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WO2008151430A1 - Nouveaux procédés d'obtention de la forme-i de l'olanzapine - Google Patents

Nouveaux procédés d'obtention de la forme-i de l'olanzapine Download PDF

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Publication number
WO2008151430A1
WO2008151430A1 PCT/CA2008/001124 CA2008001124W WO2008151430A1 WO 2008151430 A1 WO2008151430 A1 WO 2008151430A1 CA 2008001124 W CA2008001124 W CA 2008001124W WO 2008151430 A1 WO2008151430 A1 WO 2008151430A1
Authority
WO
WIPO (PCT)
Prior art keywords
olanzapine
butanol
volumes
solution
antisolvent
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/CA2008/001124
Other languages
English (en)
Inventor
Daqing Che
Kiran Kumar Kothakonda
Cameron Mcphail
Bhaskar Reddy Guntoori
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.)
Apotex Pharmachem Inc
Original Assignee
Apotex Pharmachem Inc
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
Priority claimed from CA002591644A external-priority patent/CA2591644A1/fr
Application filed by Apotex Pharmachem Inc filed Critical Apotex Pharmachem Inc
Publication of WO2008151430A1 publication Critical patent/WO2008151430A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Novel and high-yielding processes to prepare substantially pure Form-I of olanzapine are disclosed whereby crude olanzapine is dissolved in a solvent and the resulting solution is added to an antisolvent (such as heptanes or methyl terf-butyl ether).
  • an antisolvent such as heptanes or methyl terf-butyl ether.
  • Olanzapine (1 , 2-methyl-4-(4-methyl-1 -piperazinyl)-10/-/-thieno[2,3- b][ ⁇ ,5]benzo-diazepine) is a second generation anti-psychotic drug marketed as Zyprexa® by EIi Lilly and Company. It is useful for the treatment of disorders such as schizophrenia, bipolar disorder, psychotic depression and Tourette syndrome. This pharmaceutical acts as an antagonist on 5-HT 2 serotonin receptors as well as the Di/D 2 dopamine receptors and also exhibits anticholinergic and antimuscarine properties.
  • Form-I polymorph was produced according to the procedures of US '382. Obtaining the olanzapine Form-I polymorph is challenging due to the fact that, purportedly, it readily discolours on exposure to air, and therefore is unsuitable for commercial use.
  • 6,348,458 teaches three other crystalline polymorphic forms, namely Forms III, IV and
  • US 6,432,943 describes a method of obtaining substantially pure crystalline Form-I (incorrectly identified as Form-ll) using commercially undesirable methylene chloride as the crystallizing solvent. It also discloses methods of obtaining the stable polymorph Form-ll (incorrectly identified as Form-I in the patent) using solvents such as acetone, ethyl acetate and terf-butyl main disadvantage with these methods is that higher temperatures can result in conversion of desirable Form-I olanzapine to Form-ll olanzapine.
  • WO 2007/009788 A1 teaches a process for making Form-I by reducing the pressure of a supercritical fluid composition comprising carbon dioxide and olanzapine.
  • a process for obtaining crystalline Form-I olanzapine comprising the following: a) dissolving crude olanzapine in a solvent, b) optionally drying by azeotropic distillation to remove water, c) precipitating by adding the solution to an antisolvent, and d) isolating the precipitated crystalline Form-I olanzapine by filtration and drying at ambient temperature.
  • a process for obtaining a substantially pure polymorphic Form-I of olanzapine from crude olanzapine.
  • This method uses industrially acceptable class-3 solvents as listed in the ICH Q3C (R3) guidelines such as, for example, 2-butanol, heptanes, methyl terf-butyl ether (MTBE) and methyl /so-butyl ketone (MIBK).
  • 2-Butanol is particularly preferred because it has many characteristics which make it highly attractive for use as a solvent for the industrial preparation of pharmaceuticals, including olanzapine, such as it is inexpensive, has low- toxicity and is readily available.
  • a robust and high- yielding process is provided for obtaining crystalline Form-I olanzapine using, for example, 2-butanol (2-butyl alcohol, sec-butanol) and an antisolvent, for example, heptanes or MTBE, via a reverse-addition technique.
  • the crystalline Form-I olanzapine produced by this process has the characteristic x-ray diffraction pattern approximate d-values (in angstroms) of: 9.96, 8.58, 8.25, 6.90, 6.38, 5.95, 5.60, 4.98, 4.84, 4.77, 4.72, 4.63, 4.54, 4.47, 4.25, 4.10, 3.83, 3.76, 3.70, 3.59, 3.51 , 3.35, 3.29, 3.25, 3.22, 3.19, 3.12, 3.06, 2.96, 2.89, 2.82, 2.76, 2.71 , 2.66, 2.59, 2.58, 2.49, 2.47, 2.43, 2.39, 2.34.
  • crude olanzapine can be dissolved in a volume of a solvent, such as 2-butanol, at a temperature from about 50 to about 105°C to form a solution.
  • a solvent such as 2-butanol
  • the volume of solvent used can be 2 to 10 volumes, preferably 2 to 8 volumes and most preferably 2 to 6 volumes.
  • the term 'volumes' used above and throughout this patent represents the volume of solvent (in L) relative to the weight of olanzapine (in kg). For instance, 2 volumes corresponds to 2 L of solvent per kg of olanzapine.
  • anhydrous solution is defined in this case as a solution whose Karl Fisher (KF) value ranges from about 0.05-1.0%.
  • KF Karl Fisher
  • the volume of solvent distilled is typically between about 0.05 to 5 volumes, and most preferably 1 to 3 volumes.
  • the temperature of the solution can be between about 25 to 11O 0 C, preferably 50 to 105 0 C and most preferably 65-103 0 C.
  • the solution can be clarified by, for instance, filtering through a Buchner funnel packed with a filtering medium, such as Celite®.
  • the solution can then be added to an antisolvent.
