FIELD OF INVENTION:
The invention particularly relates to a purification process of Loratadine which is cost effective and results in highly pure Loratadine polymorphic form I. Further it is simple to use ethyl acetate & does not require any stringent conditions and special infrastructure. The process is reproducible, environment friendly and easy to scale up for industrial purpose.
BACKGROUD OF INVENTION:
Loratadine, chemically known as 8- chloro-11-(l-ethoxycarbonyl -4-piperidylidene)-6,11-dihydro -5 H -benzo [5,6] cyclohepta [1,2-b] pyridine is a non-sedating type antihistamine H1 receptor antagonist having structure of formula I
(Formula Removed)
possesses low central nervous system (CNS) activity indicative of non- sedation. It is also useful as antiallergant for the treatment of allergic asthma, allergic seasonal rhinitis, diabetic retinopathy and small vessel disorders associated with the diabetic mellitus.
Various compounds having antihistaminic activity including Loratadine and process for their preparation are disclosed in U.S. Patent nos. 3,326,924; 3,717,647, 4,282,233, 4,659,716, 4,731,447, 6,608,202 and Journal of Medicinal Chemistry, 1972, Vol. 15, No. 7, pp 750-754.
In order to meet the challenges of appreciable increase in the price of acetonitrile as well as problem in its availability, there is a need to replace acetonitrile by some suitable solvent in the purification of Loratadine in order to get Loratadine polymorphic form I of high purity. Furthermore, being a solvent of class II, acetonitrile is having a very tight limit as residual solvent (i.e. Not more than 410 ppm) as per ICH guidelines.
SUMMARY OF INVENTION:
According to the present invention, a cost effective purification process for Loratadine is provided. Other objective of the present invention is to provide a purification process for Loratadine which is environment friendly, and is easy to scale up for industrial purpose.
An improved process for the purification of crude Loratadine which comprises: dissolving crude Loratadine in diisopropyl ether; charcolization of resulting solution followed by filtration through hyflow;
orystallization of material by cooling the solution; filtering the resulting solid ; dissolving the wet solid of above step in aliphatic ester; charcolization of resulting solution followed by filtration thorough hyflow bed; crystallization of material by cooling the solution; and filtering the resulting solid and drying by conventional methods to get pure Loratadine as white solid.
BRIEF DESCRIPTION OF THE FIGURE:
Figure 1: Depicts the X-ray diffraction patern of Loratadine polymorphic form I prepared as per process of present invention.
Figure 2: Depicts the FTIR spectrum of Loratadine polymorphic form I prepared as per process of present invention.
DETAILED DESCRIPTION OF THE INVENTION:
The first aspect of the present invention is to provide a cost effective purification process for Loratadine to give highly pure i.e. almost impurity free Loratadine polymorphic form I.
Another aspect of the invention is to provide a purification process for Loratadine which comprises:
a) dissolving crude Loratadine in aliphatic ester followed by charcolization and filtration,
b) cooling the filtrate of step (a) and isolation of Loratadine polymorphic form I by filtration
after crystallization,
c) drying the isolated solid of step (b) optionally under vacuum to get Loratadine
polymorphic form I as white solid.
According to one embodiment, the aliphatic ester used in step (a) for dissolution of crude Loratadine is C1-C3 aliphatic esters, e.g. ethyl acetate, propyl acetate, butyl acetate or a mixture thereof.
According to other embodiment, the temperature for crystallization of Loratadine in step (b) is +30 °C to -30 °C, more preferably +20 °C to -20 °C & most preferably +10 °C to -10 °C.
According to yet another aspect of this invention, the product Loratadine in step (b) is isolated by filtration.
According to yet another aspect of the present invention, the temperature for drying of product Loratadine in step (c) is between 80 °C to 20 °C, more preferably 70 °C to 30 °C & most preferably 60 °C to 40 °C.
The present purification process results in highly pure Loratadine. The use of ethyl acetate in the purification of Loratadine is preferred over acetonitrile as ethyl acetate is class III solvent & its ICH limit as residual solvent is not more than 5000 ppm whereas acetonitrile is class II solvent &
Its ICH limit as residual solvents is not more than 410 ppm as per ICH guidelines. Therefore, being a class III solvent, ethyl acetate has edge over acetonitrile.
Furthermore, as presently the price of acetonitrile has increased appreciably and there is also problem in the availability of acetonitrile, therefore its use is not industrially/commercially viable in the present scenario. Hence the purification of Loratadine in ethyl acetate is appropriate due to its cost effectiveness.
ADVANTAGES:
1. The main advantage of purification process of Loratadine using ethyl acetate as per present invention is that it is cost effective & is industrially applicable in comparison to acetonitrile.
2. The other advantage of the use of ethyl acetate in Loratadine purification is that ethyl acetate is more suitable for use being a class III solvent (Its ICH limit as residual solvent is NMT 5000 ppm) than acetonitrile as it is class II solvent & has very tight limit as residual solvent (Its ICH limit as residual solvent is NMT 410 ppm).
3. This process results in highly pure i.e. almost impurity free Loratadine polymorphic form I.
4. This process results in the formation of Loratadine polymorphic form I consistently as confirmed by XRD, FTIR & melting range analysis.
The invention is further illustrated by non limiting examples. Thus the following examples should not construe the scope of protection sought in the invention.
