WO2006092617A1 - Crystallisation and purification of glycopyrronium bromide - Google Patents

Crystallisation and purification of glycopyrronium bromide Download PDF

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Publication number
WO2006092617A1
WO2006092617A1 PCT/GB2006/000770 GB2006000770W WO2006092617A1 WO 2006092617 A1 WO2006092617 A1 WO 2006092617A1 GB 2006000770 W GB2006000770 W GB 2006000770W WO 2006092617 A1 WO2006092617 A1 WO 2006092617A1
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solvent
product
diastereoisomers
crystallisation
particle size
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Andrew Douglas Baxter
Kenneth Walter Sinden
Stefan Kleinebekel
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Sosei R&D Ltd
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Arakis Ltd
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Priority to EP06709993A priority Critical patent/EP1856041B1/en
Priority to HK07113058.5A priority patent/HK1104817B/en
Priority to DE602006006808T priority patent/DE602006006808D1/en
Priority to AU2006219727A priority patent/AU2006219727B2/en
Priority to MX2007010729A priority patent/MX2007010729A/en
Priority to DK06709993T priority patent/DK1856041T3/en
Priority to BRPI0609057-5A priority patent/BRPI0609057A2/en
Priority to CN2006800069015A priority patent/CN101133021B/en
Priority to JP2007557594A priority patent/JP5319119B2/en
Application filed by Arakis Ltd filed Critical Arakis Ltd
Priority to US11/817,166 priority patent/US8846954B2/en
Priority to AT06709993T priority patent/ATE431337T1/en
Priority to CA2601129A priority patent/CA2601129C/en
Priority to NZ561293A priority patent/NZ561293A/en
Publication of WO2006092617A1 publication Critical patent/WO2006092617A1/en
Priority to IL185576A priority patent/IL185576A/en
Anticipated expiration legal-status Critical
Priority to NO20074558A priority patent/NO340220B1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/06—Anti-spasmodics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • This invention relates to a method of crystallisation and purification of the anti- muscarinic drug glycopyrronium bromide.
  • Glycopyrronium bromide (Glycopyrrolate, US Pharmacopeia) is the higher melting (193.2°C-194.5°C) of two possible diastereoisomeric racemates, i.e. the erythro racemate. Glycopyrronium bromide is manufactured by the method disclosed in US-A- 2956062, utilizing ⁇ /-methylpyrrolidin-3-ol (NMP) and methyl hydroxycyclopentylmandelate (MCPM), as follows:
  • the initial product from the methylation reaction in methyl ethyl ketone (MEK; stage 3) is isolated as an approximately 50:50 mixture of the two possible pairs of diastereoisomers.
  • MEK methyl ethyl ketone
  • R 1 S and S,R pair of diastereoisomers the R 1 RI S 1 S pair is removed by recrystallising the crude product from a mixture of methanol and MEK.
  • the US Pharmacopeia makes no provision for the determination of the amount of the R,R and S 1 S diastereoisomeric pair in the active pharmaceutical ingredient.
  • MCPM may contain high levels of impurities. These impurities react competitively in stage 2, to produce high levels of carried through impurities in glycopyrronium base, and then in the final salt.
  • This invention relates to the production of glycopyrronium bromide utilising a novel crystallization process (Stage 3 in scheme 1).
  • a consistent and fine particle size is controlled by the solvent, e.g. a solvent of the formula
  • the process preferably comprises also a slow cooling rate in the final crystallization steps.
  • the particle size of glycopyrronium bromide produced by this method ensures a physically stable micronised drug substance that is suitable for formulation into a drug product optimized for inhaled delivery.
  • carrying out the methylation reaction in acetone ensures that the ratio of diastereoisomeric pairs is 60:40 in favour of the desired R,S and S,R pair. This ensures a reduction in the number of recrystallisation steps that are required to remove the R 1 RI S,S pair.
  • acetone is exemplified, other solvents that may be found suitable include esters, e.g. of acetic acid such as ethyl acetate, and other ketones such as methyl isobutyl ketone (MEK).
  • R 1 and R 2 are preferably C 1-4 alkyl, and R 1 is preferably methyl.
  • a higher ketone than acetone is preferred for the recrystallisation.
  • Impurities are efficiently reduced by carrying out the methylation reaction in acetone compared to MEK. Sequential recrystallisations from MEK / methanol systematically eliminate these impurities alongside the R 1 R / S 1 S pair of diastereoisomers.
  • the overall yield of glycopyrronium bromide as a product of the methylation reaction and subsequent purification steps is typically 20-30%. Additional recrystallisation steps can be added should the material from the any given recrystallisation not meet the preferred specification of not more than 0.2% R,R/S,S.
  • the following Example illustrates the invention. "Cold” means a temperature of 0-10 0 C. Stage 3: Methylation Reaction in Acetone A solution of crude glycopyrronium base (13.0 kg; 42.8 mol) in acetone (130 L) is treated with methyl bromide gas (4.5 kg; 47.4 mol) over 30 minutes while maintaining a temperature between -5 0 C and 5 0 C.
  • the material (5.3 kg) is dissolved at reflux in a mixture of methanol (4.2 L) and MEK (33 L). Additional MEK (47 L) is added and reflux (75-85°C) maintained for 30 minutes. The mixture is then cooled to between -10 0 C and O 0 C at a rate of 30 0 C / hour allowing controlled crystallisation of a purified product that is filtered, washed with cold MEK (20 L) and oven dried.
  • the drug substance is a fine white crystalline solid (4.9 kg).
  • the purity of the product from this first recrystallisation is typically not less than 99.95% and the diastereoisomeric purity is typically not less than 99.8% (by HPLC).
  • This method uses a Waters Alliance 2695 HPLC system with a PDA 996 detector, column oven and Waters Empower data system or equivalent:
  • Run times and relative response times for H,S/S,flglycopyrronium bromide (the drug substance) and the R,R/S,S impurity are as follows:
  • the method has a limit of detection of 0.03% and a limit of quantification of 0.1%.
  • the process as described is capable of reproducing a drug substance with not more than 0.2% of the R,R/S,S pair.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyrrole Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Silicates, Zeolites, And Molecular Sieves (AREA)

