WO2009087643A1 - Novel crystalline forms of palonosetron hydrochloride - Google Patents
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Abstract
The present invention relates to novel crystalline forms, designated as Form (I) and Form (II) of Palonosetron Hydrochloride ((3as)-2[(3s)-1-Azabicyclo[2.2.2]Oct-3-yl]-2,3,3a,4,5,6- hexahydro-1H-benz[de]isoquinoline-1-one mono hydrchloride) and processes for their preparation. Palonosetron Hydrochloride is useful as anti-emetic agent during the chemotherapy of treatment of cancer patients. It is marketed globally under the brand names 'Aloxi' and 'Onicit'.
Description
JNOVEJL CRYSTALLINE FORMS OF PALONOSETRON
HYDROCHLORIDE
FIELD OF INVENTION
The present invention relates to novel crystalline forms of Palonosetron Hydrochloride and processes for their preparation. Palonosetron hydrochloride is (3as)-2[(3s)-l- Azabicyclo[2.2.2]Oct-3-yl]-2,3,3a,4,5,6-hexahydro-lH-benz[de]isoquinoline-l-one mono hydrchloride of formula-I.
I
Palonosetron Hydrochloride is useful as anti-emetic agent during the chemotherapy of treatment of cancer patients. It is marketed globally under brand names 'Aloxi' and 'Onicit'.
BACKGROUND OF INVENTION
Palonosetron Hydrochloride is introduced for the first time by Syntex Inc. a U. S based company. Palonosetron Hydrochloride is tricyclic 5-HT3 receptor antagonist containing a bridged bicyclic amine substituent.
Serotonin, a neurotransmitter with mixed and complex pharmacological characteristics, was first discovered in 1948 and subsequently has been the subject of the substantial research. Serotonin also referred to as 5-hydroxy tryptamine (5-HT), acts both centrally and peripherally on discrete 5-HT receptors.
5-HT receptors are presently delineated into three major subclasifications-5HTi, 5-HT2 and 5-HT3 each of which may also be heterogenous. Receptors of the 5-HT3 subclass
pervade autonomic neurons and appear to regulate the release of a variety of neurotransmitters in the gastrointestinal, cardiovascular and central nervous systems.
5-HT3 receptors are located in high densities on ήeμrons associated with the emetic reflex and drugs which block the interactions of serotonin at the 5-HT3 receptor level, i.e. 5-HT3 receptor antagonists posses potent anti-emetic properties. Such antagonists demonstrate utility for counteracting the emetic effects of cancer chemotherapy and radiotherapy.
The process for the preparation of Palonosetron Hydrochloride is described in EP 0430190 A2 (1991) and US 5202333 (1993) patents. Neither polymorphic forms of palonosetron hydrochloride nor any solid state characteristics have been reported till date in the literature.
We have now discovered two novel polymorphic forms of palonosetron hydrochloride. These novel forms are found to be stable, reproducible, and suitable for pharmaceutical preparations.
It is known that pharmaceutical substances can exhibit polymorphism. Polymorphism is commonly defined as the ability of any substance to have two or more different crystal structures. Pharmaceutical substances may also encapsulate water or solvent molecules when crystallized. These solvates or hydrates are referred to as pseudo polymorphs. It is also possible that the drug substance can exist in amorphous form.
A particular polymorphic form may give rise to distinct properties that may be detectable by X-ray powder diffraction (XRPD), Differential scanning calorimetry (DSC), Infrared spectroscopy (IR), and Thermo gravimetric analysis (TGA) etc. Different polymorphs differ in their physical properties such as melting point, solubility, etc.
Polymorphism of active pharmaceutical ingredients is becoming an increasingly important issue in the contemporary drug development. Polymorphic form of an active pharmaceutical ingredient (API) might influence its kinetic solubilization and thus affect
the release of API from the finished dosage form. This is especially true in case of solid dosages like tablets.
The release process of API from dosage form is crucial for drug bioavailability and therapeutic action. Due to higher activity of new generation of APIs and lower doses of API in drugs, the study of polymorphic forms of API s in finished doses have become very important both technically and commercially.
