WO2009122430A2 - Novel crystalline forms of desloratadine and process for preparing the same - Google Patents
Novel crystalline forms of desloratadine and process for preparing the same Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- desloratadine
- crystalline
- solvent
- solution
- preparation
- 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
Links
Classifications
-
- 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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides novel crystalline polymorphic forms of desloratadine designated as Form (A) and Form (B), wherein said forms are characterized by different solid state techniques such as powder X-ray diffraction, differential scanning calorimetry, thermo gravimetric analysis and moisture content. Further, this invention discloses processes for preparation of said polymorphic forms. In addition, novel processes for preparing Form (I) and Form (II) of desloratadine and mixtures thereof are also disclosed.
Description
NOVEL CRYSTALLINE FORMS OF DESLORATADINE AND PROCESS
FOR PREPARING THE SAME Field of the Invention
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.
Desloratadine
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. The resulting solution is extracted with chloroform and recrystallized using hexane to give pure desloratadine. 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. 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.
Alternatively, the present invention provides new polymorphic forms of desloratadine and the process for preparing the same.
Object and Summary of the Invention
It is a principal object of the present invention to provide novel crystalline polymorphic forms of desloratadine, referred to herein after Form A and Form B characterized by X-ray powder diffraction pattern (PXRD), thermo gravimetric
analysis (TGA), differential scanning calorimetry (DSC) and moisture content, wherein said Form A is an anhydrous form and Form B is a solvate.
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.
This and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.
In accordance with one preferred embodiment of the present invention, there is provided 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 2Θ values.
In accordance with another preferred embodiment of the present invention, 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 1450C, 1470C and 1570C .
In accordance with one other preferred embodiment of the present invention, there is provided 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 2Θ values.
In accordance with another preferred embodiment of the present invention, 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).
In accordance with yet another preferred embodiment of the present invention, DSC of Form B shows two characteristic peaks at about 1040C and 41540C.
In accordance with yet another embodiment of the present invention, there is provided a process for the preparation of crystalline desloratadine Form A, wherein the process comprises 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.
In accordance with yet another preferred embodiment of the present invention, there is provided a process for the preparation of crystalline desloratadine polymorphic Form B, wherein the process comprises 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.
In accordance with yet another preferred embodiment of the present invention, there is provided a process for the preparation of crystalline desloratadine polymorphic Form B, wherein the process comprises 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.
In accordance with yet another embodiment of the present invention, there is provided a process for preparation of crystalline desloratadine Form I, wherein the process comprises 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.
Furthermore, according to another embodiment of the present invention, there is provided a process for the preparation of crystalline desloratadine polymorphic
Form II, wherein the process comprises 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 .
In accordance with one another embodiment of the present invention, there is provided a process for the preparation of a mixture of polymorphic Form I and Form II by heating polymorphic Form A or Form B obtained according to the process above and isolating a mixture of polymorphic forms of desloratadine Form I and Form II.
In yet another embodiment of the present invention 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.
Brief Description of the Drawings
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:
Figure 1 is the X-ray powder diffraction pattern of Form A of Desloratadine
Figure 2 is the DSC of Form A of Desloratadine
Figure 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
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
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.
Further, the present invention describes the process for preparing novel polymorphic forms of desloratadine Form A and B. In addition the present invention describes improved process for preparation of polymorphic forms of desloratadine Form I, Form II and their mixtures thereof.
Powder X-ray Diffraction (PXRD)
The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu- anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
Diffrential Scanning Calorimetrv (DSO
The DSC measurements were carried out on Mettler Toledo 822 Stare 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.
Thermo gravimetric Analysis (TGA)
TGA measurements were carried out on instrument Mettler Toledo TGA/SDTA 851 Star6 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.
Karl-Fisher
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.
Lvophilization
This was carried out using a freeze dryer (Model: Virtis Genesis SQ Freeze Dryer). 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 2Θ values.
Crystalline desloratadine Form A is further characterized by DSC with three characteristic peaks first an endothermic peak at 1450C, 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 1570C 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.
In a typical procedure of the present invention desloratadine is dissolved in the cyclic ether solvent at 60-1000C, preferably between 60-800C 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 2Θ values.
Crystalline desloratadine Form B is further characterized by DSC with two endothermic peaks first at about 1040C 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. Preferably, 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.
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.
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. The resultant mass is cooled and filtered under suction followed by vacuum drying to recover Form I.
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. The resultant mass is cooled and filtered under suction followed by vacuum drying to recover Form II.
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.
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.
Example 1
Preparation of desloratadine Form A from desloratadine by lvophilization
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.
Example 2
Preparation of desloratadine Form B from desloratadine
Desloratadine (2g) was added to 1,1,2-Trichloroethane (4 ml) and heated to
80°C to obtain a clear solution. The clear solution was kept overnight for slow evaporation of the solvent at room temperature. The precipitate was isolated by
filtration and dried at room temperature. X-ray powder diffraction and DSC of the dried sample showed it to be desloratadine Form B.
Example 3
Preparation of desloratadine Form B from desloratadine
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.
