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WO2004089873A1 - Procede de cristallisation d'hydrochlorure de bupropion - Google Patents

Procede de cristallisation d'hydrochlorure de bupropion Download PDF

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Publication number
WO2004089873A1
WO2004089873A1 PCT/EP2004/050495 EP2004050495W WO2004089873A1 WO 2004089873 A1 WO2004089873 A1 WO 2004089873A1 EP 2004050495 W EP2004050495 W EP 2004050495W WO 2004089873 A1 WO2004089873 A1 WO 2004089873A1
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WO
WIPO (PCT)
Prior art keywords
bupropion hydrochloride
precipitating solvent
product
mixture
cooled
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2004/050495
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English (en)
Inventor
Massimo Ferrari
Florindo De Luca
Fiorella Lombardi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Erregierre SpA
Original Assignee
Erregierre SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Erregierre SpA filed Critical Erregierre SpA
Priority to CA002549350A priority Critical patent/CA2549350A1/fr
Publication of WO2004089873A1 publication Critical patent/WO2004089873A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton

Definitions

  • the present invention relates to a new process for crystallising Bupropion hydrochloride. This process enables Bupropion hydrochloride to be obtained in 5 the form of large crystals having a particle size distribution with D90% greater than 100 ⁇ m.
  • the particle size distribution of an active principle is a critical parameter in the production of solid and semi-solid pharmaceutical forms such as for example 0 tablets, capsules and suspensions.
  • the subdivision state of the active principle influences important properties both for technical purposes, for example flowing ability and compressibility, and for therapeutic purposes, in particular its dissolution rate and hence bio-availability.
  • Bupropion hydrochloride crystallisation conditions that allow said compound to be obtained in the form of o crystals with optimum dimensions and morphology for preparing pharmaceutical forms.
  • Bupropion hydrochloride obtained with the process of the present invention presents a particle size distribution with D90% greater than 100 ⁇ m.
  • FIGURES 5 Figure 1 shows an electron microscopic view of a Bupropion hydrochloride sample obtained with the method described in example 4.
  • Figure 2 shows an electron microscopic view of a Bupropion hydrochloride sample obtained with the method described in example 9.
  • Figures 3, 4 and 5 show electron microscopic views of samples of three different 0 batches (batch 1 , 2 and 3 respectively) of Bupropion hydrochloride obtained with the method described in example 17.
  • the present invention relates to a process for crystallising Bupropion hydrochloride comprising the following steps: a) Bupropion hydrochloride is dissolved in a mixture comprising methanol and a precipitating solvent for Bupropion hydrochloride; b) any insoluble residue is removed; c) the solution is distilled at atmospheric pressure until the precipitation reaction is triggered. d) the following are added: I) a precipitating solvent for Bupropion hydrochloride; and II) hydrochloric acid until a pH ⁇ 2 is obtained. e) the mass is cooled to a temperature less than 10°C, preferably between 0 and 3°C, and the precipitate obtained is separated.
  • the precipitate obtained is preferably washed with a precipitating solvent and dried at a temperature between 40 and 80°C.
  • the term "precipitating solvent” means a solvent in which Bupropion hydrochloride is insoluble even at temperatures greater that 60°C.
  • the same precipitating solvent is used in stages a) and d).
  • the precipitating solvents preferably used in the process of the present invention are chosen from the group consisting of C2 to C8 linear or branched alcohols, of which ethanol, 2-butanol and isopropyl alcohol are particularly preferred, acetone, acetonitrile, ethyl acetate, diglyme, toluene, 2-methoxyethanol (methyl cellosolve®) and dimethylformamide.
  • a particularly preferred precipitating solvent in the process of the present invention is 2-butanol.
  • methyl alcohol and precipitating solvent are in a ratio suitable to obtain the solubilisation of Bupropion hydrochloride.
  • the precipitating solvent is added in a quantity capable of achieving a precipitated mass with optimum operative characteristics.
  • the crystallisation process of the invention allows particles of Bupropion hydrochloride to be obtained having particle size distribution and morphology very different from those obtained using other crystallisation processes.