DESCRIPTION OF THE INVENTION
As a result of our studies on solid-state properties of Palonosetron Hydrochloride, two polymorphic forms of Palonosetron Hydrochloride are generated. These polymorphic forms are designated by us as polymorphic Form-I and polymorphic Form-II. These , polymorphs are characterized by the peak patterns appearing in powder X-ray diffraction pattern (XRD).
Accordingly the main object of the present invention is to provide stable, novel , crystalline forms of palonosetron hydrochloride and process for their preparation.
According to one aspect of the present invention there is provided a novel polymorphic form of palonosetron hydrochloride, designated as Form-I, characterized by powder x- ray diffraction pattern having the peaks expressed at 2Θ values of 12.93, 13.65, 14.10, 15.33, 16.07, 17.46, 18.35, 19.87, 23.13, and 25.02 degrees. Figure 1 shows the typical Form-I powder x-ray diffraction pattern.
According to another aspect of the present invention there is provided a process for preparation of Form-I of palonosetron hydrochloride.
Thus by dissolving 2-[(S)-l-Azabicyclo [2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benz[de]isoquinolin-l-one hydrochloride of formula-II in methanol, hydrogenating the reaction mass in the presence of palladium on charcoal catalyst at ambient temperature, filtering the catalyst, and evaporating the solvent from the filtrate, affords a residue.
The residue thus obtained is dissolved in methanol at elevated temperature (60-65°C), and the resulting solution is cooled to room temperature. The polymorphic form-I of palonosetron hydrochloride is crystallized from this solution by technique such as addition of anti- solvent and isolated by conventional technique such as filtration. The anti-solvent is selected from ethers such as diethyl ether, diisopropyl ether, tert-Butyl methyl ether and the like, more preferably tert-Butyl methyl ether.
According to another aspect of the present invention there is provided another process for preparation of Form-I of palonosetron hydrochloride. Thus the residue obtained above from catalytic hydrogenation of compound of formula-II is dissolved in methylene chloride at ambient temperature, the polymorphic Form-I of palonosetron hydrochloride is crystallized from the solution by technique such as addition of suitable anti-solvent and isolated by conventional technique such as filtration. The suitable anti-solvent is selected from esters such as methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate etc, preferably ethyl acetate, or from ethers such as diethyl ether, diisopropyl ether, tert-Butyl methyl ether, mono glyme, and diglyme etc, preferably tert-Butyl methyl ether, or from saturated aliphatic hydrocarbons such as pentane, hexane, heptane, octane etc, preferably n-hexane or from aliphatic saturated cyclic hydrocarbons such as cyclopentane, cyclohexane, cycloheptane, cyclooctane etc. preferably cyclohexane.
According to another aspect of the present invention there is provided yet another process for preparation of Form-I of palonosetron hydrochloride. Thus palonosetron base of formula-Ill, is prepared by the process which comprises:
Dissolving the residue of palonosetron hydrochloride of formula-I prepared as above, in demineralized water, basifying the solution with 25%aq. sodium hydroxide solution, and
extracting into an organic solvent. Evaporating the solvent and recrystallizing the resulting product from a solvent mixture of ethyl acetate and n-hexane affords palonosetron base.
According to one aspect of the present invention, there is provided another novel polymorphic form of palonosetron hydrochloride, designated as Form -II, characterized by powder x-ray diffraction pattern having the peaks expressed as 2Θ values of 12.03, 13.70, 14,39, 15.72, 16.87, 20.90, 24.01, 25.34, 27.67, and 32.16 degrees. Figure-II shows typical Form-II powder x-ray diffraction pattern.
According to another aspect of the present invention there is provided a process for preparation of Form-II of palonosetron hydrochloride. Thus, the product of hydrogenation of compound of formula-II is dissolved in methylene chloride at ambient temperature. The polymorphic Form-II of palonosetron hydrochloride is crystallized from the solution by technique such as addition of suitable anti-solvent and isolated by conventional technique such as filtration. The suitable anti-solvent is selected from aromatic hydro carbons such as benzene, toluene, xylene etc, preferably toluene.
