The present invention relates to a novel processes for preparation of highly pure & stable white
Dcsloratadine (Formula 1) and which includes removal of almost all impurities including one
major Desloratadine isomer impurity (Formula 11), below the desired level as per current
regulatory guideline & stringent pharmacopeia standards of different countries. It include use of
various stabilizers in order to enhance the stability of the product and the pink color development
tendency on storage for longer period of time.
H
Formula I (Desloratadine)
Chemical Name: 8-chloro-6,ll -dihydro- 1 1 -(4-piperdiny1idene)- 5H-benzo[5,6]cyclohepta[l,2-
Formula II (Desloratadine Isomer Impurity)
Chemical Name: (8-chloro-6,ll -dihydro- 1 1 - (1,2,3,6-tetrahydro-4-pyridinyl)5 HBenzo[
5,6]cyclohepta[l,2-blpyridine
CAS # 183 198-49-4
Desloratadine is marketed by CalrinexB name under different dosage forms and route.
Desloratadine is chemically named as 8-chloro-6,11-dihydro-ll-(4-piperdinylidene)-5Hbenzo[
5,6]-cyclohepta[l,2-blpyridine and has the structure as given in formula I above.
US46597 16 (US '7 16 patent) discloses process for the preparation of Desloratadine from
Loratadine by reaction using 70% sodium hydroxide solution in ethanol followed by acidifying
with glacial acetic acid to form acetate salt. Thus formed salt is extracted with chloroform,
concentrated and precipitated with hexane to give crude acetate salt having melting point
197-200°C. The crude acetate salt is recrystallized using benzene-hexane to give pure acetate salt
compound having m.p. 199-200°C.
The acetate salt is further converted to Desloratadine as described in example 05 of US '716
patent. The acetate salt prepared from Loratadine is dissolved in a minimum amount of water and
the solution is made basic with a dilute aqueous solution of potassium carbonate. Pink coloured
oil is separated. the organic material is extracted with chloroform, washed with water. The
solvent is removed under reduced pressure followed by triturating with hexane. The product is
recrystallized by large volume of hexane involving decolorization with charcoal to obtain
Desloratadine, m.p. 15 1"-1 52°C.
US '716 patent discloses the laboratory scale process for preparation of Desloratadine; from
Desloratadine acetate. It was observed that the product was not recrystallizable due to
insolubility even using large volume of hexane. The product with or without the treatment of
hexane is in pink colour which contains high level of residual solvents (chloroform content is
about 4257 ppm and hexane is about 450 ppm). The residual solvent could not be removed even
1
1
OD1v6fk--i " " i "'AL
2 ! APR
after prolonged drying. US '716 patent is resulting with high level of residual solvent which does
not meet the ICH specifications.
U.S. Pat. No. 6,506,767 (hereinafter '767) discloses two polymorphic forms of Desloratadine,
labeled Forms I and 11. The XRPD peaks and the FTIR spectrum for the forms are also disclosed
in the '767 patent. According to this patent '767 patent, discloses certain alcoholic solvents, e.g.,
hexanol and methanol produce 100% polymorph form 1, but others, e. g., 3-methyl-1-butanol
and cyclohexanol produce significant amounts of form 2. Chlorinated solvents, e. g.,
dichloromethane produce form 1 substantially free of form 2. Ether solvents such as dioxane
produced form 1 substantially free of form 2 but other alkane ethers, e.g., di-isopropyl ether
produced form 1 with significant amounts of form 2 and di-n-butyl ether favored formation of
form 2. Ketones such as methyl isobutyl ketone produced crystalline polymorph form 1
essentially free of form 2 but methyl butyl ketone produced 8:l ratio of form 1 to form 2. Use of
methyl isobutyl ketone is preferred to produce crystalline polymorph form 1 essentially free of
form 2. Only ethyl acetate and di-n-butyl ether were found to produce crystalline polymorph
form 2 substantially free of form 1. Use of di-n-butyl ether is preferred for producing crystalline
form 2 substantially free of form 1. According to this patent the polymorph form obtained from
U.S. Pat. No. 4,659,716 is a mixture of form I and form 11.
Teva Patent W02004108046 1 claims a pharmaceutical composition of Desloratadine comprising
of a mixture of crystalline Desloratadine of form I and I1 in a weight to weight ratio of about
25% to about 75% of either form to the other and a pharmaceutically acceptable excipient.
