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WO2009122430A2 - Nouvelles formes cristallines de desloratadine et procédé de préparation associé - Google Patents

Nouvelles formes cristallines de desloratadine et procédé de préparation associé Download PDF

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Publication number
WO2009122430A2
WO2009122430A2 PCT/IN2009/000086 IN2009000086W WO2009122430A2 WO 2009122430 A2 WO2009122430 A2 WO 2009122430A2 IN 2009000086 W IN2009000086 W IN 2009000086W WO 2009122430 A2 WO2009122430 A2 WO 2009122430A2
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Prior art keywords
desloratadine
crystalline
solvent
solution
preparation
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PCT/IN2009/000086
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WO2009122430A3 (fr
Inventor
Om Dutt Tyagi
Ramakoteswara Rao Jetti
Ashna Rani Gorantla
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Mylan Laboratories Ltd
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Matrix Laboratories Ltd
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Publication of WO2009122430A3 publication Critical patent/WO2009122430A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention in general relates to novel crystalline forms of desloratadine. More particularly, but without restriction to the particular embodiments herein after described in accordance with the best mode of practice, the present invention is directed to crystalline forms Form A and Form B of desloratadine wherein Form A is an anhydrous form and Form B is a solvate. In addition, the process for preparing the same are disclosed. Background of the Invention
  • Desloratadine a major active metabolite of loratadine known as DCL or Descarbonylethoxyloratadine or 8-chloro-6, l l-dihydro-l l-(4-piperidylidene)-5H- benzo[5,6] cyclohepta[l,2-b]pyridine.
  • Desloratadine is a long-acting tricyclic nonsedating antihistamine with selective Hl- receptor histamine antagonist activity and anti-inflammatory activity.
  • Desloratadine is currently marketed as Clarinex® in United States. Clarinex® is prescribed for prevention or treatment of hay fever and allergic reactions, such as sneezing, itchy eyes, runny nose, and hives.
  • Desloratadine is represented by the formula mentioned below.
  • US Pat. No. 4,659,716 discloses 8-(chloro)-substituted-6,l l-dihydro-l l-(4- piperidylidene)-5H-benzo[5 ,6]cyclohepta[l,2-b]pyridine and the pharmaceutically acceptable salts i.e. desloratadine that possesses antihistaminic with non-sedative activity.
  • US '716 further discloses a process for the preparation of desloratadine, wherein 8-chloro-6, 11 -dihydro- H-(I -ethoxycarbonyl-4-piperidylidene)-5H- benzo[5,6]cyclohepta [l,2-b]pyridine is subjected to hydrolysis reaction in presence of sodium hydroxide in ethyl alcohol, which is further treated with acetic acid to give crude desloratadine acetic acid salt. Crude desloratadine acetic acid so obtained is dissolved in water and solution is made basic with aqueous solution of potassium carbonate.
  • Desloratadine so obtained consists of a mixture of polymorphs. US '716 does not disclose polymorphic forms of desloratadine.
  • US Pat. No. 6,506,767 discloses two polymorphic forms of desloratadine designated as Form I and Form II.
  • US '767 discloses a process for preparing form I wherein loratadine is subjected to hydrolysis in presence of potassium hydroxide in a mixture of industrial methylated sprit (IMS) and water, followed by crystallization in methyl iso butyl ketone (MIBK) to obtain polymorphic Form I containing less than about 1% of Form II.
  • IMS industrial methylated sprit
  • MIBK methyl iso butyl ketone
  • US '767 discloses a method for preparing Form II by reacting 8- chloro-6,11 -dihydro- 1 l-(l-methyl-4-piperidylidene)-5H-benzo[5,6] cyclohepta[l,2-b] pyridine with cyanogen bromide in benzene to give 1-cyano derivative, which is further hydrolyzed, decarboxylated and the resulting solution is crystallized in hexane to give desloratadine. Desloratadine is redissolved in ethylacetate, treated with carbon and filtered. The filtrate is concentrated followed by rapid cooling and filtration to give polymorphic Form II containing less than about 15% of Form I.
  • US 2006/0135547 Al and US 2006/0223841 Al disclose processes for preparing polymorphic forms I and II and their mixtures.
  • the processes disclosed involve preparing a solution of desloratadine in various solvents, optionally combining the solution with anti-solvents, followed by crystallization and recovering the polymorphic forms.
  • the applications further disclose pharmaceutical compositions containing mixtures of the two polymorphic forms in various ratios along with pharmaceutically acceptable excipients.
  • US 2007/0135472 Al claims crystalline polymorphic forms of desloratadine Form III and V and process for preparation of the same.
  • the process involves heating a reaction mixture obtained by reacting loratadine with an inorganic base in an organic solvent and extracting the mixture with water immiscible organic solvent followed by stirring for 80-100 hours and isolating desloratadine Form III.