According to yet another aspect of the present invention there is provided another process for preparation of Form-II of palonosetron hydrochloride. Thus, the product of hydrogenation of compound of formula-II is dissolved in methanol at reflux' temperature, The polymorphic Form-II of palonosetron hydrochloride is isolated from the reaction mass by cooling, and filtration.
According to yet another aspect of the present invention there is provided another process for preparation of Form-II of palonosetron hydrochloride. Thus, the product of hydrogenation of compound of formula-II is dissolved in water at ambient temperature. The polymorphic Form-II of palonosetron hydrochloride is crystallized from the solution by technique such as addition of suitable anti-solvent and isolated by conventional technique such as filtration. The suitable anti-solvent for isolation includes water miscible ketones like acetone, water miscible ethers like tetrahydrofuran, and nitriles like acetonitrile.
According to another aspect of the present invention, crystalline Form-II of palonosetron hydrochloride is prepared from Form-I polymorph. By dissolving Form-I in a suitable solvent followed by addition of an anti-solvent. Suitable solvent includes chlorinated' hydrocarbons like methylene chloride, chloroform or water, or methanol. When the solvent is selected from chlorinated hydrocarbons, the anti-solvents used are aromatic hydrocarbons like benzene, toluene and xylene etc, preferably toluene. When the solvent used is water, the anti-solvents used are water miscible solvents like acetone, tetrahydrofuran and acetonitrile etc. No anti-solvent is needed when the solvent used is methanol.
According to another aspect of the present invention there is provided yet another process for preparation of Form-II of palonosetron hydrochloride. Thus palonosetron free base is dissolved in isopropyl alcohol at ambient temperature. The polymorphic Form-II of palonosetron hydrochloride is crystallized from the solution upon addition of cone. HCl at ambient temperature arid isolated by conventional techniques such as filtration.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising Form-I or Form-II of palonosetron hydrochloride. Both the forms of palonosetron hydrochloride may be formulated in a form suitable for oral administration or injection.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 is x-ray powder diffraction pattern of Form-I palonosetron hydrochloride Figure 2 is x-ray powder diffraction pattern of Form -II palonosetron hydrochloride
X-ray powdered diffraction pattern were measured on a Siemens D-5000 x-ray diffractometer having a copper -K alpha radiation. (1.5406A)
The details of the process of the invention in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example 1
A solution of 2-[(S)-l-Azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (1Og) and methanol (100ml) was hydrogenated in the presence of 10% palladium on charcoal (1Og) at 25-35°C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue.
The above residue (1Og) was treated with methanol (80ml), the reaction mass was heated to 60-650C5 and the resulting solution was cooled to 25-3O0C. tert-Butyl methyl ether (80 ml) is added and the mixture is stirred for 2h. The solid was isolated by filtration and dried at 70-750C to get Form-I of palonosetron hydrochloride
Example 2
A solution of 2-[(S)-l-Azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (5g) and methanol (50ml) was hydrogenated in the presence of 10% palladium on charcoal (5g) at 25-35°C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue
The above residue (5g) was treated with methylene chloride (300ml), and stirred at 25- 30°C. tert-Butyl methyl ether (300 ml) was added to the reaction mass and stirred for 45min. The resulting solid was isolated by filtration and dried at 70-750C to get Form -I of palonosetron hydrochloride.
Example 3
A solution of 2-[(S)-l-Azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (5g) and methanol (50ml) was hydrogenated in the presence of 10% palladium on charcoal (5g) at 25-35°C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue.
The above residue (5g) was treated with methylene chloride (300ml) and stirred at 25- 3O0C. Ethyl acetate (300 ml) was added to the reaction mass and stirred for 45min. The resulting solid was isolated by filtration and dried at 70-750C to afford Form-I of palonosetron hydrochloride.