  • Bupropion hydrochloride with crystals of large dimensions (D90% greater than 100 ⁇ m) (examples 9 to 17) are obtained with the process of the invention, with other crystallisation processes (examples 1 to 8) a microcrystalline product is obtained.
  • Acetone 1000 g are fed into a 2 litre flask.
  • the mass is stirred at 20-30°C until dissolution is complete. Starting from this temperature and without exceeding 50°C, gaseous HCI is bubbled in until pH 2 is achieved. The precipitated mass is cooled to 0-3°C and filtered off, washing with
  • the wet product is dried at 70-80°C
  • the mixture is stirred at 60-65°C until dissolution is complete, cooled slowly to a temperature between 0 and 3°C and the precipitated mass is stirred at this temperature for about half an hour.
  • the product is then filtered off and washed with:
  • the wet product is dried at 70-80°C.
  • Dimethylformamide 160 g are fed into a 1 litre flask.
  • the wet product is dried at 70-80°C.
  • the mixture is stirred at 90-95°C until dissolution is complete. Then
  • Acetone 200 g is added. The mixture is slowly cooled to a temperature between 0 and 3°C and the crystallised product is filtered off and washed with: Acetone 90 g
  • the wet product is dried at 70-80°C.
  • 2-Butanol 150 g are fed into a 500 ml flask.
  • the mixture is stirred at 20-30°C until dissolution is complete. Without exceeding
  • the wet product is dried at 70-80°C.
  • Dimethylformamide 160 g are fed into a 250 ml flask.
  • the wet product is dried at 70-80°C.
  • Ethanol 100 g are fed into a 250 ml flask.
  • the wet product is dried at 70-80°C.
  • the wet product is dried at 70-80°C.
  • Isopropyl alcohol 80 g are fed into a 250 ml flask. 5 The mixture is stirred at 60-70°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant
  • the wet product is dried at 70-80°C.
  • Acetone 80 g are fed into a 250 ml flask.
  • the mixture is stirred at 60-65°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant
  • the wet product is dried at 70-80°C.
  • Bupropion hydrochloride 36.4 g are obtained and sifted with a 36 mesh sieve.
  • Diglyme 80 g are fed into a 250 ml flask.
  • the mixture is stirred at 50-55°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant
  • the wet product is dried at 70-80°C.
  • Bupropion hydrochloride 36.4 g are obtained and sifted with a 36 mesh sieve.
  • Ethanol 80 g are fed into a 250 ml flask.
  • the mixture is stirred at 40-45°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant
  • the wet product is dried at 70-80°C.
  • Toluene 80 g are fed into a 250 ml flask. The mixture is stirred at 40-45°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant
  • the wet product is dried at 70-80°C. 35.5 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.
  • Methyl cellosolve® 80 g are fed into a 250 ml flask.
  • the mixture is stirred at 35-40°C until dissolution is complete, then distilled at atmospheric pressure to 90°C.
  • the wet product is dried at 70-80°C. 27.8 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.
  • Dimethylformamide 80 g are fed into a 250 ml flask.
  • the mixture is stirred at 35-40°C until dissolution is complete, then distilled at atmospheric pressure to 95°C.
  • the wet product is dried at 70-80°C. 27 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.
  • Example 17 o The method described in example 9 was repeated on an industrial scale, using the following components:
  • Example 18 Samples of Bupropion hydrochloride obtained with the process described in example 4, example 5 or example 17 were analysed by electron microscopy (SEM analysis) under the following experimental conditions:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de cristallisation d'hydrochlorure de bupropion consistant (a) à dissoudre de l'hydrochlorure de bupropion dans un mélange comprenant du méthanol et un solvant de précipitation pour l'hydrochlorure de bupropion, (b) à enlever tout résidu insoluble, (c) à distiller la solution à une pression atmosphérique jusqu'au déclenchement de la réaction de précipitation, (d) à ajouter (I) un solvant de précipitation pour l'hydrochlorure de bupropion et (II) de l'acide chlorhydrique jusqu'à l'obtention d'un pH inférieur ou égal à 2, (e) à refroidir la masse à une température inférieure à 10 °C, de préférence entre 0 et 3 °C, et à séparer le précipité ainsi obtenu.
PCT/EP2004/050495 2003-04-11 2004-04-09 Procede de cristallisation d'hydrochlorure de bupropion Ceased WO2004089873A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA002549350A CA2549350A1 (fr) 2003-04-11 2004-04-09 Procede de cristallisation d'hydrochlorure de bupropion