  • This type of addition is known in the art as a reverse addition.
  • the volume of antisolvent can be between about 1 to 15 volumes, preferably 2 to 12 volumes and most preferably 3 to 10 volumes.
  • Suitable antisolvents are selected from the group consisting of C 5 to Cio hydrocarbons such as heptanes, C 4 to Cs alkyl ethers such as MTBE, C 3 to C 7 alkyl ketones such as methyl /so-butyl ketone (MIBK), or mixtures thereof.
  • the antisolvent is heptanes or
  • the addition and precipitation temperature ranges from about -2O 0 C to about 2O 0 C, preferably from about -1O 0 C to about 15 0 C and most preferably from about -5 to about 1O 0 C.
  • pure seed crystals of Form-I olanzapine can be added to the antisolvent before or after addition of the 2-butanol solution.
  • the amount of seed crystals ranges from about 0.01 to 10% weight- by-weight (w/w) of crude olanzapine, preferably 0.05 to 5% w/w and most preferably 0.1 to 2% w/w
  • Example 1 Crude olanzapine (10 g) was charged to a three necked flask along with 40 ml_ of 2-butanol and heated to dissolve. 10 ml_ of solvent was removed by atmospheric distillation and the hot solution was clarified and then added to MTBE (30 ml_) ( ⁇ 5 min) and the temperature was maintained between -5 and 5 0 C for precipitation. After complete precipitation, the product was isolated by filtration and dried at ambient temperature in a vacuum oven to obtain 7 g of pure Form-I.
  • Example 2 Crude olanzapine (10 g) was charged to a three necked flask along with 40 ml_ of 2-butanol and heated to dissolve. 10 ml_ of solvent was removed by atmospheric distillation and the hot solution was clarified and then added to MTBE (30 ml_) ( ⁇ 5 min) and the temperature was maintained between -5 and 5 0 C for precipitation. After complete precipitation, the product was isolated by filtration and dried at ambient temperature in a vacuum
  • Olanzapine (10 g) was charged to a three necked flask along with 40 mL of 2- butanol and heated to dissolve. 10 mL was removed by atmospheric distillation and the hot saturated solution was added to 50 mL of MTBE at - 15°C. Form-I seeds (1% relative to the weight of the olanzapine) were added and the temperature was maintained between -5 0 C and 5 0 C for precipitation. After complete precipitation, the product was isolated by Buchner filtration and dried in a vacuum oven at ambient temperature to provide 7 g of pure Form-I olanzapine.
  • Olanzapine (10 g) was charged to a three necked flask along with 40 mL of 2- butanol and the mixture was heated to dissolve. 10 mL of 2-butanol was removed by distillation and 10 mL of the hot saturated solution was added to MTBE (50 mL) (at -15 0 C) followed by Form-I olanzapine seeds [0.25% (w/w)] and the temperature was maintained between -5 0 C and 5 0 C for precipitation. The remaining 20 mL were added and another portion of seeds [0.25% (w/w)] was added. After complete precipitation, the precipitated Form-I olanzapine was isolated by filtration and dried at ambient temperature in a vacuum oven to provide 7 g.
  • Olanzapine 100 g was charged to a three necked flask along with 600 mL of 2-butanol and the mixture was heated to dissolve. The solution was clarified by Buchner filtration and 200 mL of 2-butanol were removed by distillation. The hot saturated solution was added to MTBE (400 mL) at -15 0 C followed by Form-I olanzapine seeds [0.2% (w/w)] and the temperature was maintained between -5 0 C and 5 0 C for precipitation. After complete precipitation, the precipitated Form-I olanzapine was isolated by filtration and dried at ambient temperature in a vacuum oven to provide 81 g.
  • Example 5 Example 5:
  • Olanzapine (10 g) was charged to a three necked flask, followed by 60 ml_ of 2-butanol and this mixture was heated to dissolution. It was filtered into other flask and refluxed. 20 mL of 2-butanol were removed by distillation and the hot saturated solution was added to 40 mL of heptanes and the temperature was maintained between -5 0 C and 5 0 C for precipitation. After complete precipitation, the product was isolated by filtration and dried at ambient temperature in a vacuum oven to provide 9 g Form-I olanzapine.
  • Olanzapine 100 g was charged to a three necked flask, followed by 600 mL of 2-butanol and the mixture was heated to dissolution. The solution was then clarified by filtration into a flask and refluxed. 200 mL of 2-butanol were removed by atmospheric distillation, the hot saturated solution was added to heptanes (400 mL) at -15 0 C containing 0.1% Form-I seeds (w/w) and thereafter the temperature was maintained between -5 0 C and 15 0 C for precipitation. After complete precipitation, the solution was filtered and the isolated product was dried in a vacuum oven at ambient temperature to obtain 86 g of pure Form-I olanzapine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne un procédé d'obtention de la forme-I cristalline de l'olanzapine comprenant les étapes suivantes consistant à : a) dissoudre l'olanzapine brute dans un solvant afin de former une solution, b) éventuellement sécher par une distillation azéotrope afin d'éliminer l'eau, c) précipiter en ajoutant la solution de l'étape (a) à un antisolvant, et d) isoler la forme-I cristalline précipitée par filtration et sécher à température ambiante.
PCT/CA2008/001124 2007-06-14 2008-06-12 Nouveaux procédés d'obtention de la forme-i de l'olanzapine Ceased WO2008151430A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CA002591644A CA2591644A1 (fr) 2007-06-14 2007-06-14 Nouvelles methodes de synthese de la forme-i de l'olanzapine
CA2,591,644 2007-06-14
US11/976,944 US20080312433A1 (en) 2007-06-14 2007-10-30 Novel process to Form-I of olanzapine
US11/976,944 2007-10-30