1
A OR1Zd -. ;*%L
US2004t0229896 discloses pharmaceutical compositions of Desloratadine comprising a
mixture of crystalline polymorphic form I and form I1 in a ratio of about 25% to about 75%
of either form to the other and pharmaceutically acceptable excipient.
US2004102426 19 discloses a process for preparing crystalline Desloratadine form I. The process
involves preparing a solution of Desloratadine in a solvent and recovering the crystalline form I.
Solvent is selected from the group consisting of acetonitrile, di-methylformamide,
tetrahydrofuran, diethylcarbonate, and may be selected from the group consisting of chloroform,
ethyl acetate and C 1 -C4 alcohol.
EP 1860105 patent discloses a process for preparation of Desloratadine form-2
comprises: providing a solution of Desloratadine in a suitable solvent and recovering form-2
by spray dryinglagitated thin film drying technique. Suitable solvents may include organic
solvents or mixtures of organic solvents with or without water. The organic solvents used are
alkyl acetates and dipolar aprotic solvents.
EP1862462 discloses process for the preparation of Desloratadine form I essentially free from
form 2. The process comprises hydrolysis of Loratadine, extracting the reaction mixture to the
residue and isolating Desloratadine form I. The first solvent is selected from the group
comprising of alkyl acetates, ethers, acetonitrile, N,N-dimethylformamide, chlorinated
hydrocarbons, alcohols andor mixtures thereof and second solvent is selected from the group
comprising of ketones, alcohols, chlorinated hydrocarbons, ethers, acetonitrile, N Ndimethylformarnide,
acetonitrile and mixture thereof.
EP 1542986 of our own organization discloses process for the preparation of Desloratadine. The
process comprises reacting Loratadine with neat alcohol in presence of inorganic base,
precipitating the compound in crystalline fonn by addition of excess water and isolating the
crystals.
U. S. Pat. No. 6,100,274 claims a stable pharmaceutical composition of Desloratadine comprising
a Desloratadine protective amount of a pharmaceutically acceptable basic salt and at least one
pharmaceutically acceptable disintegrant. The patent mentions that acidic excipients discolor and
decompose Desloratadine. Desloratadine compositions were found to discolor when stored at
75% relative humidity ("RH") and a temperature of 40" C., alone or in combination with various
excipients. This color instability in the active ingredient was attributed to a very minute amount
of degradation product, the N-formal impurity of Desloratadine, which is formed due to the
presence of a wide variety of excipients commonly used in oral formulations-especially tablet
formulations. The unsuitable excipients include acidic excipients including, but not limited to,
stearic acid, povidone and crospovidone, and other acidic excipients having a pH of less than 7 in
water, preferably in the range of about 3 to 5, as well as excipients such as lactose, lactose
monohydrate, sodium benzoate, and the like. The patent teaches the use of calcium, magnesium
and aluminum salts of carbonates, phosphates, silicates and sulfates, or mixtures thereof as
stabilizers. However, the patent does not teach any other means of stabilizing Desloratadine.
The methods for preparation of Desloratadine described in prior art are not satisfactory as the
material produced by following these processes is coloured, contains high level of impurities,
and high levels of residual solvents beyond the acceptable ICH specifications.
Therefore, there was a need of the purification process involving suitable solvents to avoid
pinkish colour development in the final API Desloratadine during storage for longer period under
normal as well as accelerated conditions.
SUMMARY OF INVENTION:
The present invention provides improved processes for the preparation of highly pure & stable
white Desloratadine using different solvent systems. The use of different anti-oxidants /
stabilizers is also established to enhance the stability of API as well as to tackle the issue of
pinkish colour development in the Desloratadine during storage for longer period. Furthermore,
an improved HPLC method of analysis for Desloratadine API is also reported which enables the
separation of all major potential impurities of Desloratadine.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a process for preparation of highly
pure Desloratadine of formula I which comprises:
i. adding of crude 8-Chloro-6,ll -dihydro- 1 1 -(4-piperidiny1idene)-5Hbenzo[
5,6]cyclo hepta[l,2-blpyridine in C1-C4 aliphatic alcohol and water
ii. Adding an aliphatic ketone
. . .
111. stirring
iv. adding a suitable base
v. heating of reaction mass
vi. stirring for 1 hour
vii. filtration of resulting solid
viii. Slurry washing of resulting wet cake of step (0 in a mixture of water, aliphatic
alcohol & a suitable base
ix. Heating the reaction mass.
x. stirring of the reaction mass for 30 minutes.
xi. isolating product by filtration
xii. running washing with water of the wet cake as obtained above.
xiii. drying of the wet cake under vacuum at 50-60 "C for 10-12 hours to get stable
Desloratadine or 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidiny1idene)-5Hbenzo[
5,6]cyclohepta[l,2-blpyridine.