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI20030762 ITMI20030762A1 (it) 2003-04-11 2003-04-11 Processo di cristallizzazione del bupropione cloridrato.
ITMI2003A000762 2003-04-11

Publications (1)

Publication Number Publication Date
WO2004089873A1 true WO2004089873A1 (fr) 2004-10-21

Family

ID=33156348

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2004/050495 Ceased WO2004089873A1 (fr) 2003-04-11 2004-04-09 Procede de cristallisation d'hydrochlorure de bupropion

Country Status (3)

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CA (1) CA2549350A1 (fr)
IT (1) ITMI20030762A1 (fr)
WO (1) WO2004089873A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7241805B2 (en) 2005-06-27 2007-07-10 Biovail Laboratories, Inc. Modified release formulations of a bupropion salt
WO2008099418A3 (fr) * 2007-02-12 2008-11-13 Alembic Ltd Procédé amélioré de préparation de chlohydrate de bupropion
CN106431943A (zh) * 2016-09-13 2017-02-22 威海迪素制药有限公司 一种盐酸安非他酮结晶的制备方法
US11844797B1 (en) 2023-04-20 2023-12-19 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression
WO2024006904A1 (fr) * 2022-06-30 2024-01-04 Axsome Therapeutics, Inc. Microparticules contenant du bupropion
US11883373B1 (en) 2022-07-07 2024-01-30 Antecip Bioventures Ii Llc Treatment of depression in certain patient populations
US11896563B2 (en) 2020-12-01 2024-02-13 Antecip Bioventures Ii Llc Bupropion and dextromethorphan for reduction of suicide risk in depression patients
US11925636B2 (en) 2022-06-30 2024-03-12 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US11969421B2 (en) 2013-11-05 2024-04-30 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11986444B2 (en) 2022-06-30 2024-05-21 Antecip Bioventures Ii Llc Treatment of poor metabolizers of dextromethorphan with a combination of bupropion and dextromethorphan
US12109178B2 (en) 2013-11-05 2024-10-08 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US12138260B2 (en) 2013-11-05 2024-11-12 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12156914B2 (en) 2022-06-30 2024-12-03 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising bupropion and cysteine
US12194036B2 (en) 2022-07-07 2025-01-14 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression
US12194006B2 (en) 2013-11-05 2025-01-14 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
TWI895749B (zh) 2022-06-30 2025-09-01 美商艾克薩姆治療公司 含有安非他酮的微粒
US12433884B2 (en) 2020-06-05 2025-10-07 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12447138B2 (en) 2013-11-05 2025-10-21 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US12472156B2 (en) 2020-06-05 2025-11-18 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3819706A (en) * 1969-12-04 1974-06-25 Burroughs Wellcome Co Meta chloro substituted-alpha-butylamino-propiophenones
US6238697B1 (en) * 1998-12-21 2001-05-29 Pharmalogix, Inc. Methods and formulations for making bupropion hydrochloride tablets using direct compression
US6306436B1 (en) * 2000-04-28 2001-10-23 Teva Pharmaceuticals Usa, Inc. Stabilized, acid-free formulation for sustained release of bupropion hydrochloride

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3819706A (en) * 1969-12-04 1974-06-25 Burroughs Wellcome Co Meta chloro substituted-alpha-butylamino-propiophenones
US6238697B1 (en) * 1998-12-21 2001-05-29 Pharmalogix, Inc. Methods and formulations for making bupropion hydrochloride tablets using direct compression
US6306436B1 (en) * 2000-04-28 2001-10-23 Teva Pharmaceuticals Usa, Inc. Stabilized, acid-free formulation for sustained release of bupropion hydrochloride

