WO2006082597A2 - Modification cristalline de derive de 2-oxazolidone 5-substituee et procede associe - Google Patents

Modification cristalline de derive de 2-oxazolidone 5-substituee et procede associe Download PDF

Info

Publication number
WO2006082597A2
WO2006082597A2 PCT/IN2006/000024 IN2006000024W WO2006082597A2 WO 2006082597 A2 WO2006082597 A2 WO 2006082597A2 IN 2006000024 W IN2006000024 W IN 2006000024W WO 2006082597 A2 WO2006082597 A2 WO 2006082597A2
Authority
WO
WIPO (PCT)
Prior art keywords
polymorphic form
formula
compound
thermal stability
improved thermal
Prior art date
Application number
PCT/IN2006/000024
Other languages
English (en)
Other versions
WO2006082597A3 (fr
Inventor
Mohan Anand Chandavarkar
Rajaram Uday Bapat
Vivek Manohar Khare
Original Assignee
Fdc Limited
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 Fdc Limited filed Critical Fdc Limited
Publication of WO2006082597A2 publication Critical patent/WO2006082597A2/fr
Publication of WO2006082597A3 publication Critical patent/WO2006082597A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the invention relates to novel crystalline Polymorphic Form I of 5- (3,5- Dimethylphenoxymethyl)-2-oxazolidinone (Metaxalone), to process for the preparation thereof and to its pharmaceutical compositions containing this crystal form.
  • 5-Aryloxymethyl-2-oxazolidinones are a group of compounds, which are well-known for exhibiting activity as depressants of central synaptic transmission.
  • 5-Aryloxymethyl-2-oxazolidinones is 5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone genetically known as Metaxalone is indicated for the relief of discomforts associated with acute, painful musculoskeletal conditions. It acts on the central nervous system (CNS) to produce the muscle relaxant effects.
  • CNS central nervous system
  • United States Patent No. 3062827 refers to 5- (3', 5'-dialkyl ⁇ henoxymethyl)-2- oxazolidinone and by way of an example describes preparation of 5-(3',5'- dimethylphenoxymethyl)-2- oxazolidinone.
  • United States Patent No. 3446814 claims a method of preparing 5-(3,5- dimethylphenoxymethyl)-2-oxazolidinone.
  • WO2003061552 claims a novel process for the preparation of 5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone and also claims a process for purifying 5- (3, 5- dimethylphenoxy methyl)-2-oxazolidinone by crystallizing 5- (3, 5- dimethylphenoxy methyl)-2-oxazolidinone from a mixture of organic solvents. It further claims that the crystallized 5- (3, 5- dimethylphenoxy m ⁇ thyl)-2-oxazolidinone thus obtained is substantially pure form having purity greater than 99.5% and none of the individual impurity is more than 0.05%.
  • polymorphism The occurrence of different crystalline forms of the same compound is termed as polymorphism.
  • the physical properties vary with crystal structure, hence polymorphism can influence many important properties of pharmaceuticals such as bioavailability, dissolution rate, compressibility, solubility, stability, etc.
  • the melting points and the X-ray diffraction pattern also differ.
  • the aim of the present invention is to provide a stable crystalline Polymorphic Form of metaxalone which is useful in stable pharmaceutical preparations.
  • the present invention is aimed to provide a crystalline Polymorphic Form of metaxalone referred herein further as Polymorph Form I, which has many advantageous properties like stability, solubility, enhanced bioavailability, compressibility and better dissolution rate.
  • An object of the invention is to provide a stable crystalline Polymorphic Form-I of the Compound, 5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone.
  • Another object of the invention is to provide Polymorphic Form -I of compound, 5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone with various advantageous properties which is useful to pharmacist.
  • Yet another object is to provide Polymorphic Form -I of a compound, 5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone which has better thermal stability.
  • the improved thermal stability of the Polymorphic Form I provide substantial therapeutic benefit to the patients through use of dosage forms, compositions and combinations thereof.
  • the present invention discloses a novel crystalline Polymorphic Form I of a compound, 5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone, which provide substantial therapeutic benefit to the patients through use of dosage forms, compositions and combinations thereof.
  • the present invention also discloses processes for preparation of the said Polymorphic Form 1 of 5- (3, 5- dimethylphenoxymethyl)-2-oxazolidinone.
  • the process which comprises dissolving amorphous form or a mixture containing Polymorphic Form I and amorphous form of 5- (3, 5-dimethylphenoxymethyl)-2-oxazolidinone in a polar solvent, charcoalising the solution thus obtained, filtering, adding an anti solvent to the filtrate, optionally heating to clarity; cooling to 5 0 C - 1O 0 C under stirring and filtering to obtain the crystalline Polymorphic Form I.
  • Figure 1 Thermal Analysis Result of Crystal form Polymorphic Form I.
  • Figure 2 XRPD data of Crystal form Polymorphic Form I.
  • Polymorphic Form I a crystalline form of the compound of formula (1), which is referred herein as Polymorphic Form I.