EXAMPLES:
Example 1:
The compound 11-(N-Methyl-4-piperidinylidene)-8- chloro-6, 11-dihydro-5H-benzo(5,6)cyclohepta (l,2-b)pyridine (100 g) is reacted with ethyl chloroformate in presence of N,N-diisopropylethylamine in toluene at reflux temperature. After completion of reaction, the reaction mass is quenched in water and organic layer is washed with water followed by recovery of toluene at reduced pressure to get crude 11-(N-Ethoxycarbonyl)-4-piperidinylidene)-8-chloro-6,1 l-dihydro-5H-benzo (5,6) cyclohepta (l,2-b)pyridine (crude Loratadine).
The crude Loratadine is dissolved in ethyl acetate followed by charcolization & filtration through hyflo bed. The resulting ethyl acetate solution is cooled & the solid, thus crystallized, is filtered & dried at 45-50° C under vaccum to get Loratadine as white solid (95 g) which is confirmed as Loratadine polymorphic form I by its XRD, FTIR & melting range. (HPLC purity = 99.94%; Assay by HPLC - 99.35%; Melting range = 133-135 °C)
Example 2:
The crude 1 l-(N-Ethoxycarbonyl)-4-piperidinylidene)-8-chloro-6,l l-dihydro-5H-
benzo(5,6)cyclohepta(l,2-b)pyridine (crude Loratadine ; lOOg) prepared as per process of Example 1, is dissolved in diisopropylether followed by charcolization and filtration. The resulting diisopropylether solvent is cooled & the solid, thus crystallized, is filtered. The wet solid is dissolved in ethyl acetate followed by charcolization & filtration. The resulting ethyl acetate solution is cooled and the solid, thus crystallized, is filtered & dried to get Loratadine as white solid (92 g) which is confirmed as Loratadine polymorphic form I by its XRD, FTIR & melting range. (HPLC purity = 99.93%; Assay by HPLC = 99.40%; Melting range - 132-134 °C)
Example 3:
Loratadine (1 methyl-4-piperidinyl)[3-[2-(3-chlorophenyl]-2-pyridinyl]methanone hydrochloride
(lOOg) is reacted with hydrofluoric acid (100%) & boron trifluoride (HF/BF3) at -35°C to -45°C
for 3-5 hrs. After completion of reaction, the reaction mass was quenched in 25-30% aqueous
potassium hydroxide solution at 0-10 °C & the pH of quenched mass was adjusted to 8.0-8.5.
The compound 11 -(N-methyl-4-piperidinylidine)-8-chloro-6,11 -dihydro-5H-
benzo(5,6)cyclohepta(l,2-b) pyridine,thus formed, was extracted in toluene and the toluene layer
was washed with aqueous sodium chloride solution followed by water. The toluene layer
containing compound 1 l-(N-methyl-4-piperidinylidine)-8-chloro-6,l l-dihydro-5H-
benzo(5,6)cyclohepta(l,2-b)pyridine is reacted with ethyl chloroformate in N,N-diisopropylethylamine at 70-75°C. After completion of reaction, the reaction mass is quenched in water & its pH was adjusted to 5.0-5.5. The resulting 11-(N-Ethoxycarbonyl)-4-piperidinylidene)-8-chloro-6, 1 l-dihydro-5H-benzo (5,6) cyclohepta (l,2-b)pyridine (Loratadine) was extracted in toluene followed by its washing with water and the toluene is removed completely from organic layer at reduced pressure to get crude Loratadine (70 g).
Example 4:
The sample of crude Loratadine of example 3 (25 g) was dissolved in diisopropylether at 60-70 °C, followed by its charcolization and filtration through hyflo bed. The resulting solution was cooled to 0-5 °C & the solid, thus crystallized, was filtered. The wet solid, thus obtained, is purified by complete dissolution in ethyl acetate followed by cooling to crystallize the product. The solid is filtered & dried at reduced process to get Loratadine as white solid (20 g) which is confirmed as Loratadine polymorphic form I by its XRD, FTIR & Melting range. (HPLC purity = 99.94%; Assay by HPLC = 99.90%; Melting range = 132-134 °C).
Example 5:
The crude Loratadine of example 3 (25 g) is dissolved in ethyl acetate followed by charcolization & filtration through hyflo bed. The resulting ethyl acetate solution is cooled to 0-5°C & the crystallized solid, is filtered and dried at 45-50 °C under vacuum to get Loratadine as white solid (15 g) which is confirmed as Loratadine polymorphic form I by its XRD, FTIR & Melting range. (HPLC purity = 99.95%; Assay by HPLC = 99.75%; Melting range = 133-135 °C).

We claim:
1. An improved process for the purification of crude Loratadine which comprises:-
a) dissolving crude Loratadine in diisopropyl ether;
b) charcolization of resulting solution followed by filtration through hyflow ;
c) crystallization of material by cooling the solution;
d) filtering the resulting solid ;
e) dissolving the wet solid of step (d) in aliphatic ester;
f) charcolization of resulting solution followed by filtration thorough hyflow bed;
g) crystallization of material by cooling the solution; and
h) filtering the resulting solid and drying by conventional methods to get pure Loratadine as white solid.
2. Another process for the purification of crude Loratadine which comprises
a) dissolving crude Loratadine in ethyl acetate
b) charcolization of resulting solution followed by filtration through hyflow
c) crystallization of material by cooling the solution
d) filtering the resulting solid and drying by conventional methods to get pure Loratadine as white solid.
3. A process of claim 1 & 2 wherein the aliphatic ester is ethyl acetate, methyl acetate, n-propyl
acetate, isopropyl acetate & n-butyl acetate or a mixture thereof.
4. Product Loratadine of claim 1 & 2 is polymorphic form I as characterized by its XRD pattern (Fig 1), IR (Fig 2) and melting range between 132-135 °C.
5. An improved process for purification of lortadine as herein described with reference to the accompanying specification, examples and drawings.