WO2010082216A2 - Nouveaux sels de sibutramine et leurs formes cristallines - Google Patents

Nouveaux sels de sibutramine et leurs formes cristallines Download PDF

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Publication number
WO2010082216A2
WO2010082216A2 PCT/IN2009/000705 IN2009000705W WO2010082216A2 WO 2010082216 A2 WO2010082216 A2 WO 2010082216A2 IN 2009000705 W IN2009000705 W IN 2009000705W WO 2010082216 A2 WO2010082216 A2 WO 2010082216A2
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WO
WIPO (PCT)
Prior art keywords
sibutramine
fumarate
maleate
solvent
crystalline
Prior art date
Application number
PCT/IN2009/000705
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English (en)
Other versions
WO2010082216A3 (fr
Inventor
Ramakoteswara Raro Jetti
Neelima Bhagavatula
Ramireddy Bommareddy Aggi
Debashish Datta
Original Assignee
Matrix Laboratories Ltd
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 Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2010082216A2 publication Critical patent/WO2010082216A2/fr
Publication of WO2010082216A3 publication Critical patent/WO2010082216A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups

Definitions

  • the present invention relates to novel acid addition salt of Sibutramine namely, Sibutramine Maleate and process for the preparation of the same.
  • the present invention also relates to novel polymorphic forms of Sibutramine Fumarate such as amorphous, anhydrate and dihydrate forms.
  • Sibutramine, l-(4-chlorophenyl)-N,N-dimethyl- ⁇ -(2-methylpropyl)cyclobutane- methanamine has the structure represented by formula (I), is a inhibitor of 5- hydroxytryptamine and noradrenaline reuptake in vivo (neuropharmacology,28,pl29- 134), is useful in the treatment of depression, Parkinson's disease, obesity, insulin- independent diabetes mellirus, epilepsy, and the like.
  • Sibutramine reduces body weight gain by dual action to reduce food intake by enhancing satiety and to increase energy expenditure by stimulating heat generation.
  • Korean Patent Publication No. 1900-0000274 discloses that Sibutramine is utilized in as salts formed with acids providing non-toxic acid addition salts containing pharmaceutically acceptable anions, for example in the form of hydrochloride, malate, citrate, fumarate, tartarate, succinate, aspartate or glutamate salt.
  • Brazilian patent application 0105486 discloses Sibutramine sulfate. Also methanesulfonate hemihydrate salt of Sibutramine is disclosed in KR 10-03-53752.
  • WO 2006/073290 Al discloses oxalate and malonate salts.
  • WO 2006/073291 Al [eq. US 7,429,679] discloses sulfonic acid salts like besylate, camsylate, tosylate, edisylate, esylate hemihydrate salts of Sibutramine. Hydrogen sulfate, bromate and phosphate monohydrate salts of Sibutramine have been disclosed in US 7,432,398.
  • Sibutramine Maleate and Sibutramine Fumarate three novel polymorphic forms of Sibutramine Fumarate have been found to exist as anhydrate, hydrate and an amorphous form.
  • the main object of the present invention is to provide novel salt Sibutramine Maleate and process for preparing the same.
  • Another object of the present invention relates to novel polymorphic forms of Sibutramine Fumarate such as amorphous, Form I and Form II.
  • Yet another object of the present invention relates to process for the preparation of polymorphic forms of Sibutramine Fumarate such as amorphous, Form I and Form II.
  • This invention encompasses acid addition salt of Sibutramine namely Sibutramine Maleate and process for preparation of the same.
  • the present invention also encompasses Sibutramine Fumarate polymorphic forms amorphous, Form-I (anhydrous) and Form-II (dihydrate) and processes for preparing the same.
  • anhydrous crystalline Sibutramine Maleate with a moisture content of 0-1% characterized by Thermo gravimetric analysis (TGA) and KF method.
  • Figure 1 is the X-ray powder diffraction pattern of Sibutramine Maleate
  • Figure 2 is the DSC of crystalline Sibutramine Maleate.
  • Figure 3 is the TGA/DTA of crystalline Sibutramine Maleate.
  • Figure 4 is the X-ray powder diffraction pattern of Sibutramine Fumarate Form I
  • Figure 5 is the DSC of crystalline Sibutramine Fumarate Form I.
  • Figure 6 is the TGA/DTA of crystalline Sibutramine Fumarate Form I.
  • Figure 7 is the X-ray powder diffraction pattern of Sibutramine Fumarate Form II.
  • Figure 8 is the DSC of crystalline Sibutramine Fumarate Form II.
  • Figure 9 is the TGA of crystalline Sibutramine Fumarate Form II.
