FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION "POLYMORPHS OF RUPATADINE FUMARATE"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad-380015, Gujarat, India.
The following specification describes the invention:

FIELD OF THE INVENTION:
The present invention relates to the novel polymorphic forms of Rupatadine fumarate
and its solvate or hydrated forms thereof. The present invention further provides the process
for preparing and novel polymorphic forms of Rupatadine fumarate and its use in
pharmaceutical composition. Rupatadine fumarate, which is chemically known as 8-Chloro-
6,11 -dihydro-11 -(1 -((5-methyl-3-pyridyl) methyl)-4-piperidylidene)-5H-
benzo(5,6)cyclohepta(l,2-b)pyridine fumarate and it is useful as pharmaceutical agents for the treatment of Allergies. Rupatadine fumarate is represented by below mentioned formula
(I)

BACKGROUND AND PRIOR ART
Allergic rhinitis (AR) is a global health concern and shares a high comorbidity with asthma. Recent research suggests that different allergic diseases, such as AR, asthma, allergic conjunctivitis and chronic idiopathic urticaria (CIU), are evoked by common pathological mechanisms characterised by the release of histamine and other inflammatory mediators.
Rupatadine is useful for the management of diseases with allergic inflammatory conditions, such as seasonal and perennial rhinitis. The pharmacological profile of rupatadine offers particular benefits in terms of a strong antagonist activity towards both histamine HI receptors and platelet-activating factor (PAF) receptors. Rupatadine has a rapid onset of action, and its long-lasting effect permits once-daily dosing. Rupatadine is clinically effective in relieving symptoms in patients with seasonal and perennial allergic rhinitis.
US Patent No. 5,407,941, which is herein incorporated by reference, discloses the process for preparation of Rupatadine. Accordingly, 3,5-lutidine is treated with N-bromosucccinimide to yield 3-bomomethyl-5-methyl pyridine, which is condensed with 8-chloro-11 -(4-piperidyliden)-6,11 -dihydro-5H-benzo[5,6]cyclohepta [ 1,2-b]pyridine of formula (II) in presence of 4-(dimethylamino)pyridine and triethyl amine in carbon
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tetrachloride to give Rupatadine, which is isolated by column chromatography with use of carbon tetrachloride as solvent in low yield of 40% as depicted in below Scheme -1
Scheme -1