Abstract

A method for the production of crystalline glycopyrronium bromide, comprises the reaction of glycopyrronium base with methyl bromide in a solvent, in which the solvent is selected such that the diastereoisomeric ratio of the product favours the R,S and S,R diastereoisomers over the R,R, and S,S diastereoisomers, and separating the desired diastereoisomers by one or more controlled crystallisation steps. This method gives a product having a particle size of narrow distribution.

Description

CRYSTALLISATION AND PURIFICATION OF GLYCOPYRRONIUM BROMIDE Field of the Invention
This invention relates to a method of crystallisation and purification of the anti- muscarinic drug glycopyrronium bromide. Background of the Invention
Glycopyrronium bromide (Glycopyrrolate, US Pharmacopeia) is the higher melting (193.2°C-194.5°C) of two possible diastereoisomeric racemates, i.e. the erythro racemate. Glycopyrronium bromide is manufactured by the method disclosed in US-A- 2956062, utilizing Λ/-methylpyrrolidin-3-ol (NMP) and methyl hydroxycyclopentylmandelate (MCPM), as follows:
Figure imgf000002_0001
Recryst.
Figure imgf000002_0002
Glycopyrronium Bromide
The initial product from the methylation reaction in methyl ethyl ketone (MEK; stage 3) is isolated as an approximately 50:50 mixture of the two possible pairs of diastereoisomers. In order to obtain the desired drug, i.e. the racemic mixture of the
R1S and S,R pair of diastereoisomers, the R1RI S1S pair is removed by recrystallising the crude product from a mixture of methanol and MEK.
In the established manufacturing process, there is no provision to control the particle size of the drug substance. The large and inconsistent particle size produces a physically unstable drug substance following micronisation. Material is difficult to formulate into a drug product suitable for inhalation.
Further, apart from controlling the melting point, the US Pharmacopeia makes no provision for the determination of the amount of the R,R and S1S diastereoisomeric pair in the active pharmaceutical ingredient.
Commercially available MCPM may contain high levels of impurities. These impurities react competitively in stage 2, to produce high levels of carried through impurities in glycopyrronium base, and then in the final salt.
Summary of the Invention This invention relates to the production of glycopyrronium bromide utilising a novel crystallization process (Stage 3 in scheme 1). In addition to high purity, a consistent and fine particle size is controlled by the solvent, e.g. a solvent of the formula
R1COR2 or R1COOR2 wherein R1 and R2 are each alkyl of 1 to 8 C atoms. In addition, the process preferably comprises also a slow cooling rate in the final crystallization steps. The particle size of glycopyrronium bromide produced by this method ensures a physically stable micronised drug substance that is suitable for formulation into a drug product optimized for inhaled delivery.
In a preferred embodiment of the invention, carrying out the methylation reaction in acetone ensures that the ratio of diastereoisomeric pairs is 60:40 in favour of the desired R,S and S,R pair. This ensures a reduction in the number of recrystallisation steps that are required to remove the R1RI S,S pair.
Description of the Invention
Based on information provided herein, one of ordinary skill in the art can readily determine a solvent that is suitable for use in the invention. While acetone is exemplified, other solvents that may be found suitable include esters, e.g. of acetic acid such as ethyl acetate, and other ketones such as methyl isobutyl ketone (MEK). In the given formulae, R1 and R2 are preferably C1-4 alkyl, and R1 is preferably methyl. A higher ketone than acetone is preferred for the recrystallisation.
Impurities are efficiently reduced by carrying out the methylation reaction in acetone compared to MEK. Sequential recrystallisations from MEK / methanol systematically eliminate these impurities alongside the R1R / S1S pair of diastereoisomers.
The overall yield of glycopyrronium bromide as a product of the methylation reaction and subsequent purification steps is typically 20-30%. Additional recrystallisation steps can be added should the material from the any given recrystallisation not meet the preferred specification of not more than 0.2% R,R/S,S. The following Example (stage 3 of the 3-stage process shown above) illustrates the invention. "Cold" means a temperature of 0-100C. Stage 3: Methylation Reaction in Acetone A solution of crude glycopyrronium base (13.0 kg; 42.8 mol) in acetone (130 L) is treated with methyl bromide gas (4.5 kg; 47.4 mol) over 30 minutes while maintaining a temperature between -50C and 50C. The mixture is then warmed to between 150C and 250C and maintained at this temperature for 2 hours to ensure complete crystallisation of the glycopyrronium bromide has taken place. The product is filtered by centrifugation, washed with cold acetone (40-60 L) and collected (15 kg). Stage 3.1: First Recrvstallisation