Publications (1)

Publication Number Publication Date
WO2008151430A1 true WO2008151430A1 (fr) 2008-12-18

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PCT/CA2008/001124 Ceased WO2008151430A1 (fr) 2007-06-14 2008-06-12 Nouveaux procédés d'obtention de la forme-i de l'olanzapine

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WO (1) WO2008151430A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097650A1 (fr) * 2002-05-17 2003-11-27 Institut Farmaceutyczny Procedes de preparation d'olanzapine polymorphe de forme i
WO2004094433A1 (fr) * 2003-04-22 2004-11-04 EGIS Gyógyszergyár Rt. Nouveaux polymorphismes du chlorhydrate d'olanzapine
WO2005107375A2 (fr) * 2004-05-06 2005-11-17 Matrix Laboratories Ltd Procede pour la preparation de forme i d'olanzapine
WO2007138376A1 (fr) * 2006-06-01 2007-12-06 Aurobindo Pharma Limited Procédé amélioré de préparation de la forme i d'olanzapine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097650A1 (fr) * 2002-05-17 2003-11-27 Institut Farmaceutyczny Procedes de preparation d'olanzapine polymorphe de forme i
WO2004094433A1 (fr) * 2003-04-22 2004-11-04 EGIS Gyógyszergyár Rt. Nouveaux polymorphismes du chlorhydrate d'olanzapine
WO2005107375A2 (fr) * 2004-05-06 2005-11-17 Matrix Laboratories Ltd Procede pour la preparation de forme i d'olanzapine
WO2007138376A1 (fr) * 2006-06-01 2007-12-06 Aurobindo Pharma Limited Procédé amélioré de préparation de la forme i d'olanzapine

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