  • Figure 10 is the X-ray powder diffraction pattern of amorphous Sibutramine Fumarate
  • the present invention relates to novel crystalline Maleate salt of Sibutramine.
  • the present invention also relates to novel polymorphic forms of Sibutramine Fumarate; Form-I, Form-II and amorphous.
  • the said salts differ from the other prior art salts in its physical properties and method of preparation. These salts and their polymorphs are further characterized by its X-ray powder diffraction pattern, Differential scanning calorimetry (DSC), Thermo gravimetric analysis and/or moisture content (MC).
  • One aspect of the present invention is to provide Sibutramine Maleate.
  • One embodiment of the present invention is to provide Sibutramine Maleate characterized by PXRD pattern as shown in Figure I having peaks at about 12.84, 14.22, 15.37, 17.19, 17.54, 19.26, 22.63, 24.16, 24.73, 25.26, 25.57, 25.87, 28.70, ( ⁇ 0.2° ⁇ ).
  • Sibutramine Maleate is further characterized by PXRD peaks at about 12.48, 12.84, 14.22, 15.37, 16.01, 16.47, 17.19, 17.54, 19.26, 21.42, 22.63, 24.16, 24.73, 25.26, 25.57, 25.87, 26.45, 28.70, 32.38 ( ⁇ 0.2° ⁇ ).
  • One more embodiment of the present invention is to prepare Sibutramine Maleate further characterized by DSC (Figure 2) with sharp endothermic peak at 14O 0 C corresponding to melting of the product and TGA shows no significant weight loss ( ⁇ 1%) as depicted in Figure 3.
  • the water content determined by Karl-Fisher method ranges from approx. 0.1- 0.5 %.
  • the Sibutramine Maleate is crystalline anhydrous form.
  • Sibutramine base is reacted with maleic acid in a solvent, which is selected from ketone, ester solvents such as acetone and ethylacetate.
  • a solvent which is selected from ketone, ester solvents such as acetone and ethylacetate.
  • the reaction can be carried out at about 20-50°C preferably at 25-30°C.
  • the obtained mass is then cooled to 0-10 0 C preferably 0-5 0 C.
  • Precipitated solid is filtered to isolate Sibutramine Maleate.
  • Sibutramine base is reacted with maleic acid in a solvent which is selected from alcohol such as methanol, ethanol, isopropyl alcohol preferably methanol.
  • a solvent which is selected from alcohol such as methanol, ethanol, isopropyl alcohol preferably methanol.
  • Anti solvent can be selected from ether solvent such as isopropyl ether, diethyl ether preferably isopropyl ether. Precipitated solid is filtered to isolate Sibutramine Maleate.
  • Yet another embodiment of the present invention is to provide Sibutramine Fumarate Form I, characterized by PXRD pattern as shown in Figure 4 having peaks at 10.84, 11.88, 16.38, 17.77, 19.66, 20.57, 22.96, 23.54, 24.03, 24.43, 25.14 ( ⁇ 0.2 ⁇ ).
  • Sibutramine Fumarate Form I is further characterized by PXRD peaks at about 10.84, 11.88, 14.24, 16.38, 17.77, 18.10, 18.93, 19.66, 20.57, 21.75, 22.96, 23.54, 24.03, 24.43, 25.14, 25.87, 26.16, 28.93, 30.43, 30.91, 31.16, 34.88, 36.73 ( ⁇ 0.2 ⁇ ).
  • Form I further characterized by DSC ( Figure 5) with sharp endothermic peak at 155 0 C corresponding to melting of the product and TGA shows no significant weight loss (less than 0.5%) as depicted in Figure 6.
  • the moisture content determined by the Karl-Fisher method is in the range of 0.2 to 1.0 %.
  • the Sibutramine Fumarate Form I is crystalline anhydrous form
  • Sibutramine is reacted with fumaric acid in a solvent selected from alcohol solvent such as methanol, ethanol, isopropyl alcohol preferably methanol.
  • the reaction can be carried out at temperatures 20-75°C preferably 50-60°C.
  • the obtained reaction mass is cooled to 0-10 0 C preferably 0-5°C.
  • Precipitated solid is filtered to isolate Sibutramine Fumarate Form I.
  • Another embodiment of the present invention provides novel Sibutramine Fumarate Form-II characterized by PXRD pattern as depicted in Figure 7 having peaks at about 11.57, 14.82, 15.43, 15.98, 16.84, 18.97, 19.99, 23.74, 24.74, 26.76, 27.63, ( ⁇ 0.2° ⁇ ).
  • Sibutramine Fumarate Form-II is further characterized by PXRD peaks at about 11.57, 13.44, 14.09, 14.82, 15.43, 15.98, 16.84, 18.97, 19.99, 21.23, 23.74, 24.74, 25.22, 25.48, 25.95, 26.76, 27.63, 28.89 ( ⁇ 0.2° ⁇ ).
  • Form II is further characterized by the DSC ( Figure 8), which shows two melting endothermic peaks; first broad endotherm at an onset temperature ranging from 30 to 110°C with peak maxima at 96°C attributed to loss of water and a second sharp endotherm at 152 0 C corresponding to complete melting of the product.
  • Crystalline Sibutramine Fumarate Form II is a dihydrate with water content approx. 9.25 % which is analyzed by TGA as shown in Figure 9 and moisture content of 9-11% determined by KF method.