The material (15 kg) is dissolved at reflux in a mixture of methanol (13.0 L) and MEK (90 L). Additional MEK (135 L) is added and reflux (75-850C) maintained for 30 minutes. The mixture is then cooled to between -100C and O0C at a rate of 30°C/hour, allowing controlled crystallisation of a purified product which is filtered by centrifugation, washed with cold MEK (30-50 L) and collected (7 kg). The purity of the product from this first recrystallisation is typically not less than 99% and the diastereoisomeric purity is typically 94-95% (by HPLC). Stage 3.2: Second Recrvstallisation The material (7 kg) is dissolved at reflux in a mixture of methanol (10.2 L) and
MEK (45 L). Additional MEK (65 L) is added and reflux (75-850C) maintained for 30 minutes. The mixture is then cooled to between -100C and 00C at a rate of 30°C/hour, allowing controlled crystallisation of a purified product which is filtered by centrifugation, washed with cold MEK (20-30 L) and the product collected (5.3 kg). The purity of the product from this recrystallisation is typically not less than 99.9% and the diastereoisomeric purity is typically not less than 99.5% (by HPLC). Stage 3.3: Third Recrvstallisation
The material (5.3 kg) is dissolved at reflux in a mixture of methanol (4.2 L) and MEK (33 L). Additional MEK (47 L) is added and reflux (75-85°C) maintained for 30 minutes. The mixture is then cooled to between -100C and O0C at a rate of 300C / hour allowing controlled crystallisation of a purified product that is filtered, washed with cold MEK (20 L) and oven dried. The drug substance is a fine white crystalline solid (4.9 kg). The purity of the product from this first recrystallisation is typically not less than 99.95% and the diastereoisomeric purity is typically not less than 99.8% (by HPLC). Analytical Methods
This method uses a Waters Alliance 2695 HPLC system with a PDA 996 detector, column oven and Waters Empower data system or equivalent:
Column: Astec Cyclobond I 2000; 250 mm x 4.6 mm ID Temperature: 150C Injection Volume: 20 μL Detection: UV at 230 nM Run Time: 20 min Mobile Phase: 1.0 M triethyl ammonium acetate buffer solution (5.0 ml) mixed with acetonitrile (750 ml) and HPLC water (245 ml)
Flow Rate: 1.0 ml /min Gradient: lsocratic
Run times and relative response times for H,S/S,flglycopyrronium bromide (the drug substance) and the R,R/S,S impurity are as follows:
Figure imgf000005_0001
The method has a limit of detection of 0.03% and a limit of quantification of 0.1%. The process as described is capable of reproducing a drug substance with not more than 0.2% of the R,R/S,S pair.
A HPLC method has been developed and validated providing an in-process check and test method to control levels of this impurity to < 0.2% in batches of the drug substance. Due to the efficiency of the crystallization required to meet this specification, all other impurities are eliminated. Impurities carried through from impure MCPM can readily be eliminated in the recrystallisation steps. Stage 1, Purity of MCPM
Figure imgf000005_0002
Figure imgf000006_0001
Impurity 1 Impurity 2
Stage 2, Glycopyrronium Base Formation from impure MCPM
Figure imgf000006_0003
Figure imgf000006_0002
Impurity 2.1
Impurity 1.1
Stage 3, Glycopyrronium Bromide Formation and Purification.
Figure imgf000006_0004
Figure imgf000007_0001
Impurity 1.2 Impurity 2.2
ND = Not Detected
This Example validates the purification procedure, demonstrating that even poor quality MCPM can be processed to drug substance of excellent quality. The elimination of these impurities is apparently the consequence of controlled recrystallisation. Uncontrolled crystallization leads to an impure product with an inconsistent particle size distribution. It was surprising to find the controlled cooling rate employed not only defined a high level of purity but also provided control of particle size distribution and uniform morphological habit, as shown by imaging. Subsequent micronisation of this product has provided a physically stable drug substance that is suitable for formulation into a drug product optimized for inhaled delivery.