Example 4 A solution of 2-[(S)-I -Azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (5g) and methanol (50ml) was hydrogenated in the presence of 10% palladium on charcoal (5g) at 25-350C at 50 psi. After completion of reaction,. the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue
The above residue (5g) was treated with methylene chloride (300ml) and stirred at 25- 3O0C. n-Hexane (300 ml) was added to the reaction mass and stirred for 45min. The resulting solid was isolated by filtration and dried at 70-750C to get Form-I of palonosetron hydrochloride.
Example 5
A solution of 2-[(S)-l-Azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (5g) and methanol (50ml) was hydrogenated in the presence of 10% palladium on charcoal (5g) at 25-350C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue.
The above residue (5g) was treated with methylene chloride (300ml) and stirred at 25- 3O0C. Cyclohexane (300 ml) was added to the reaction mass and stirred for 45min. The resulting solid was isolated by filtration and dried at 70-75°C to get Form-I of palonosetron hydrochloride.
Example 6 A solution of 2-[(S)-l-Azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (1Og) and methanol (100ml) was hydrogenated in the presence of 10% palladium on charcoal (1Og) at 25-35°C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue.
The above residue (1Og) was dissolved in 10 ml of DM water and basified with 25% aq. . Sodium hydroxide solution to pH 12. Resulting precipitate was extracted into ethyl acetate (3x50ml), solvent was evaporated under reduced pressure to get pale yellow colored product. The product was recrystallized from Ethyl acetate: n-Hexane to yield off-white colored palonosetron base.
Palonosetron base (5g) was treated with ethanol (30ml) stirred to dissolve at 25-30°C. Cone. Hydrochloric acid (2ml) was added to above solution, and the. reaction mass was cooled to 0-50C, maintained for 2.5h. The resulting solid was filtered and dried at 70- 750C to afford Form-I of palonosetron hydrochloride.
Example 7
A solution of 2-[(S)-l-Azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (5g) and methanol (50ml) was hydrogenated in the presence of 10% palladium on charcoal (5g) at 25-35°C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue.
The above residue (5g) was treated with DM water (10ml), and stirred at 25-30°C. Acetone (150 ml) was added to the reaction mass stirred for 2h. The resulting solid was isolated by filtration and dried at 70-75°C to get Form-II of palonosetron hydrochloride.
Example 8
A solution of 2-[(S)-l-Azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (5g) and methanol (50ml) was hydrogenated in the presence of 10% palladium on charcoal (5g) at 25-35°C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue.
The above residue (5g) was treated with DM water (10ml), and stirred at 25-3O0C. Tetrahydrofuran (150 ml) was added to the reaction mass and stirred for 2h. The resulting solid was isolated by filtration and dried at 70-750C to get Form-II of palonosetron hydrochloride.
Example 9
A solution of 2-[(S)-l-Azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (5g) and methanol (50ml) was hydrogenated in the presence of 10% palladium on charcoal (5g) at 25-35°C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue.
The above residue (5g) was treated with methanol (25ml) and was heated to 60-65°C to dissolve. Reaction mass cooled to 25-300C, and further cooled to 0-5°C, stirred for 1.5h. The resulting solid was isolated by filtration and dried at 70-750C to afford Form-II of palonosetron hydrochloride
Example 10
A solution of 2-[(S)-l-Azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula-II (5g) and methanol (50ml) was hydrogenated in the presence of 10% palladium on charcoal (5g) at 25-350C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue.
The above residue (5g) was treated with methylene chloride (300ml) and stirred at 25- 3O0C. Toluene (300 ml) was added to the reaction mass and stirred for Ih. The resulting solid was isolated by filtration and dried at 70-750C to get Form-II of palonosetron hydrochloride.
Example 11
Palonosetron hydrochloride Form-I (5g, prepared as in example 1 described above) was treated with DM water (10ml), stirred to dissolve at 25-3O0C. Acetone (150 ml) was added to the reaction mass and stirred for 2h. The resulting solid was isolated by filtration and dried at 70-750C to afford Form-II of palonosetron hydrochloride.
Example 12 Palonosetron hydrochloride Form-I (5g. prepared as in example 1 described above) was treated with DM water (10ml), stirred to dissolve at 25-300C. Tetrahydrofuran (150 ml) was added to above reaction mass and stirred for 2h. The resulting solid was isolated by filtration and dried at 70-750C to give Form-II of palonosetron hydrochloride.