Example 4
Preparation of desloratadine Form B by Seeding
Desloratadine (1 g) was dissolved in 1,1,2-Trichloroethane (2 ml) at hot condition to form a saturated solution. The saturated solution was seeded with Form
B obtained in above Example 3 or Example 4 and stirred for 1 hour at room temperature. The solid was isolated by filtration and dried at room temperature under atmospheric pressure to give Form B.
Example 5
Preparation of admixture of desloratadine Form I and Form II from desloratadine Form B by heating
Desloratadine Form B (2 g) obtained in above Example 2 or Example 3 was heated at 40-600C under vacuum in a static dryer. The analysis of the resultant solid showed it to be an admixture of desloratadine Form I and II.
Example 6
Preparation of admixture of desloratadine Form I and Form II from desloratadine Form A by heating
Desloratadine Form A (2 g) obtained in above Example 1 was kept in a static dryer and heated at 40-600C under vacuum. The analysis of the resultant solid showed it to be an admixture of desloratadine Form I and II.
Example 7
Preparation of desloratadine Form II from desloratadine
Desloratadine (1 g) was dissolved in nitromethane (10 ml) at 80°C and the resultant solution was kept overnight for crystallization at room temperature. The precipitate was isolated by filtration and dried under vacuum at room temperature. The analysis of the resultant solid showed it to be Form II.
Example 8
Preparation of desloratadine Form II from desloratadine
Desloratadine (2 g) was dissolved in 1,4-dioxane (4 ml) at 80°C. The resultant solution was cooled to -1O0C for 5 hours. The resulting precipitate was isolated by filtration and dried under vacuum at room temperature. The analysis of the resultant solid showed it to be Form II.
Example 9
Preparation of desloratadine Form II from desloratadine
Desloratadine (2 g) was dissolved in 2-methoxy ethanol (4 ml) at 80°C. The resulting solution was kept overnight for crystallization at room temperature. The resulting precipitate was isolated by filtration and dried under vacuum at room temperature. The analysis of the resultant solid showed it to be Form II.
Example 10
Preparation of desloratadine Form I from desloratadine
Desloratadine (1 g) was dissolved in l-methyl-2-pyrrolidinone (5 ml) at 80°C and the resultant solution was kept overnight for crystallization at room temperature. The precipitate was isolated by filtration and dried under vacuum at room temperature. The analysis of the resultant solid showed it to be Form I
Example 11
Preparation of desloratadine Form I
Desloratadine (1 g) was dissolved in pyridine (5 ml) at 80°C and the resulting solution was kept overnight for crystallization at room temperature. The resulting precipitate was filtered and dried under vacuum at room temperature to give Form I
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.
Claims
1. A crystalline desloratadine Form A, wherein said Form A is characterized by an 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 2Θ values.
2. The crystalline desloratadine Form A according to claim 1, wherein said Form A is characterized by an X-ray powder diffraction pattern having 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 2Θ values.
3. The crystalline desloratadine Form A according to claim 1, wherein
' said Form A is having a substantially similar X-ray powder diffraction pattern as shown in Figure 1.
4. The crystalline desloratadine Form A according to claim 1, wherein said Form A is characterized by differential scanning calorimetry (DSC) as shown in Figure 2.
5. The crystalline desloratadine Form A according to claim 5, wherein DSC pattern has three characteristic peaks, at about 145°C, 147°C and 157°C.
6. The crystalline desloratadine Form A according to claim 1, wherein said Form A is characterized by thermo gravimetric analysis (TGA) as shown in Figure 3.
7. The crystalline desloratadine Form A according to claim 1, wherein said Form A is an anhydrous form.
8. A process for preparing crystalline desloratadine Form A of claim 1, the process comprising:
a. dissolving desloratadine in a solvent;
b. removing the solvent; and
c. recovering desloratadine Form A.
9. The process according to claim 8, wherein the solvent is selected from cyclic ethers, preferably from a group comprising of 1 ,4-dioxane, tetrahydrofuran or mixtures thereof.
10. The process according to claim 8, wherein the solvent is removed by using freeze drying, lyophilization or spray drying.
11. A crystalline desloratadine Form B, wherein said Form B is 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 2Θ values.
12. The crystalline desloratadine Form B according to claim 11, wherein said Form B is characterized by an X-ray powder diffraction pattern having 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 2Θ values.
13. The crystalline desloratadine Form B according to claim 11, wherein said Form B is having a substantially similar X-ray powder diffraction pattern as shown in Figure 4.
14. The crystalline desloratadine Form B according to claim 11, wherein said Form B is characterized by DSC as shown in Figure 5.
15. The crystalline desloratadine Form B according to claim 11, wherein DSC pattern shows two characteristic peaks at about 104°C and 154 ° C.
16. The crystalline desloratadine Form B according to claim 11, wherein said Form B is characterized by thermo gravimetric analysis (TGA) as shown in Figure 6.
17. The crystalline desloratadine Form B according to claim 11 , wherein said Form B is a solvate of 1,1,2 -trichloroethane.
18. A process for preparing crystalline desloratadine Form B of claim 11, the process comprising: a. preparing a solution by dissolving desloratadine in 1,1,2- trichloroethane;
b. evaporating 1,1,2-trichloroethane from the solution; and
c. recovering crystalline desloratadine Form B.