  • This Polymorphic Form I has better thermal stability.
  • the improved thermal stability of the Polymorphic Form I provide substantial therapeutic benefit to the patients through use of dosage forms, compositions and combinations thereof.
  • the Polymorphic form I is characterized by x-ray diffraction pattern having peaks at 10.355, 14.285,18.625, 19.030, 20.810 and 22.475 ⁇ 0.30 degrees 2 theta angle.
  • the crystalline Polymorphic Form I which comprises at least 95% by weight of crystals of the Polymorphic Form I; remains essentially dry in a glass climatic chamber at 40 0 C and relative humidity up to75 %.
  • the crystalline Polymorphic Form I which comprises at least 99% by weight of crystals of Polymorphic Form I remains dry in a glass climatic chamber at 40% relative humidity and at 75 0 C.
  • Melting point is determined by means of a DSC thermogram using a Shimadzu DSC -60.
  • DSC thermogram using a Shimadzu DSC -60.
  • (Differential Scanning Calorimetry) is the technique used in determining the melting point that can be measured by heating the samples until a thermal i.e. an endothermic or exothermic reaction is detected by means of ultra sensitive sensors.
  • the melting point is determined using about 3.0 to 4.0 mg of the sample in an aluminium crucible with a perforated plate under a quiescent atmosphere of air at a heating rate of 2 0 C per minute.
  • the invention relates to crystal form Polymorphic Form I of a compound of formula (1) having irregular, elongated rod shaped crystals.
  • the invention relates to essentially pure crystal form, referred to hereinafter as the
  • the new crystal form, the Polymorphic Form I has the following properties. i) The melting point of the Polymorphic Form I form in the DSC thermogram has a melting point less than 125 0 C, especially between 121° to 125° C as indicated in Figure 1. ii) The X-ray diffraction diagram of the Polymorphic Form I as indicated in Figure 2. iii) Crystalline Polymorphic Form I of the compound of formula (1) has a melting point less than 125°C,especially between 122.5 0 C and 124 0 C. iv) Preference is for the crystalline Polymorphic Form I of the compound of formula (1) which shows the peak marked in Figure 2.
  • Polymorphic Form I of the compound of formula (1) comprising the ' corresponding above-mentioned crystal form is also taken to be meant in a wider aspect of the invention.
  • the Polymorphic Form I of a compound of formula (1) is prepared by a) dissolving an amorphous form or a mixture containing crystal and amorphous form of the compound of formula (1) in a suitable polar solvent at reflux temperature, b) adding activated charcoal to the solution of step (a) generally at a temperature ranging from 50- 65 0 C and preferably at 60-65 °C under stirring for a suitable period of time; c) filtering the solution through hyflo and washing with suitable polar solvent; d) adding an anti solvent to step (c) solution , optionally heating to clarity, cooling to 25° " C to 35 0 C under stirring for about 12 hours, e) cooling the solution of step( d) further to a temperature of 5 0 C-10° " C,and f) filtering the solution to isolate the polymorphic Form I of the compound of formula (I)-
  • the polar solvent is selected from the group consisting of methanol, ethanol and isopropanol.
  • One preferred solvent is methanol.
  • the anti solvent is a hydrocarbon solvent, selected from the group consisting of pet. ether, ethyl acetate, ether, diisopropyl ether, n-hexane, toluene, xylene and benzene.
  • the preferred solvent is toluene.
  • parameter such as the weight ratio of a compound of formula (1) to the solvent can be varied. It is also possible to vary the time needed for the preparation of the Polymorphic Form I.
  • the Polymorphic Fo ⁇ n I of the present invention can be used in pharmaceutical preparations such as tablets, capsules, solutions, suspensions etc.
  • the present invention also describes the use of the said polymorphic form of metaxalone in the treatment of depression of central synaptic transmissions.
  • a mixture containing amorphous and Polymorphic Form I of 5-(3,5-dimethylphenoxy-) methyl)-2-oxazolidinone(10 gms) was heated with methanol (35 ml )to a clear solution at reflux temperature .To it added charcoal (0.5 gm) in methanol slurry and further heated to reflux. Charcoalised solution was filtered through hyflo at 60-65°C,added toluene( 5ml) to the filtered solution, heated to clarity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme I polymorphe cristalline d'un composé de 5-(3,5- diméthylphénoxy-) méthyl)-2-oxazolidinone, caractérisée par un diagramme de diffraction aux rayons X présentant des pics aux valeurs 10,355, 14,285, 18,625, 19,030, 20,810 et 22,475 ± 0,30 degrés d'angle 2 thêta, et un point de fusion compris entre 122,5 °C et 124 °C qui est caractérisé par analyse calorimétrique différentielle. La présente invention concerne également des procédés de préparation de ladite forme, des préparations pharmaceutiques comprenant ledit polymorphe et son utilisation dans le traitement de la dépression de transmissions synaptiques centrales.
PCT/IN2006/000024 2005-01-24 2006-01-24 Modification cristalline de derive de 2-oxazolidone 5-substituee et procede associe WO2006082597A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN71/MUM/2005 2005-01-24
IN71MU2005 2005-01-24