  • Sibutramine Fumarate Form II is dihydrate.
  • Sibutramine Fumarate Form I is dissolved in a solvent selected from aprotic solvents, polar protic solvents or mixtures thereof.
  • Aprotic solvent is selected from the dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and dimethyl acetamide (DMA).
  • Polar solvent is selected from methanol, ethanol, propanol or mixtures thereof.
  • DMSO dimethyl sulfoxide
  • DMF dimethyl formamide
  • DMA dimethyl acetamide
  • Polar solvent is selected from methanol, ethanol, propanol or mixtures thereof.
  • To the reaction mass water is added to isolate crystalline Sibutramine Fumarate Form II.
  • Another embodiment of the present invention relates to amorphous Sibutramine Fumarate as depicted in Figure 10.
  • Sibutramine Fumarate is suspended in a solvent selected from methanol, ethanol, isopropyl alcohol, preferably methanol at a temperature selected from 25-75°C preferably 50-60 0 C. Solvent is removed by distillation under reduced pressure to obtain Sibutramine Fumarate amorphous.
  • Another embodiment of the present invention provides a process for preparation of crystalline Sibutramine Fumarate Form I by slurring Sibutramine Fumarate Form II in a suitable solvent followed by filtration and drying under vacuum at 40-80 0 C preferably at 50-60 0 C for several hours.
  • the solvents used are selected from the group consisting of ethyl acetate, isopropyl ether (IPE), n-heptane, acetonitrile (ACN) and mixtures thereof.
  • Another embodiment of the present invention provides a process for the preparation of crystalline Sibutramine Fumarate Form I by drying crystalline Sibutramine Fumarate Form II above 50 0 C for several hours.
  • Still another embodiment of the present invention provides process for the preparation of crystalline Sibutramine Fumarate Form I by contacting Sibutramine Fumarate amorphous to atmosphere.
  • Still another embodiment of the present invention provides process for the preparation of crystalline Sibutramine Form I by suspending Sibutramine base, Fumaric acid in suitable solvent and further heating the suspension to get clear solution.
  • the clear solution is cooled to low temperatures and seeded with Form I.
  • Precipitated solid is filtered and vacuum dried to get Sibutramine Form I.
  • Solvent employed for the dissolution of Sibutramine base in Fumaric acid can be selected from ethanol, methanol, isopropyl alcohol preferably methanol.
  • Dissolution of Sibutramine can be carried out at 50-60°C.
  • the said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu-anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • the DSC measurements were carried out on Mettler Toledo 822 star 6 and TA QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.
  • TGA was recorded on out using ' the instrument Mettler Toledo TGA/SDTA 85 l e and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.
  • the following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.
  • the solid state stability of the anhydrous Sibutramine Maleate and Sibutramine Fumarate salts prepared in above examples was determined by storing approximately 3.O g of the sample a) at 5O 0 C, b) at 40°C/75% relative humidity (RH), open exposure, and c) at 40°C/75% relative humidity (RH), close exposure for 10 days.
  • the material was tested by HPLC for final purity and degradation products in both the cases. The results are given in Table 3.
  • Sibutramine Maleate and Fumarate salts shows no significant degradation, no substantial increase in moisture content and no change in PXRD pattern when stored at 40°C/75% relative humidity (RH) for 1 month which suggests that these salts are physically and chemically stable.
  • Sibutramine Maleate and Fumarate salts shows no substantial increase in moisture content when stored in different relative humidity conditions for a period of 1 month which suggests that these salts are non-hygroscopic in nature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un nouveau sel d'addition acide de la Sibutramine [l-(4-chlorophényl)-N,N-diméthyl-a-(2-méthylpropyl)-cyclobutane-éthanamine], le maléate de Sibutramine, et son procédé de synthèse. La présente invention concerne en outre de nouvelles formes polymorphiques du fumarate de Sibutramine, qui incluent un anhydrate (Forme I), un dihydrate (Forme II) et une forme amorphe.
PCT/IN2009/000705 2008-12-08 2009-12-07 Nouveaux sels de sibutramine et leurs formes cristallines WO2010082216A2 (fr)