ES 2,087,818 incorporated herein as reference, discloses two approaches for the preparation of Rupatadine and its fumarate salts, according to the process, hydrolytic removal of the N-ethoxycarbonyl group of Loratadine to give compound of formula (II) which is N-acylated with 5-methylnicotinic acid using DCC and HOBT to give Rupatadine or 5-methylnicotinic acid is chlorinated with POCl3 and subsequently condensed with formula (II) is to give compound of formula (V), which upon reduction by using NaBH4 gives Rupatadine as shown in below Scheme -2.
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However, the process is not easy and cost effective because of the below mentioned reasons
a) The process requires commercially limited available and costly raw materials such as 1,3-dicyclohexylcabodiimide (DCC) and 1-hydroxybenzotriazole hydrate (HOBT).
b) The process generates lot of effluent waste such as dicyclohexyl urea and hence is not eco-friendly.
c) Dicyclohexyl urea generated during the reaction cannot be easily removed during the work up at large scale and repeated purification of crude and impure N-(5-methylnicotinoyl)4-hydroxy piperidine leads to overall loss of yield and makes this process less economically viable.
US Patent No. 6,803,468 incorporated herein as reference, discloses the process for synthesis of N-(5-methylnicotinoyl)-4 hydroxypiperidine, a key intermediate of Rupatadine.
Therefore, there is a need to have easy and simple process for the preparation of Rupatadine, which devoid of costlier material and does not involve laborious column chromatography technique.
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Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci, 64, 1269 (1975), all of which are incorporated herein by reference.
The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density (important in formulation and product manufacturing) and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e. g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form may be important in pharmaceutical processing. For example, a particular crystalline form may form solvates more readily or may be more difficult to filter and wash free of impurities than other forms (i.e., particle shape and size distribution might be different between one crystalline form relative to other forms).
On the other hand amorphous form have better profile for formulation. We have
found that after the advent of crystalline Rupatadine, the production of amorphous
Rupatadine is desirable for formulation. It has been disclosed that the amorphous forms in a
number of drugs exhibit different dissolution characteristics and in some cases
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different bioavailability patterns compared to the crystalline form (Konno T., Chem. Pharm. Bull, 1990; 38; 2003-2007). For some therapeutic indications one bioavailablity pattern may be favoured over another. Therefore, it is desirable to have a procedure for converting cyrstalline form of a drug to the amorphous form.
OBJECT OF THE INVENTION
The object of the present invention is to provide polymorphic forms of Rupatadine fumarate of formula (I).
Another object of the present invention is to provide a novel crystalline form of Rupatadine fumarate.
Yet, another object of the present invention is to provide novel amorphous form of Rupatadine fumarate.
Further object of the present invention is to provide a process for the preparation of Rupatadine in novel crystalline and amorphous form.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG 1. represents the PXRD of Crystalline Form A of Rupatadine Fumarate. FIG 2. represents the PXRD of Amorphous Form of Rupatadine Fumarate DESCRIPTION OF THE INVENTION
The present invention provides the novel polymorphic forms of Rupatadine fumarate of formula (I) and the or its pharmaceutically acceptable salts, solvates and the process for the preparation thereof.
According to the present invention, there is provided a novel crystalline form of Rupatadine fumarate of formula (I) designated as Form A. The present invention further provides the process for the preparation of Form A of Rupatadine fumarate.
According to the present invention, there is provided a novel amorphous form of Rupatadine fumarate of formula (I). The present invention further provides the process for the preparation of amorphous form of Rupatadine fumarate.
According to one aspect of the present invention, there is provided a novel crystalline form of Rupatadine fumarate. The crystalline form of Rupatadine fumarate is herein after designated as "Form A". The Form A of Rupatadine fumarate is characterized by its powder X-ray diffraction pattern having peaks expressed as 2θ at about 8.1, 13.8, 19.7, 24.5 ± 0.2degrees. The form A of Rupatadine fumarate is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2θ at about 11.8, 12.7, 16.8, 20.4± 0.2degrees degrees. FIG. 1 shows typical x-ray powder diffraction pattern of Form A of Rupatadine fumarate.
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The present invention also provides a process for preparing crystalline Form A Rupatadine fumarate. The process for the preparation of crystalline Form A of Rupatadine fumarate, which comprises treating Rupatadine with fumaric acid in organic solvent.
The reaction is preferably carried out in organic solvent. The organic solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting crystalline Rupatadine fumarate Form A. Advantageously, both Rupatadine and the fumaric acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Rupatadine and a solvent may be contacted with a fumaric acid, or conversely, a mixture, slurry, or solution of fumaraic acid and a solvent may be contacted with Rupatadine. In another embodiment, Rupatadine and fumaric acid may be combined with a solvent system prior to being contacted together, whereby the solvent system used for fumaric acid may be identical with or different from the organic solvent system used for the Rupatadine.
The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the. Suitable solvents include a lower alcohol (C1- C6) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisoproipyl ether, dioxane or dimethylformamide, dimethyl sulfoxide and the like.
The temperature of contact of Rupatadine and fumaric acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e., a slurry or two phase solution are also possible, though a single solution is generally preferred.
The crystalline Form A of Rupatadine fumarate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the Rupatadine fumarate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Rupatadine fumarate is less soluble. Seed crystals of Form A of Rupatadine fumarate may also be added to help induce precipitation. The precipitated Form A of Rupatadine fumarate compound can be isolated by conventional