Publications (2)

Publication Number Publication Date
WO2006082597A2 true WO2006082597A2 (fr) 2006-08-10
WO2006082597A3 WO2006082597A3 (fr) 2006-12-21

Family

ID=36777616

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000024 WO2006082597A2 (fr) 2005-01-24 2006-01-24 Modification cristalline de derive de 2-oxazolidone 5-substituee et procede associe

Country Status (1)

Country Link
WO (1) WO2006082597A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007074477A2 (fr) * 2005-12-29 2007-07-05 Dabur Pharma Limited Polymorphes de métaxalone
WO2009085637A1 (fr) * 2007-12-21 2009-07-09 Url Pharma, Inc. Métaxalone amorphe et ses dispersions amorphes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3062827A (en) * 1959-06-19 1962-11-06 Robins Co Inc A H 5-(3', 5'-dialkylphenoxymethyl)-2-oxazolidones
US3446814A (en) * 1965-07-24 1969-05-27 Henkel & Cie Gmbh Process for the preparation of substituted oxazolidones
WO2003061552A2 (fr) * 2002-01-14 2003-07-31 Sun Pharmaceutical Industries Limited Procede relatif a l'elaboration de 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone sensiblement pure

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3062827A (en) * 1959-06-19 1962-11-06 Robins Co Inc A H 5-(3', 5'-dialkylphenoxymethyl)-2-oxazolidones
US3446814A (en) * 1965-07-24 1969-05-27 Henkel & Cie Gmbh Process for the preparation of substituted oxazolidones
WO2003061552A2 (fr) * 2002-01-14 2003-07-31 Sun Pharmaceutical Industries Limited Procede relatif a l'elaboration de 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone sensiblement pure