Applications Claiming Priority (2)

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IN3084/CHE/2008 2008-12-08
IN3084CH2008 2008-12-08

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WO2010082216A2 true WO2010082216A2 (fr) 2010-07-22
WO2010082216A3 WO2010082216A3 (fr) 2012-06-21

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2098602A (en) * 1981-04-06 1982-11-24 Boots Co Plc Therapeutic agents
WO1998013034A1 (fr) * 1996-09-25 1998-04-02 Knoll Aktiengesellschaft Utilisation d'analogues de sibutramine pour abaisser les taux de lipides
WO2004096202A1 (fr) * 2003-04-28 2004-11-11 Cipla Limited Formulation pharmaceutique contenant un agent anti-obesite et un acidulant
KR20070081233A (ko) * 2006-02-10 2007-08-16 대화제약 주식회사 시부트라민 염을 함유하는 약학 조성물 및 이의 제조방법
KR20080055765A (ko) * 2008-05-16 2008-06-19 에이큐팜 주식회사 시부트라민 및 베타히스틴을 포함하는 비만 또는 비만관련 질환의 예방 및 치료용 조성물, 이를 병용 투여하는치료방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2098602A (en) * 1981-04-06 1982-11-24 Boots Co Plc Therapeutic agents
WO1998013034A1 (fr) * 1996-09-25 1998-04-02 Knoll Aktiengesellschaft Utilisation d'analogues de sibutramine pour abaisser les taux de lipides
WO2004096202A1 (fr) * 2003-04-28 2004-11-11 Cipla Limited Formulation pharmaceutique contenant un agent anti-obesite et un acidulant
KR20070081233A (ko) * 2006-02-10 2007-08-16 대화제약 주식회사 시부트라민 염을 함유하는 약학 조성물 및 이의 제조방법
KR20080055765A (ko) * 2008-05-16 2008-06-19 에이큐팜 주식회사 시부트라민 및 베타히스틴을 포함하는 비만 또는 비만관련 질환의 예방 및 치료용 조성물, 이를 병용 투여하는치료방법

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