FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)
A PROCESS FOR THE PREPARATION OF EBASTINE BY CRYSTALIZATION AND THE EBASTINE PRODUCED BY THE SAID FORMS HAVING DESIRED PARTICLE
SIZE
M/S. TONIRA PHARMA LIMITED, 301, Yogi Complex, 44, Sampatrao Colony, Alkapuri, Vadodara - 390 005, an Indian Company incorporated under the Companies Act,
1956.
The following specification particularly describes and ascertains the nature of this invention, and the manner in which it is to be performed.
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This invention relates to "A process for the preparation of Ebastine by crystallization and the Ebastine produced by the said process having desired particle size."
More particularly this invention relates to a process for the preparation of Ebastine using crystallization process having particle size in the range of 35 to 120um.
The present invention relates to a process for the preparation of Ebastine by crystallization and the Ebastine produced by the said process having desired particle size. The Chemical name of Ebastine is 4-diphenylmethoxy-l-[3-(4-tert-butyl- enzoyl)propyl]piperidine of formula

This invention also relates to the Ebastine treated by crystallization having particle size in the range of 50 to 120um and more preferably between 35 to 110 um.
Ebastine is a new antiallergic drug which belongs to this new generation of Hl-antihistamines and although discovered as a result of an intensive screening program of several hundred new chemical entities, it is structurally almost a hybrid between diphenylpyraline, a potent classical antihistamine, and terfenadine, already referred to as the first of the non-sedating antihistamines. As such it combines potent, long lasting and selective blockade of histamine HI-receptors with an absence of sedative side effects, and tike terfenadine, is subject to biotransformation to active carboxylic acid metabolites by oxidation of one of the methyl groups of the tertiarybutyl moiety. Never the less, whereas the acid metabolite of terfenadine has less antihistamine activity than the parent compound the equivalent metabolite of ebastine has considerably more activity and undoubtedly plays a major role in the activity of ebastine in vivo.
U S Patent 5460829 (equivalent to EP 0614362, JP 3518601 and WO 9310782) no Indian equivalent patent is available which describes "Pharmaceutical compositions based on Ebastine or analogues". These patents describe a solid administration form in which the active principle displays an improved solubility and an improved bioavailability. According to this patent the preparation of the solid dosage form involves
• Micronisation
• Hydrophilisation The particle size are as under:
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Maximum size smaller than 30um.
Preferably with 90%, by number, of particles having a particle size smaller than 25|Jm and preferably smaller than 20|jm.
The micronisation is effected in a stainless steel microniser, having a filtering sleeve made of polyester.
The prior art describes pharmaceutical compositions based on Ebastine or analogues there of involving lypholisation micronisation using a jet mill having filtering sleeve and using cooled ompressed air in order to fractionate the particles. This means there could be variation in the particle size which needs to be segregated resulting in non uniform compositions and wastage of material, which donot fit in the range of particle size. In the crystallization process the material obtained can be more uniform, avoiding the wastage.
The main object of this invention is to overcome the limitation if the micronisation process for preparing Ebastine and to provide a process of preparation of Ebastine by crystallization using reparative crystallization process to achive desired particle size in the range of 35 to 120um and more preferably between 50 to 110um resulting into better efficacy of Ebastine.
The concept of varying particle size, by varying in reflux time for ferrites has been reported by Jyotsnendu Giri et al. in their publication entitled "Optimization of parameters for the synthesis of nano-sizedCo1.x ZnxFe204, (0 < x < 0.8) by microwave refluxing". This publication describes with respect to variation of crystal size of heated sample of Coo.4Zno.6Fe204.
The process for the preparation of Ebastine by crystallization process having desired particle size comprises:
Ebastine was dissolved in an alcoholic solvent having C1-4 atoms and the solution is heated under reflux for 60 minutes to 120 minutes and cooled in an ice salt bath and cooled to 0°C to 3°C in about 25 to 30 minutes to give a crystalline slurry. The crystalline slurry is heated once again to reflux temperature, after making up for the loss of methanol in the earlier crystallization. After maintaining at the reflux temperature for 30 minutes, and cooled once again to 0°C to 3°C to give a crystalline slurry. The above operation of heating to dissolve once gain and cooling to 0°C to 3°C was repeated once again to give a crystalline slurry, which was filtered and dried to give Ebastine.
Particle size analysis of the aliquots drawn after each crystallization indicated that:
• after the first crystallization the average particle size of X50 was found to be 106.88 mp.(Fig.l)
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• after the second crystallization the average particle size of X50 was found to be 67.70 mp.(Fig.2)
• after the third crystallization the average particle size of X50 was found to be 50.78 mp. (Fig.3)
The figures 1, 2 & 3 of the drawings accompanying illustrates the relevant histograms of the above three crystallized products respectively.