19. A process for preparation of crystalline desloratadine Form B, the process comprising:
a. preparing a solution by dissolving desloratadine in 1,1,2- trichloroethane;
b. seeding the solution with Form B obtained according to claim 18; and
c. recovering the crystalline desloratadine Form B.
20. A process for preparation of crystalline desloratadine Form I comprising the steps of:
a. dissolving desloratadine in a solvent to obtain a solution, wherein the solvent is selected from l-methyl-2- pyrrolidinone or pyridine;
b. evaporating the solvent; and
c. recovering desloratadine Form I.
21. A process for preparation of crystalline desloratadine Form II comprising the steps of:
a. dissolving desloratadine in a solvent to obtain a solution, wherein the solvent is selected from nitromethane, 1,4-dioxane or 2-methoxy ethanol;
b. evaporating the solvent; and
c. recovering desloratadine Form II.
22. A process for the preparation of a mixture of crystalline desloratadine Form I and II, the process comprising: a. heating desloratadine Form A or Form B; and
b. isolating a mixture of crystalline desloratadine Form I and Form II.
23. A process for the preparation a mixture of desloratadine Form I and II the process comprising:
a. slurring desloratadine Form A or Form B in a solvent; and
b. isolating a mixture of desloratadine Form I and Form II.
24. The process according to claim 23, wherein the solvent is selected from a group comprising of isopropyl ether, petroleum ether, diethyl ether and methyl tertiary butyl ether, hexane, heptane, pentane, cyclohexane, toluene and mixtures thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN319CH2008 | 2008-02-07 | ||
| IN319/CHE/2008 | 2008-02-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2009122430A2 true WO2009122430A2 (en) | 2009-10-08 |
| WO2009122430A3 WO2009122430A3 (en) | 2010-06-10 |
Family
ID=41136017
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2009/000086 Ceased WO2009122430A2 (en) | 2008-02-07 | 2009-02-06 | Novel crystalline forms of desloratadine and process for preparing the same |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2009122430A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116120281A (en) * | 2022-11-28 | 2023-05-16 | 山东达因海洋生物制药股份有限公司 | Preparation method of high-purity small-granularity desloratadine crystals |
Family Cites Families (2)
| 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 (en) * | 2006-05-24 | 2007-11-28 | Ranbaxy Laboratories Limited | Process for the preparation of desloratadine |
-
2009
- 2009-02-06 WO PCT/IN2009/000086 patent/WO2009122430A2/en not_active Ceased
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116120281A (en) * | 2022-11-28 | 2023-05-16 | 山东达因海洋生物制药股份有限公司 | Preparation method of high-purity small-granularity desloratadine crystals |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009122430A3 (en) | 2010-06-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2510849A1 (en) | Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates | |
| WO2004083192A1 (en) | Polymorphis of valsartan | |
| WO2016131431A1 (en) | Solid forms of empagliflozin | |
| WO2007109799A2 (en) | Polymorphs of eszopiclone malate | |
| US20080167477A1 (en) | Novel polymorphic forms of carvedilol dihydrogen phosphate and process for preparing the same | |
| SK8332002A3 (en) | Novel processes for making- and a new crystalline form of leflunomide | |
| EP2601178A2 (en) | Salts of lapatinib | |
| EP2925753A1 (en) | Novel polymorphs of azilsartan medoxomil | |
| WO2008114279A2 (en) | Novel polymorphs of lamivudine | |
| WO2016200919A1 (en) | Crystalline forms of a histone deacetylase inhibitor | |
| CA2410227A1 (en) | Crystal modification of fexofenadine | |
| WO2011153221A1 (en) | Solid state forms of ixabepilone | |
| WO2007076116A2 (en) | Intermediates for preparing solifenacin | |
| WO2009122430A2 (en) | Novel crystalline forms of desloratadine and process for preparing the same | |
| WO2006030449A1 (en) | Crystalline alfuzosin base | |
| KR20090014225A (en) | Polymorph of (R) -5- (2-aminoethyl) -1- (6,8-difluorochroman-3-yl) -1,3-dihydroimidazole-thione hydrochloride | |
| WO2011027324A1 (en) | Polymorphic forms of atazanavir sulfate | |
| EP2393786A2 (en) | Novel polymorphs of lopinavir | |
| EP2260037A2 (en) | A polymorphic form of a pyrazino [2,3-h] [3] benzazepine derivative | |
| EP1950204A1 (en) | Amorphous form of valsartan | |
| WO2008020453A2 (en) | A process for the preparation of a novel crystalline polymorph of aripiprazole | |
| US20120267533A1 (en) | Processes for the preparation of form i and form ii of palonosetron hydrochloride | |
| WO2014049609A2 (en) | Novel salts of vilazodone | |
| CA2577406A1 (en) | Process for the production of levorphanol and related compounds | |
| WO2010001408A2 (en) | Novel polymorphic forms of gemifloxacin mesylate |
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: 09727713 Country of ref document: EP Kind code of ref document: A2 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 09727713 Country of ref document: EP Kind code of ref document: A2 |