  • the process for the preparation of desloratadine Form V is different in that it involves stirring for 2 to3 hours, optionally washing with an organic solvent and subsequently isolating desloratadine polymorphic Form V.
  • WO 2005/084674 application discloses amorphous desloratadine and the process for its preparation, wherein desloratadine is dissolved in an organic solvent to get clear solution, subjecting the solution to spray drying or agitated thin film drying to give amorphous desloratadine.
  • EP 1 862 462 Al discloses process for preparation of Form I of desloratadine, wherein loratadine is hydrolyzed followed by extracting the reaction mixture with a first solvent, partially recovering the first solvent, adding a second solvent to the residue and isolating desloratadine Form 1.
  • EP 1 860 105 Al discloses process of preparation of Form II of desloratadine by providing a solution of desloratadine in a suitable solvent (may include organic solvents or mixtures of organic solvents, with or without water) followed by spray drying or agitated thin film drying to recover Form 2 of desloratadine.
  • the present invention provides new polymorphic forms of desloratadine and the process for preparing the same.
  • PXRD X-ray powder diffraction pattern
  • TGA thermo gravimetric analysis
  • DSC differential scanning calorimetry
  • Another object of the present invention is to provide a process for the preparation of novel crystalline polymorphic forms of desloratadine Form A and Form B by using different solvent systems and recovering techniques.
  • Yet another object of the present invention provides improved processes for preparation of crystalline polymorphic forms of desloratadine Form I, Form II and mixtures thereof without contaminating other polymorphic forms.
  • a crystalline desloratadine Form A characterized by X-ray powder diffraction pattern having peaks at 10.74, 16.09, 18.26, 19.04, 19.87, 20.50, 21.70, 20.95, 23.41 and 25.88 ⁇ 0.2 2 ⁇ values.
  • crystalline desloratadine Form A is an anhydrous form with a moisture content of 0.3 - 0.6 % (by KF method) supported by TGA, and DSC that shows three characteristic peaks at about 145 0 C, 147 0 C and 157 0 C .
  • a crystalline desloratadine Form B characterized by X-ray powder diffraction pattern having peaks at 12.72, 15.08, 16.98, 18.14, 18.76, 19.15, 20.17, 22.86, 23.96, 24.50, 25.22, 26.29 and 29.30 ⁇ 0.2 2 ⁇ values.
  • Form B is a solvate of 1,1,2-trichloroethane with 10-17% of 1,1,2-trichloroethane content supported by TGA and moisture content of 3-4% (by KF Method).
  • DSC of Form B shows two characteristic peaks at about 104 0 C and 4154 0 C.
  • a process for the preparation of crystalline desloratadine Form A comprising of dissolving desloratadine in a solvent, removing the solvent from the resultant solution and recovering desloratadine Form A, wherein said solvent is selected from cyclic ethers.
  • a process for the preparation of crystalline desloratadine polymorphic Form B comprising of dissolving desloratadine in a solvent 1,1,2-trichloroethane to prepare a solution, evaporating the solvent from the solution by slow or fast evaporation and recovering desloratadine Form B.
  • a process for the preparation of crystalline desloratadine polymorphic Form B comprising of preparing a solution by dissolving desloratadine in 1,1,2-trichloroethane, seeding the solution with Form B obtained according to the above method and recovering the crystalline desloratadine Form B.
  • a process for preparation of crystalline desloratadine Form I comprising of dissolving desloratadine in a solvent to obtain a solution, evaporating the solvent from the solution by slow or fast evaporation, and subsequently cooling and filtering to recover crystalline desloratadine Form I, wherein the solvent is selected from pyridine, 1 -methyl -pyrrolidine or mixtures thereof.
  • a process for the preparation of crystalline desloratadine polymorphic Form II comprising of dissolving desloratadine in a solvent to obtain a solution, evaporating the solvent from the solution by slow or fast evaporation, and subsequently cooling and filtering to recover desloratadine Form II wherein said solvent is selected from nitromethane, 1,4-dioxane, 2-methoxy ethanol and mixture thereof .
  • mixture of polymorphic forms of desloratadine Form I and II are prepared by slurring Form A or Form B in a solvent and filtering to isolate a mixture of polymorphic forms Form I and II, wherein the solvent is selected from organic solvents, preferably isopropyl ether, petroleum ether, diethyl ether and methyl tertiary butyl ether, hexane, heptane, pentane, cyclohexane, toluene or mixtures thereof.
  • organic solvents preferably isopropyl ether, petroleum ether, diethyl ether and methyl tertiary butyl ether, hexane, heptane, pentane, cyclohexane, toluene or mixtures thereof.