In addition to the above, an alternative method has been developed to control the particle size by a "wet milling" technique. Wet milling technique is used in dyes, inks, minerals and other industries where particle sizes of the order of 0.5 mp to 5.0 mp are obtained.
The ebastine was mixed with methanol in the ratio of 1:2 to 1: 5 and the resulting slurry was introduced into a wet milling equipment, like a ball mill, homogenizer or a high speed blending machine.
A process for the preparation of Ebastine by crystallization having desired particle size comprising the following steps:
a. Mixing Ebastine (crude) with alchoholic solvent in the ratio of 1:2 to 1:5
w/v;
b. Heating the mixture of step (i) at temperature 64 to 66°C to get a clear
solution;
c. Adding activated carbon to the solution of step (u) and maintaining the
mixture at temperature 64 to 66°C from 10 to 20 minutes and then filtering
to obtain a clear solution;
d. Cooling the solution of step (iii) to a temperature of 5 to 0°C to obtain a
crystalization solution;
e. Adding to the crystalization slurry of step (iv) in an amount of 50% of the
crude ebastine (w/v) to prepare a solution and heating to a temperature of 64
to 66°C to achieve a clear solution;
f Cooling the solution of step (v) to a temperature of 5 to 0°C to achieve a
crystalization slurry;
g. Adding alcoholic solvent to a crystalline slurry of step (vi) in an amount of
50% of the crude ebastine (w/v) to prepare a solution and heating to a
temperature of 64 to 66°C to achieve a clear solution;
h. Cooling the solution of step (vii) to a temperature of 5 to 0 C to achieve a
crystalization slurry;
i. Filtering the crystalization slurry of step (viii) and washing with chilled
solvent and drying at temperature of 50 to 60°C preferably 55°C to obtain
Ebastine of desired particle size.
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The said solvent is alcoholic solvent such as Methanol.
The desired particle size distribution of the Ebastine is around 50 to 55um.
The Ebastine crude is prepared by the condensation of -4-(benzhydryloxy)piperidine hydrochloride and l-(4-tert-butylphenyl)-4-chlorobutan-l-one.
The crystalline slurry is having average particle size of 105 to 120um.
The crystalline slurry is having average particle size around 60 to 70um
The aliquots is filtered and dried to check the particle size distribution of the slurry obtained at various step.
The slurry is having average particle size around 105 to 120um is wet milled to obtain average particle size of Ebastine around 35 to 40um.
The said wet milling is carried out in a ball mill using ceramic / stainless steel balls preferably of 10mm diameter filled to half of the volume of the ball mill and rotated for 20 to 40 minutes followed by filtering, washing with chilled methanol and drying.
The following examples are illustrations of the process of preparation of Ebastine by crystalization having desired particle size.
Example 1
Ebastine (Crude) (200g), which is prepared by the condensation of 4-(benzhydryloxy)piperidine hydrochloride and l- (4-tert-butylphenyl)-4-chlorobutan-l-one was mixed with methanol (700 ml) under agitation, mixed well for fifteen minutes and heated to 64°C to 66°C to get a clear solution . Activated carbon (20 g) was added to this solution and the mixture was maintained at 64°C to 66°C for 15 minutes and filtered to get a clear, colorless to pale yellow solution. The solution is cooled to 0°C to 3°C and a crystalline slurry is obtained. An aliquot is filtered and dried to check the particle size distribution which would be around 106.88 mp at X50. To the crystalline slurry methanol (100 ml) is added and heated to 64°C to 66°C to give a clear solution. The solution is cooled to 0°C to 3°C to give a crystalline slurry. An aliquot is filtered and dried to check the particle size distribution which would be around 67.70m|J at X50. To the crystalline slurry methanol (100 ml) is added and heated to 64°C to 66°C to give a clear solution. The solution is cooled to 0°C to 3°C to give a crystalline slurry. An aliquot is filtered and dried to check the particle size distribution which would be around 50-55 mp at X50.
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If the particle size distribution is around 50.78m|J at X50, the crystalline slurry is filtered , washed with chilled methanol (50 ml) and dried at 55°C.
Example 2
Ebastine (Crude) (200g), which is prepared by the condensation of 4-(benzhydryloxy)piperidine hydrochloride and l-(4-tert-butylphenyl)-4-chlorobutan-l-one was mixed with methanol (700 ml) under agitation, mixed well for fifteen minutes and heated to 64°C to 66°C to get a clear solution . Activated carbon ( 20 g) was added to this solution and the mixture was maintained at 64°C to 66°C for 15 minutes and filtered to get a clear, colorless to pale yellow solution. The solution is cooled to 0°C to 3°C and a crystalline slurry is obtained. An aliquot is filtered and dried to check the particle size distribution which would be around 106.88mp at X50- The slurry is fed in to a Ball mill of 2.0 liter volume in which the ceramic/stainless steel balls of 1.0 cm diameter and the balls are filled to the volume of 1.0 liter. The ball mill is rotated for 0.5 hrs and the slurry is separated from the ceramic / stainless steel balls and the slurry is filtered and washed with chilled methanol and dried at 55°C. The average particle size of the material is 37.88 mp at X50.