Claims

1. A method for the production of crystalline glycopyrronium bromide, which comprises the reaction of glycopyrronium base with methyl bromide in a solvent, in which the solvent is selected such that the diastereoisomeric ratio of the product favours the R1S and S,R diastereoisomers over the R,R, and S,S diastereoisomers, and separating the desired diastereoisomers by one or more controlled crystallisation steps.
2. A method according to claim 1 , wherein the reaction solvent and also the solvent in which the crystallization is conducted each comprise the same or different compounds of the formula R1COR2 or R1COOR2 wherein R1 and R2 are independently C1-S alkyl.
3. A method according to claim 2, wherein the reaction solvent is acetone.
4. A method according to claim 2 or claim 3, wherein the crystallisation solvent comprises methyl ethyl ketone or methyl isobutyl ketone.
5. A method according to claim 4, wherein the crystallisation solvent is a mixture of methyl ethyl ketone and methanol.
6. A method according to any preceding claim, wherein the diastereoisomeric purity of the product is more than 99.8% R,S/S,R.
7. A method according to any preceding claim, wherein the particle size of the product is less than 100 μm.
8. A method according to claim 7, wherein the particle size is less than 50 μm.
9. A method according to any preceding claim, wherein the diastereoisomeric ratio is at least 60:40 in favour of the R1S/ S,R- pair.
10. Crystalline glycopyrronium bromide obtainable by a method according to any preceding claim, having a particle size of narrow distribution.
PCT/GB2006/000770 2005-03-03 2006-03-03 Crystallisation and purification of glycopyrronium bromide Ceased WO2006092617A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
JP2007557594A JP5319119B2 (en) 2005-03-03 2006-03-03 Crystallization and purification of glycopyrronium bromide
DE602006006808T DE602006006808D1 (en) 2005-03-03 2006-03-03 CRYSTALLIZATION AND PURIFICATION OF GLYCOPYRRONIUM BROMIDE
US11/817,166 US8846954B2 (en) 2005-03-03 2006-03-03 Crystallisation and purification of glycopyrronium bromide
MX2007010729A MX2007010729A (en) 2005-03-03 2006-03-03 Crystallisation and purification of glycopyrronium bromide.
DK06709993T DK1856041T3 (en) 2005-03-03 2006-03-03 Crystallization and purification of glycopyrronium bromide
BRPI0609057-5A BRPI0609057A2 (en) 2005-03-03 2006-03-03 crystallization and purification of glycopyrranium bromide
CN2006800069015A CN101133021B (en) 2005-03-03 2006-03-03 Crystallisation and purification of glycopyrronium bromide
EP06709993A EP1856041B1 (en) 2005-03-03 2006-03-03 Crystallisation and purification of glycopyrronium bromide
AU2006219727A AU2006219727B2 (en) 2005-03-03 2006-03-03 Crystallisation and purification of glycopyrronium bromide
HK07113058.5A HK1104817B (en) 2005-03-03 2006-03-03 Crystallisation and purification of glycopyrronium bromide
AT06709993T ATE431337T1 (en) 2005-03-03 2006-03-03 CRYSTALLIZATION AND PURIFICATION OF GLYCOPYRRONIUM BROMIDE
CA2601129A CA2601129C (en) 2005-03-03 2006-03-03 Crystallisation and purification of glycopyrronium bromide
NZ561293A NZ561293A (en) 2005-03-03 2006-03-03 Crystallisation and purification of glycopyrronium bromide
IL185576A IL185576A (en) 2005-03-03 2007-08-29 Crystallisation and purification of glycopyrronium bromide
NO20074558A NO340220B1 (en) 2005-03-03 2007-09-10 Crystalline glycopyrronium bromide