  • Figure 1 is the X-ray powder diffraction pattern of Form A of Desloratadine
  • Figure 2 is the DSC of Form A of Desloratadine
  • FIG. 3 is the TGA of Form A of Desloratadine
  • Figure 4 is the X-ray powder diffraction pattern of Form B of Desloratadine
  • Figure 5 is the DSC of Form B of Desloratadine
  • Figure 6 is the TGA of Form B of Desloratadine
  • the present invention describes the crystalline desloratadine polymorphic forms, Form A which is an anhydrous form and Form B which is a solvate form, and is intended to be encompassed with in the scope of the present invention.
  • the said forms are different from each other in their physical properties, spectral data and method of preparation and characterized by their X-ray powder diffraction patterns, thermo gravimetric analysis (TGA), differential scanning calorimetric patterns (DSC) and moisture content.
  • the present invention describes the process for preparing novel polymorphic forms of desloratadine Form A and B.
  • the present invention describes improved process for preparation of polymorphic forms of desloratadine Form I, Form II and their mixtures thereof.
  • 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.
  • Diffrential Scanning Calorimetrv The DSC measurements were carried out on Mettler Toledo 822 Star e 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-250°C purging with nitrogen at a flow rate of 40ml/min. In case of Form-A a higher heating rate of 25.0° C/min was used to determine the melting temperature more accurately. Standard aluminum crucibles covered by lids with three pin holes were used.
  • TGA measurements were carried out on instrument Mettler Toledo TGA/SDTA 851 Star 6 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 20ml/min.
  • Water content was determined on Metrohm Karl-Fisher titrator (Model: 794 Basic Titrino) using pyridine free single solution (Merck, Mumbai) with sample mass between 450mg to 550mg.
  • the virtis Genesis SQ Freeze Dryer operates on the principle of lyophilization, i.e., a process of stabilizing initially wet materials (aqueous solution or suspensions) by freezing them, then subliming the ice while simultaneously desorbing some of the bound moisture (primary drying). Following removal of the ice, desorption may be continued (secondary drying). This process may be carried out under vacuum.
  • Crystalline desloratadine Form A is characterized by powder X-ray diffraction pattern as shown in Figure 1 with peaks at 10.24, 10.74, 13.03, 13.90, 16.09, 18.26, 19.04, 19.87, 20.50, 20.95, 21.70, 22.38, 23.41, 24.78, 25.88, 26.36, 26.84, 28.04, 28.41, 29.10, 29.98, 30.86, 32.40, 33.50, 34.25, 35.24 and 36.44 ⁇ 0.2 2 ⁇ values.
  • Crystalline desloratadine Form A is further characterized by DSC with three characteristic peaks first an endothermic peak at 145 0 C, corresponding to melting of the crystalline Form A followed by a immediate second exothermic peak at 147°C, indicating crystallization of the Form A into a stable crystalline Form I, and a third endothermic peak at 157 0 C corresponding to melting of Form I as shown in Figure 2.
  • the DSC of Form A shows no peak for solvent loss indicating it to be in anhydrous form.
  • the crystalline Form A showed no significant weight loss in TGA data as shown in Figure 3, further indicating anhydrous nature of Form A. (The water content determined by the Karl-Fisher method is 0.3 to 0.6%).
  • the present invention also provides a process for the preparation of the crystalline desloratadine Form A, the process involves dissolving desloratadine in a suitable solvent such as cyclic ether, preferably selected from 1,4-dioxane, tetrahydrofuran (THF) or mixture thereof, subsequently removing the solvent by one of the processes known in the literature such as drying, freeze-drying, lyophilization or spray drying, and recovering the desloratadine Form A.
  • a suitable solvent such as cyclic ether, preferably selected from 1,4-dioxane, tetrahydrofuran (THF) or mixture thereof
  • desloratadine is dissolved in the cyclic ether solvent at 60-100 0 C, preferably between 60-80 0 C to get a clear solution.
  • the solvent is removed preferably by lyophilization in a freeze dryer.
  • Crystalline desloratadine Form B is characterized by powder X-ray diffraction pattern as shown in Figure 4 with peaks at 7.13, 7.95, 9.65, 9.80, 10.06, 10.67, 11.48, 12.25, 12.72, 13.21, 13.90, 14.20, 14.68, 15.08, 15.41, 15.63, 15.91, 16.40, 16.98, 17.71, 18.14, 18.76, 19.15, 20.17, 21.24, 22.22, 22.86, 23.44, 23.96, 24.50, 25.22, 25.59, 26.29, 27.96, 29.30, 29.97, 31.06, 32.62, 35.91, 37.03, and 38.43 ⁇ 0.2 2 ⁇ values.
  • Crystalline desloratadine Form B is further characterized by DSC with two endothermic peaks first at about 104 0 C attributed to the loss of solvent followed by a second peak at 154°C corresponding to melting of the product as shown in Figure 5.
  • Crystalline desloratadine Form B is a solvate ofl,l,2-trichloroethane having 10-17 % of 1,1,2-trichloroethane content which is analyzed by its TGA data as shown in Figure 6.