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We claim:
1. A process for the preparation of Ebastine by crystalization having desired particle
size comprising the following steps:
i. mixing Ebastine (crude) with alcoholic solvent in the ratio of 1:2 to 1:5
w/v;
ii. heating the mixture of step (i) at temperature 64 to 66°C to get a clear
solution;
iii. adding activated carbon to the solution of step (ii) and maintaining the
mixture at temperature 64 to 66°C from 10 to 20 minutes and then
filtering to obtain a clear solution;
iv. cooling the solution of step (iii) to a temperature of 5 to 0°C to obtain a
crystalline slury;
v. adding solvent to the crystaline slurry of step (iv) in an amount of 50%
of the crude ebastine (w/v) to prepare a solution and heating to a
temperature of 64 to 66°C to achieve a clear solution;
vi. cooling the solution of step (v) to a temperature of 5 to 0°C to achieve a
crystaline slurry;
vii. adding alcoholic solvent to a crystalline slurry of step (vi) in an amount
of 50% of the crude ebastine (w/v) to prepare a solution and heating to a
temperature of 64 to 66°C to achieve a clear solution;
viii. cooling the solution of step (vii) to a temperature of 5 to 0°C to achieve a
crystaline slurry;
ix. filtering the crystaline slurry of step (viii) and washing with chilled
solvent and drying at temperature of 50 to 60°C preferably 55°C to
obtain Ebastine of desired particle size.
2. The process as claimed in claim 1 wherein the said solvent is alcoholic solvent such as Methanol.
3. The process as claimed in claim 1 wherein the desired particle size distribution of the Ebastine is around 50 to 55um.
4. The process as claimed in claim 1 wherein the Ebastine crude is prepared by the condensation of -4-(benzhydryloxy)piperidine hydrochloride and l-(4-tert-butylphenyl)-4-chlorobutan-1 -one.
5. The process as claimed in claim 1 wherein the crystalline slurry of step (iv) is having average particle size around 105 to 120um.

6. The process as claimed in claim 1 wherein the crystaline slurry of step (vi) is having average particle size around 60 to 70um.
7. The process as claimed in claim 1, 5 or 6 wherein the aliquots is filtered and dried to check the particle size distribution of the slurry obtained at various step.
8. The process as claimed in claim 1 wherein the slurry of step (iv) having average particle size around 105 to 120um is wet mill to obtain average particle size of Ebastine around 35 to 40pm.
9. The process as claimed in claim 1 wherein the said wet milling is carried out in a ball mill using ceramic / stainless steel balls preferably of 10mm diameter filled to half of the volume of the ball mill and rotated for 20 to 40 minutes followed by filtering, washing with chilled methanol and drying.
10. The process for the preparation of Ebastine by crystalization and the Ebastine produced by the said process having desired particle size substantially as herein described and illustrated in figure 1 to 3 of the drawings accompanying the specification.
11. The Ebastine prepared by crystalization process as claimed in any of the claim 1 to 10 having average particle size around 35 to 120pm.
VRAMU Agent for the Applicant
Dated this 13th day of April 2006
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ABSTRACT
A process for the preparation of Ebastine by crystalization having desired particle size comprising the following steps:
i. mixing Ebastine (crude) with alcoholic solvent in the ratio of 1:2 to 1:5
w/v;
ii. heating the mixture of step (i) at temperature 64 to 66°C to get a clear
solution;
iii. adding activated carbon to the solution of step (ii) and maintaining the mixture at temperature 64 to 66°C from 10 to 20 minutes and then filtering to obtain a clear solution;
iv. cooling the solution of step (iii) to a temperature of 5 to 0°C to obtain a crystalline slury;
v. adding solvent to the crystalline slurry of step (iv) in an amount of 50%
of the crude ebastine (w/v) to prepare a solution and heating to a temperature of 64 to 66°C to achieve a clear solution;
vi. cooling the solution of step (v) to a temperature of 5 to 0°C to achieve a crystalline slurry;
vii. adding alcoholic solvent to a crystalline slurry of step (vi) in an amount of 50% of the crude ebastine (w/v) to prepare a solution and heating to a temperature of 64 to 66°C to achieve a clear solution;
viii. cooling the solution of step (vii) to a temperature of 5 to 0°C to achieve a crystalline slurry;
ix. filtering the crystalline slurry of step (viii) and washing with chilled solvent and drying at temperature of 50 to 60°C preferably 55°C to obtain Ebastine of desired particle size.
Dated this 13th day of April 2006
V RAMU
Agent for the Applicant
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