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007074477A2 (fr) * 2005-12-29 2007-07-05 Dabur Pharma Limited Polymorphes de métaxalone
WO2007074477A3 (fr) * 2005-12-29 2007-08-30 Dabur Pharma Ltd Polymorphes de métaxalone
US7750165B2 (en) 2005-12-29 2010-07-06 Fresenius Kabi Oncology Limited Metaxalone polymorphs
WO2009085637A1 (fr) * 2007-12-21 2009-07-09 Url Pharma, Inc. Métaxalone amorphe et ses dispersions amorphes

Also Published As

Publication number Publication date
WO2006082597A3 (fr) 2006-12-21

Similar Documents

Publication Publication Date Title
EP3248983B1 (fr) Forme cristalline a de l'acide obéticholique et son procédé de préparation
JP6511083B2 (ja) ピロール誘導体の結晶
WO2006024863A1 (fr) Forme cristalline stable d'imatinib mesylate et son procede de preparation
KR101604501B1 (ko) Ｎ-[2-(다이에틸아미노)에틸]-5-[(5-플루오로-1,2-다이하이드로-2-옥소-3ｈ-인돌-3-일리덴)메틸]-2,4-다이메틸-1ｈ-피롤-3-카복스아미드의 결정 형태 및 이의 제조 방법
EP3337485B1 (fr) Formes cristallines d'ibrutinib
WO2007109799A2 (fr) Polymorphes de malate d'eszopiclone
EP1853571A1 (fr) Formes cristallines d un intermédiaire du linézolide
US9624207B2 (en) Polymorphs of azilsartan medoxomil
WO2009037538A2 (fr) Procédé de préparation de lamivudine de forme i
US9169257B2 (en) Crystal forms of adefovir dipivoxil and processes for preparing the same
WO2006082597A2 (fr) Modification cristalline de derive de 2-oxazolidone 5-substituee et procede associe
WO2013150544A2 (fr) Dispersion solide de chlorhydrate d'ivabradine
WO2004085426A1 (fr) Nouvelles formes cristallines de candesartan cilexetil
WO2006090263A1 (fr) Chlorhydrate de donepezil de formule i stable et son procede de preparation et d'utilisation dans des compositions pharmaceutiques
JP2024500665A (ja) ２－ヒドロキシ－５－［２－（４－（トリフルオロメチルフェニル）エチルアミノ）］安息香酸結晶形およびこの製造方法
CN103242291A (zh) 一种多晶型高含量苯甲酸阿格列汀的批量生产工艺
EP2085397A1 (fr) Forme cristalline d'abacavir
CN113801189A (zh) 一种d因子阻滞剂的晶型及其制备方法
US20100104649A1 (en) Lercanidipine Hydrochloride Polymorphs and an Improved Process for Preparation of 1,1,N-Trimethyl-N-(3,3-Diphenylpropyl)-2-Aminoethyl Acetoacetate
EP1981501A2 (fr) Compositions pharmaceutiques stables de desloratadine et procédés de préparation de formes polymorphes de desloratadine
WO2000073303A1 (fr) Polymorphes de (2-benzhydril-1-azabicyclo[2.2.2]oct-3-yl)-isopropyl-2-methoxybenzyl)-amine citrate cristallins comme antagonistes recepteurs nk-1
JPH01197470A (ja) 非対称ジヒドロピリジン類の製造方法
JP5308030B2 (ja) ケモカインレセプターアンタゴニストの固体形態およびその使用方法
CA3215792A1 (fr) Procedes de synthese de valbenazine
US20150291574A1 (en) Novel polymorphs of azilsartan

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 06728386

Country of ref document: EP

Kind code of ref document: A2