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methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.
In a preferred embodiment, the process for preparation of cyrstalline Form A of Rupatadine Fumarate comprises of:
a) dissolving Rupatadine in an organic solvent to get clear solution at ambient temperature
b) dissolving fumaric acid in an organic solvent to get clear solution
c) addition of fumaric acid solution to reaction mixture at ambient temperature
d) stirring the reaction mixture, cool to below 0°C and store under inter atmosphere.
e) filter, washing with an organic solvent or mixture of organic solvent and dry to obtain crystalline Form A of Rupatadine fumarate.
Preferably, the process step a) comprises of dissolving Rupatadine in an organic solvent, which includes, methanol, ethanol, propanol, butanol, isopropanol, ethyl acetate, methyl acetate, acetone, tetrahydrofuran, dimethylforamide and the like. Preferably, dissolving Rupatadine in ethyl acetate or methyl acetate, more preferably ethyl acetate to get clear solution at an ambient temperature i.e. at room temperature 25°C to 30°C.
Preferably, the process step b) comprises of dissolving fumaric acid in an organic solvent, which includes, methanol, ethanol, propanol, butanol, isopropanol, ethyl acetate, methyl acetate, acetone, and the like. Preferably, dissolving Rupatadine in methanol or ethanol, more preferably methanol to get clear solution.
Preferably, the process step c) comprises of addition of fumaric acid solution to the reaction mixture at ambient temperature i.e. room temperature 25°C to 30°C.
Preferably, the process step d) comprises of stirring the reaction mixture for about 15 minutes followed by cooling at -5°C to 0°C and storing under inert atmosphere i.e. under nitrogen atmosphere to precipitate the white solid of Form A Rupatadine Fumarate.
Preferably, the process step e) comprises of filtering the white solid, washing with the organic solvent or mixture of organic solvent, for examples, methanol, ethanol, propanol, butanol, isopropanol, ethyl acetate, methyl acetate, acetone, tetrahydrofuran, dimethylforamide and the like. Preferably washing with the mixture of organic solvent, which includes, ethyl acetate and methanol followed by drying for an appropriate period of time at 55°C to 60°C to obtain crystalline Form A of Rupatadine Fumarate.
The present invention further provides amorphous form of Rupatadine fumarate. According to the present invention, the amorphous form of Rupatadine fumarate is in substantially amorphous form and can be characterized by its' powder X-ray diffractogram as shown in Fig.2.
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The present invention provides a novel process for the preparation of amorphous Rupatadine fumarate, which comprises:
a) dissolving crystalline Rupatadine fumarate in a hydroxylic solvent; and
b) removing the solvent to obtain amorphous Rupatadine fumarate.
The solvent is removed, for example by drying technology such as, for example, vacuum drying, spray drying, freeze drying (Lyophilyzation), and the like. Preferably, the drying procedure uses spray dryer technique to produce amorphous Rupatadine Fumarate
Amorphous Rupatadine fumarate of the present invention can exist in anhydrous forms as well as hydrated forms. In general, the hydrated forms, are equivalent to anhydrous forms and are intended to be encompassed within the scope of the present invention.
As previously described, amorphous Rupatadine is useful for the management of diseases with allergic inflammatory conditions, such fumarate as seasonal and perennial rhinitis. The pharmacological profile of rupatadine offers particular benefits in terms of a strong antagonist activity towards both histamine H1 receptors and platelet-activating factor (PAF) receptors.
Preferably, amorphous form of Rupatadine fumarate can be prepared by dissolving crystalline Rupatadine in a hydroxylic solvent such as, for example, methanol, ethanol, propanol, isopropanol, a mixture thereof or optionally there mixture with water to obtain solution and removing the solvent from solution to obtain amorphous form of Rupatadine fumarate. The solvent is removed, for example, drying technology such as, for example, vacuum drying, spray drying, freeze drying (Lyophilyzation), and the like. Preferably, the drying procedure uses spray dryer technique. Morepreferably, crystalline Rupatadine is dissolved in methanol and solvent is removed by spray drying technique.
The following non-limiting examples illustrate the inventor's preferred methods for preparing the compounds of the invention.
X-RAY POWDER DIFFRACTION
Amorphous Form and Crystalline Form were characterized by their X-ray powder diffraction patterns. Thus, the X-ray diffraction patterns of amorphous and Crystalline Form were measured on a Rigaku D-Max 500 Diffractometer with CuKa radiation.
Equipment
Rigaku D/Max-2200/PC Diffractometer, software - MDI JADA 6.5
CuKa radiation (40mA, 40 kV, λ, = 1.5406 Å) Slits I and II at 1°) electronically filtered (Slits: III and IV at 0.15°).
Methodology
The silicon standard is run each day to check the X-ray tube alignment.
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Continuous θ/2θ coupled scan: 2.00° to 40.00° in 2θ, scan rate of 3º/min: 0.02/0.3 for
amorphous Rupatadine
Sample width - 0.02°, Samples are stored and run at room temperature.
Examples:
Example-l: Preparation of Form A of Rupatadine Fumarate:
To the solution of 1.0 Kg (2.40 mole) of 8-Chloro-11-{1-[(5-methyl-3-pyridyl)methyl]-piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine in 5.6 L of ethyl acetate obtained by stirring for 15 minutes to get clear solution at 25°C to 30°C was added 0.307 Kg (2.64 mole) of fumaric acid dissolved in 5.0 L of methanol. The content was allowed to stir for 15 minutes and cooled to -5°C to 0°C. The content was stirred under nitrogen atmosphere to get white solid at -5°C to 0°C. The product thus obtained was filtered, washed with mixture of 200 mL of ethyl acetate and 50 mL of methanol. Dry the solid for 6.0 hours at 55°C to 60°C temperature to obtain crystalline Form A of Rupatadine Fumarate.
Example-2: Preparation of Rupatadine Fumarate:
10 g of Rupatadine Fumarate was dissolved in 250 mL of methanol by heating at 40°C
- 55°C to get clear solution. The reaction mixture was cooled to 25°C-35°C. The reaction
mixture was filtered through hyflow and washed with 10 mL of methanol. The product was
spray dried with following conditions of a spray dryer.
Aspirator : 1300 RPM
Feed Pump : 15 RPM
Air Pressure : 2 Kg
Inlet Temp : 60°C (Actual Temp: 61.3°C)
Outlet Temp : 45°C (Actual Temp: 41.4°C)
Dry wt = 4.0 g
The dry product thus obtained is amorphous form of Rupatadine Fumarate.



Dated this the 13th day of September 2006

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