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7241805B2 (en) 2005-06-27 2007-07-10 Biovail Laboratories, Inc. Modified release formulations of a bupropion salt
US7884136B2 (en) 2005-06-27 2011-02-08 Biovail Laboratories International S.R.L. Modified-release formulations of a bupropion salt
US8932628B2 (en) 2005-06-27 2015-01-13 Valeant International Bermuda Modified release formulations of a bupropion salt
US9504640B2 (en) 2005-06-27 2016-11-29 Valeant Pharmaceuticals Luxembourg S.Á.R.L. Modified release formulations of a bupropion salt
WO2008099418A3 (fr) * 2007-02-12 2008-11-13 Alembic Ltd Procédé amélioré de préparation de chlohydrate de bupropion
US12377091B2 (en) 2013-11-05 2025-08-05 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12138260B2 (en) 2013-11-05 2024-11-12 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12194006B2 (en) 2013-11-05 2025-01-14 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11969421B2 (en) 2013-11-05 2024-04-30 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US12447138B2 (en) 2013-11-05 2025-10-21 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US12109178B2 (en) 2013-11-05 2024-10-08 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
CN106431943B (zh) * 2016-09-13 2021-03-26 迪嘉药业集团有限公司 一种盐酸安非他酮结晶的制备方法
CN106431943A (zh) * 2016-09-13 2017-02-22 威海迪素制药有限公司 一种盐酸安非他酮结晶的制备方法
US12472156B2 (en) 2020-06-05 2025-11-18 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12433884B2 (en) 2020-06-05 2025-10-07 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12390428B2 (en) 2020-12-01 2025-08-19 Antecip Bioventures Ii Llc Bupropion and dextromethorphan for reduction of suicide risk in depression patients
US11896563B2 (en) 2020-12-01 2024-02-13 Antecip Bioventures Ii Llc Bupropion and dextromethorphan for reduction of suicide risk in depression patients
US12478622B2 (en) 2022-06-30 2025-11-25 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US12472174B2 (en) 2022-06-30 2025-11-18 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US12156914B2 (en) 2022-06-30 2024-12-03 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising bupropion and cysteine
US12036191B1 (en) 2022-06-30 2024-07-16 Antecip Bioventures Ii Llc Treatment of poor metabolizers of dextromethorphan with a combination of bupropion and dextromethorphan
US11986444B2 (en) 2022-06-30 2024-05-21 Antecip Bioventures Ii Llc Treatment of poor metabolizers of dextromethorphan with a combination of bupropion and dextromethorphan
US11925636B2 (en) 2022-06-30 2024-03-12 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US12239642B2 (en) 2022-06-30 2025-03-04 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US12263161B2 (en) 2022-06-30 2025-04-01 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US12310961B2 (en) 2022-06-30 2025-05-27 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US12357697B2 (en) 2022-06-30 2025-07-15 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising bupropion and cysteine
TWI895749B (zh) 2022-06-30 2025-09-01 美商艾克薩姆治療公司 含有安非他酮的微粒
US12370154B2 (en) 2022-06-30 2025-07-29 Antecip Bioventures Ii Llc Treatment of poor metabolizers of dextromethorphan with a combination of bupropion and dextromethorphan
WO2024006904A1 (fr) * 2022-06-30 2024-01-04 Axsome Therapeutics, Inc. Microparticules contenant du bupropion
US12146889B1 (en) 2022-07-07 2024-11-19 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12364674B2 (en) 2022-07-07 2025-07-22 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12194036B2 (en) 2022-07-07 2025-01-14 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression
US12194005B2 (en) 2022-07-07 2025-01-14 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12042473B2 (en) 2022-07-07 2024-07-23 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12472155B2 (en) 2022-07-07 2025-11-18 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US11883373B1 (en) 2022-07-07 2024-01-30 Antecip Bioventures Ii Llc Treatment of depression in certain patient populations
US11844797B1 (en) 2023-04-20 2023-12-19 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression

Also Published As

Publication number Publication date
CA2549350A1 (fr) 2005-10-21
ITMI20030762A1 (it) 2004-10-12

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