  • the solvate is hemi- 1,1,2-trichloroethane solvate. (The water content determined by the Karl-Fisher method is 3.0 to 4.0 %).
  • the present invention also provides a process for preparation of crystalline desloratadine Form B, which comprises slow or fast evaporation of solvent from a saturated solution of desloratadine at room temperature for several days, the saturated solution being obtained by dissolving desloratadine in a solvent, such as 1,1,2- trichloroethane.
  • a solvent such as 1,1,2- trichloroethane.
  • Form B may also be prepared by dissolving desloratadine in a solvent such as 1,1,2-trichloroethane, by heating from about room temperature to reflux temperature. The obtained solid is filtered under suction followed by vacuum drying to recover desloratadine Form B.
  • a solvent such as 1,1,2-trichloroethane
  • Crystalline desloratadine Form B can also be prepared by seeding the saturated solution of desloratadine with crystalline Form B obtained from the above process in 1,1,2-trichloroethane.
  • the present invention also provides a process for the preparation of crystalline desloratadine Form I, which comprises slow or fast evaporation of solvent from a saturated solution of desloratadine at room temperature for several days, the saturated solution being prepared by dissolving desloratadine in a solvent, such as pyridine, 1- methyl-pyrrolidone or mixtures thereof.
  • a solvent such as pyridine, 1- methyl-pyrrolidone or mixtures thereof.
  • the present invention also provides a process for the preparation of crystalline desloratadine Form II, which comprises slow or fast evaporation of solvent from a saturated solution of desloratadine at -15°C to room temperature for several days, the saturation solution being prepared by dissolving desloratadine in a solvent, such as nitromethane, 1 ,4-dioxane, 2-methoxy ethanol or mixtures thereof.
  • a solvent such as nitromethane, 1 ,4-dioxane, 2-methoxy ethanol or mixtures thereof.
  • the present invention also provides a process for the preparation of crystalline desloratadine Form I or admixture of crystalline Forms I and II, by heating the crystalline form of desloratadine i.e. Form A and Form B.
  • Essentially pure Form I or admixture of Forms I and II may also be prepared by slurring Form A in a solvent and filtering the solution to recover a mixture of polymorphs, the solvent is selected form the group consisting of but not limited to isopropyl ether, petroleum ether, diethyl ether and methyl tertiary butyl ether, hexane, heptane, pentane, cyclohexane, toluene and mixtures thereof.
  • Desloratadine (5g) was dissolved in 1,4-dioxane (25 ml) and the resultant solution was subjected to freeze drying. X-ray powder diffraction and DSC of the dried sample showed it to be desloratadine Form A.
  • Desloratadine (2 g) was dissolved in 1,1,2-Trichloroethane (4ml) at 80°C to obtain a solution. The solution was cooled and resulting saturated solution was agitated for 12 hours at room temperature. The precipitate was isolated by filtration and dried at room temperature. X-ray powder diffraction and DSC of the resultant solid showed it to be desloratadine Form B.
  • Desloratadine Form B (2 g) obtained in above Example 2 or Example 3 was heated at 40-60 0 C under vacuum in a static dryer. The analysis of the resultant solid showed it to be an admixture of desloratadine Form I and II.
  • Desloratadine Form A (2 g) obtained in above Example 1 was kept in a static dryer and heated at 40-60 0 C under vacuum. The analysis of the resultant solid showed it to be an admixture of desloratadine Form I and II.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles formes cristallines polymorphes de desloratadine désignées forme (A) et forme (B), lesdites formes étant caractérisées par différentes techniques à l’état solide comme la diffraction par rayons X sur poudre, la calorimétrie à balayage différentiel, une analyse thermo-gravimétrique et la teneur en eau. La présente invention concerne en outre des procédés de préparation desdites formes polymorphes. La présente invention concerne également de nouveaux procédés de préparation de la forme (I) et de la forme (II) de desloratadine et des mélanges de celles-ci.
PCT/IN2009/000086 2008-02-07 2009-02-06 Nouvelles formes cristallines de desloratadine et procédé de préparation associé Ceased WO2009122430A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116120281A (zh) * 2022-11-28 2023-05-16 山东达因海洋生物制药股份有限公司 一种高纯度小粒度地氯雷他定结晶的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506767B1 (en) * 1997-07-02 2003-01-14 Schering Corporation 8-chloro-6,11-dihydro-11-(4-piperidylidine)-5H-benzo[5,6]cyclohepta[1-2-b] pyridine
EP1860105A1 (fr) * 2006-05-24 2007-11-28 Ranbaxy Laboratories Limited Procédé de préparation de desloratadine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116120281A (zh) * 2022-11-28 2023-05-16 山东达因海洋生物制药股份有限公司 一种高纯度小粒度地氯雷他定结晶的制备方法

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