.4±0.1 1.7±0.1 776±17.4
Compared with the crystalline form of the citric acid monohydrate of the marantan,#P<0.05,##P<0.01。
the test results in table 3 show that: compared with the existing product, namely the citric acid monohydrate of the marariptan, the average blood concentration-area under time curve (AUC) value of the amorphous marariptan citric acid is improved by about 21.7%, and the peak concentration (Cmax) is improved by 26%, which shows that under the condition of the same administration dosage, the dosage of the amorphous marariptan citric acid is improved by about 21.7% compared with the dosage of the crystalline form of the marariptan citric acid monohydrate in the prior art, the highest blood concentration which can be reached is improved by 26% compared with the crystalline form of the marariptan citric acid monohydrate in the prior art, the bioavailability is higher, and the medicinal effect can be better exerted.
In conclusion, compared with the crystalline form of the marafortian citric acid monohydrate and the marafortian free base disclosed in the prior art, the amorphous marafortian citric acid provided by the invention is more stable in property, better in water solubility and remarkably improved in bioavailability, and an effective solution is provided for improving the effectiveness and safety of a medicament; in addition, the preparation process of the compound is simple, the yield is higher than that of the preparation method in the prior art, and the compound is suitable for industrial production.

Claims (9)

1. An amorphous malopitan citric acid, which is characterized in that: the amorphous marantan citric acid has no characteristic peak in X-ray powder diffraction.
2. Amorphous maratanan citric acid according to claim 1, characterized in that: having the X-ray powder diffraction pattern characteristics substantially as shown in figure 1, figure 4 or figure 5.
3. Amorphous maratanian citric acid according to any one of claims 1-2, characterized in that: the preparation method comprises the following steps:
A. heating and dissolving a crude product of the marantan citric acid hydrate by using a solvent;
B. filtering, concentrating the filtrate under reduced pressure to dryness, and drying the obtained product under reduced pressure to obtain the final product;
in the step A, the solvent is acetone, and the temperature range for heating and dissolving is 25-60 ℃; the volume mass ratio of the solvent acetone to the crude product of the marantan citric acid is 12: 1-2: 1mL/g, preferably 4: 1-6: 1 mL/g; in the step B, the temperature range of the reduced pressure concentration is 35-50 ℃; the temperature range of reduced pressure drying is 60-75 ℃.
4. The preparation method according to claim 3, wherein the crude marantan citric acid hydrate is prepared by the following method:
C. dissolving free hippeasant alkali and citric acid monohydrate in acetone;
D. refluxing for dissolution, hot filtering, adding dropwise methyl tert-butyl ether into the filtrate, standing at room temperature for crystallization, filtering, and washing the filter cake with methyl tert-butyl ether.
5. The method for preparing a crude maropiptan citrate hydrate according to claim 4, comprising: in the step C, the mass ratio of citric acid monohydrate to free alkali of marantan is as follows: 0.45: 1-0.5: 1; the volume-mass ratio of the acetone to the free alkali of the malpigtan is 5: 1-10: 1 mL/g.
6. The method for preparing a crude maropiptan citrate hydrate according to claim 4, comprising: in the step D, the volume mass ratio of the methyl tert-butyl ether to the free matriptan is 5: 1-10: 1.
7. A pharmaceutical composition characterized by: the pharmaceutical preparation comprises the amorphous malopiptan citric acid as an active ingredient in the claim 1 or the claim 2 and pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
8. The pharmaceutical composition of claim 7, wherein: the preparation is liquid preparation, gas preparation, solid preparation and semisolid preparation, preferably solution, injection, mixture, lotion, aerosol, spray, powder, pill, tablet, membrane, ointment, suppository and paste.
9. Amorphous malopitan citric acid as claimed in claim 1 or claim 2, for use in the manufacture of a medicament for the treatment and prevention of emesis.
CN201911299978.1A 2019-12-16 2019-12-16 Novel crystal form of Maropitan and preparation method thereof Pending CN112979639A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1353711A (en) * 1999-06-01 2002-06-12 辉瑞产品公司 Polymorphs of crystalline azabicyclo (2,2,2) octan-3-amine citrate and their pharmaceutical compositions
CN1914202A (en) * 2004-02-02 2007-02-14 辉瑞产品有限公司 Process for preparation of 1-(2s,3s)-2-benzhydryl-n-(5-tert-butyl-2-methoxybenzyl)quinuclidin-3-amine
CN106977512A (en) * 2017-05-04 2017-07-25 海门慧聚药业有限公司 The method for preparing the smooth free alkali of horse sieve
CN109320510A (en) * 2018-11-27 2019-02-12 海门慧聚药业有限公司 Preparation method of Maropitan free base

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1353711A (en) * 1999-06-01 2002-06-12 辉瑞产品公司 Polymorphs of crystalline azabicyclo (2,2,2) octan-3-amine citrate and their pharmaceutical compositions
CN1914202A (en) * 2004-02-02 2007-02-14 辉瑞产品有限公司 Process for preparation of 1-(2s,3s)-2-benzhydryl-n-(5-tert-butyl-2-methoxybenzyl)quinuclidin-3-amine
CN106977512A (en) * 2017-05-04 2017-07-25 海门慧聚药业有限公司 The method for preparing the smooth free alkali of horse sieve
CN109320510A (en) * 2018-11-27 2019-02-12 海门慧聚药业有限公司 Preparation method of Maropitan free base

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