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GB0504463.1 2005-03-03
GBGB0504463.1A GB0504463D0 (en) 2005-03-03 2005-03-03 Method of crystallisation and purification

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US (1) US8846954B2 (en)
EP (1) EP1856041B1 (en)
JP (1) JP5319119B2 (en)
KR (1) KR101267108B1 (en)
CN (1) CN101133021B (en)
AT (1) ATE431337T1 (en)
AU (1) AU2006219727B2 (en)
BR (1) BRPI0609057A2 (en)
CA (1) CA2601129C (en)
DE (1) DE602006006808D1 (en)
DK (1) DK1856041T3 (en)
ES (1) ES2326132T3 (en)
GB (1) GB0504463D0 (en)
IL (1) IL185576A (en)
MX (1) MX2007010729A (en)
NO (1) NO340220B1 (en)
NZ (1) NZ561293A (en)
PT (1) PT1856041E (en)
WO (1) WO2006092617A1 (en)
ZA (1) ZA200707512B (en)

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EP2417106B1 (en) 2009-04-09 2016-11-30 Novartis AG Process for preparing pyrrolidinium salts
WO2017212273A1 (en) * 2016-06-08 2017-12-14 Hovione Scientia Limited Crystalline pharmaceutical co-crystals of glycopyrronium bromide with lactose
WO2022079194A1 (en) 2020-10-14 2022-04-21 Pcas Process for the production of glycopyrronium tosylate

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US20090005577A1 (en) * 2007-06-29 2009-01-01 Nikolai Kraiouchkine Method of producing 1-substituted 3-pyrrolates
ES2528957T3 (en) * 2010-06-14 2015-02-13 Chiesi Farmaceutici S.P.A. Crystalline form of glycopyrronium chloride
CN103159659A (en) * 2011-12-19 2013-06-19 沈阳药科大学 Preparation method of muscarinic receptor antagonist glycopyrronium bromide
CN102627595A (en) * 2012-03-09 2012-08-08 徐奎 Method for preparation of glycopyrronium bromide
EP3473615B1 (en) 2013-02-28 2022-01-19 Journey Medical Corporation Glycopyrrolate salts
US9006462B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Glycopyrrolate salts
US8558008B2 (en) 2013-02-28 2013-10-15 Dermira, Inc. Crystalline glycopyrrolate tosylate
CN105175304A (en) * 2013-11-13 2015-12-23 李兴惠 Cholinolytic drug glycopyrronium bromide and composition
US9926270B2 (en) 2014-08-20 2018-03-27 Dermira, Inc. Process for production of glycopyrronium tosylate
CZ2014680A3 (en) 2014-10-06 2016-04-13 Zentiva, K.S. Process for preparing glycopyrronium bromide
US9925168B2 (en) * 2016-01-22 2018-03-27 Chiesi Farmaceutici S.P.A. Preparation of micronized particles of an antimuscarinic compound by hydrodynamic cavitation
CN107345945B (en) * 2016-05-05 2019-12-17 辽宁药联制药有限公司 High performance liquid chromatography method for resolving glycopyrronium bromide enantiomer and checking impurities
CN107915666A (en) * 2016-10-09 2018-04-17 四川海思科制药有限公司 A kind of glycopyrronium bromide compound
CN113234003B (en) * 2021-04-23 2024-02-02 广东嘉博制药有限公司 Glycopyrronium bromide and preparation method thereof
CN114428131B (en) * 2021-12-27 2023-09-15 山东泰合医药科技有限公司 A detection method for resolving diastereoisomers of glycopyrrolate intermediates

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EP2417106B1 (en) 2009-04-09 2016-11-30 Novartis AG Process for preparing pyrrolidinium salts
WO2017212273A1 (en) * 2016-06-08 2017-12-14 Hovione Scientia Limited Crystalline pharmaceutical co-crystals of glycopyrronium bromide with lactose
US10662152B2 (en) 2016-06-08 2020-05-26 Hovione Scientia Limited Crystalline pharmaceutical co-crystals of glycopyrronium bromide with lactose
AU2017278484B2 (en) * 2016-06-08 2020-10-22 Hovione Scientia Limited Crystalline pharmaceutical co-crystals of glycopyrronium bromide with lactose
WO2022079194A1 (en) 2020-10-14 2022-04-21 Pcas Process for the production of glycopyrronium tosylate

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