Example 13
Palonosetron hydrochloride Form-I (5g. prepared as in example 1 described above) was treated with methanol (25ml). The reaction mass was heated to 60-65°C to dissolve. The resulting clear solution was cooled to 25-30°C, and further cooled to 0-5°C, stirred for 1.5h. The resulting solid was isolated by filtration and dried at 70-750C to get Form-II of palonosetron hydrochloride.
Example 14
Palonosetron hydrochloride Form-I (5g. prepared as in example 1 described above) was treated with methylene chloride (300ml), stirred to dissolve at 25-3O0C. Toluene (300 ml) was added to above reaction mass and stirred for Ih. The resulting solid was isolated by filtration and dried at 70-750C to afford Form-II of palonosetron hydrochloride.
Example 15 A solution of 2-[(S)-l-Azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]- isoquinolin-1-one hydrochloride of formula- II (1Og) and methanol (100ml) was hydrogenated in the presence of 10% palladium on charcoal (1Og) at 25-350C at 50 psi. After completion of reaction, the catalyst was filtered off, solvent was evaporated from the filtrate to get pale yellow colored residue.
The above residue (1Og) was dissolved in 10 ml of DM water and basified with 25% aq. Sodium hydroxide solution to pH 12. The resulting precipitate was extracted into ethyl acetate (3x50ml), solvent was evaporated under reduced pressure to get pale yellow colored product. The product was recrystallized from Ethyl acetate: n-Hexane to yield off-white colored palonosetron free base.
Palonosetron free base (5g) was treated with isopropyl alcohol (60ml) stirred at 25-300C. Cone. Hydrochloric acid (2ml) was added to above clear solution. The reaction mass was maintained for 2.5h. The resulting solid was isolated by filtration and dried at 70-750C to afford Form-II of palonosetron hydrochloride.
ADVANTAGES OF THE PRESENT INVENTION
1. Present invention discloses two novel polymorphic forms of palonosetron hydrochloride designated as form-I, and form-II of palonosetron hydrochloride.
2. Novel polymorphic forms of palonosetron hydrochloride disclosed in present invention are stable, and suitable for pharmaceutical formulations.
Claims
1. A polymorphic Form-I of palonosetron hydrochloride of formula-I characterized by peak patterns appearing in X-ray powder diffraction pattern expressed as 2Θ at about 12.93, 13.65, 14.10, 15.33, 16.07 17.46, 18.35, 19.87, 23.13, 25.02 degrees.
2. A polymorphic Form-I of palonosetron hydrochloride as defined in claim 1 and as further characterized by an X-ray powder diffraction pattern given in figure 1.
3. A process for the preparation of polymorphic Form-I of palonosetron hydrochloride as defined in claim 1, which comprises:
Dissolving the reaction product residue obtained by hydrogenation of the compound of formula-II in lower aliphatic alcohols from Ci to C3 at reflux temperature, cooling the reaction mass, isolating Form-I of palonosetron hydrochloride by addition of suitable anti solvent; wherein the suitable solvent is selected from diethyl ether, diisopropyl ether, tert-Butyl methyl ether, ethyl acetate, n-Hexane or cyclohexane.
4. A process for the preparation of polymorphic Form-I of palonosetron hydrochloride as defined in claim 1, which comprises:
Dissolving the reaction product residue obtained by hydrogenation of the compound of formula-II in methylenechloride at 25-3O0C, isolating Form-I of palonosetron hydrochloride by addition of suitable anti solvent; wherein the suitable solvent selected from diethyl ether, diisopropyl ether, tert-Butylmethyl ether, ethylacetate, n-
Hexane or cyclohexane.
5. A process for the preparation of polymorphic Form-I of palonosetron hydrochloride as defined in claim 1, which comprises:
Dissolving palonosetron free base in ethyl alcohol at 25-30°C, adding Cone. Hydrochloric acid and isolating polymorphic Form-I of palonosetron hydrochloride by cooling the reaction mass 0-5°C.
6. A polymorphic Form-II of palonosetron hydrochloride of formula-I characterized by peak patterns appearing in X-ray powder diffraction pattern expressed as 2Θ at aboutl2.03, 13.70, 14,39, 15.72, 16.87, 20.90, 24.01, 25.34, 27.67, and 32.16 degrees.
I
7. A polymorphic Form-II of palonosetron hydrochloride as defined in claim 6 and as further characterized by an X-ray powder diffraction pattern as in figure 2.
8. A process for the preparation of polymorphic Form-II of palonosetron hydrochloride as defined in claim 6, which comprises:
Dissolving the reaction product residue obtained by hydrogenation of the compound of formula-II in water at 25-3O0C, isolating polymorphic Form-II of palonosetron hydrochloride by addition of suitable anti-solvent; wherein the anti-solvent employed
. is selected from acetone, tetrahydrofuran, or acetonitrile.
9. A process for the preparation of polymorphic Form-II of palonosetron hydrochloride as defined in claim 6, which comprises: Dissolving the reaction product residue obtained by hydrogenation of the compound of formula-II in methanol at reflux temperature, cooling the reaction mass to 0-15°C, preferably 0-5 °C, isolating polymorphic Form-II of palonosetron hydrochloride by filtration.
10. A process for the preparation of polymorphic Form-II of palonosetron hydrochloride as defined in claim 6, which comprises:
Dissolving palonosetron hydrochloride Form-I in water at 25-30°C, isolating polymorphic Form-II of palonosetron hydrochloride by addition of suitable anti- solvent; wherein the anti-solvent employed is selected from acetone, tetrahydrofuran, or acetonitrile
11. A process for the preparation of polymorphic Form-II of palonosetron hydrochloride as defined in claim 6, which comprises:
Dissolving palonosetron hydrochloride Form-I in methanol at reflux temperature, cooling the reaction mass to 0-15°C preferably 0-5°C, and isolating polymorphic Form-II of palonosetron hydrochloride by filtration.
12. A process for the preparation of polymorphic Form-II of palonosetron hydrochloride as defined in claim 6, which comprises:
Dissolving palonosetron free base in isopropylalcohol at 25-30°C, adding Cone. Hydrochloric acid and isolating polymorphic Form-II of palonosetron hydrochloride by stirring at 0-35°C, preferably 25-35°C.
13. The novel polymorphic forms, Form-I and Form-II of palonosetron hydrochloride as defined in claim 1 and claim 6 are stable, and suitable for pharmaceutical formulations.
14. The novel polymorphic Form-I of palonosetron hydrochloride as defined in claim las a stable crystal form, suitable for pharmaceutical formulations.
15. The novel polymorphic Form-II of palonosetron hydrochloride as defined in claim 8 as a stable crystal form, suitable for pharmaceutical formulations.
16. The novel polymorphic Form-I of palonosetron hydrochloride as defined in claim 1 prepared essentially as per examples 1-6.
17. The novel polymorphic Form-II of palonosetron hydrochloride as defined in claim 6 prepared essentially as per examples 7-15.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011001400A3 (en) * | 2009-06-30 | 2011-05-12 | Ranbaxy Laboratories Limited | Processes for the preparation of form i and form ii of palonosetron hydrochloride |
| US8614225B2 (en) | 2006-08-30 | 2013-12-24 | Dr. Reddy's Laboratories Limited | Process for the purification of palonosetron or its salt |
| CN114315822A (en) * | 2021-12-23 | 2022-04-12 | 北大医药股份有限公司 | Palonosetron hydrochloride hydrate crystal form and preparation method thereof |
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| WO2011001400A3 (en) * | 2009-06-30 | 2011-05-12 | Ranbaxy Laboratories Limited | Processes for the preparation of form i and form ii of palonosetron hydrochloride |
| CN114315822A (en) * | 2021-12-23 | 2022-04-12 | 北大医药股份有限公司 | Palonosetron hydrochloride hydrate crystal form and preparation method thereof |
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