According to one aspect of the present invention, the C1'C4 aliphatic alcohol used in step (i) &
(viii) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol
& diethylene glycol or a mixture thereof
According to another aspect of present invention, the aliphatic ketone used in step (ii) above may
be selected from acetone, methyl ethyl ketone, 2-butanone, methyl isobutyl ketone, diethyl
ketone, dipropyl ketone, dibutyl ketone or a mixture thereof.
According to yet another aspect of present invention, the temperature in step (v) & (ix) is 30-60
"C, more preferably 35-50 "C and most preferably 40-45 "C.
According to still another aspect of present invention, the base used in step (iv) & (viii) can be
selected from either sodium hydroxide or sodium bisulphate.
According to second embodiment of the present invention a process for highly pure
Desloratadine of formula I which comprises:
a) dissolving crude 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidinyli dene)-5Hbenzo[
5,6]cyclohepta[1,2-blpyridine in an aliphatic ester
b) heating to reflux
c) adding suitable antioxidant / stabilizer
d) partial recovery of solvent under vacuum
e) cooling of reaction mass & stirring for 2-3 hours.
f) further cooling to 0-5 O C to enhance crystallization
g) filtration of solid
h) running washing with an aliphatic ester
i) washing of wet cake of step (h) with a mixture of an aliphatic ether &
antioxidants 1 stabilizer twice.
j) drying of the wet cake under vacuum at 50-60 "C for 10-12 hours to get stable
white Desloratadine or 8-Chloro-6,ll -dihydro- 1 1 -(4-piperidiny1idene)-5Hbenzo[
5,6]cyclohepta[l ,Zb]pyridine.
According to one aspect, the aliphatic ester used in step (a) & (h) is CI-C3 aliphatic esters. e.g.
ethyl acetate, propyl acetate, butyl acetate or a mixture thereof.
According to another aspect of present invention, the temperature in step (b) is 70-80 "C.
According to still another aspect, the antioxidant/stabilizer used in step (c) & (i) is selected from
butylated hydroxy anisole, butylated hydroxy toluene or propyl gallate.
According to one more aspect of the present invention, the aliphatic ether used in step (i) above
is selected from diisopropyl ether, diethyl ether, tert-butyl methyl ether or a mixture thereof.
According to third embodiment of the present invention, a process for highly pure
Desloratadine of formula I which comprises:
a) dissolving crude 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidinyli dene)-5Hbenzo[
5,6]cyclohepta[1,2-blpyridine in an aliphatic ester
b) heating to reflux
c) adding suitable antioxidant / stabilizer
d) partial recovery of solvent under vacuum
e) cooling of reaction mass & stirring for 2-3 hours,
f) further cooling to 0-5 O C to enhance crystallization
g) filtration of solid
h) running washing with an aliphatic ester
i) washing of wet cake of step (g) with a mixture of an aliphatic ether &
antioxidants / stabilizer.
j) slurry washing of wet cake with a mixture of C1-C4 aliphatic alcohol, water & a
suitable base
k) isolation of product as wet cake by filtration
1) drying of the wet cake under vacuum at 50-60 "C for 10-12 hours to get stable
white Desloratadine or 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidiny1idene)-5Hbenzo[
5,6]cyclohepta[l,2-blpyridine.
According to one aspect, the aliphatic ester used in step (a) & (h) is CI-C3 aliphatic esters. e.g.
ethyl acetate, propyl acetate, butyl acetate or a mixture thereof,
According to another aspect of present invention, the temperature in step (b) is 70-80 "C.
10
According to still one more aspect of the present invention, the Cl-C4 aliphatic alcohol used in
step Cjl is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol
& diethylene glycol or a mixture thereof.
According to still another aspect, the antioxidantJstabilizer used in step (c) & (i) is selected from
butylated hydroxy anisole, butylated hydroxy toluene or propyl gallate.
According to one more aspect of the present invention, the aliphatic ether used in step (i) above
is selected from diisopropyl ether, diethyl ether, tert-butyl methyl ether or a mixture thereof.
According yet another aspect of present invention, the base used in step (j) can be selected from
either sodium hydroxide or sodium bisulphate.
According to fourth embodiment of current invention, a process for preparation of
Desloratadine is disclosed which comprises:
11.
111.
IV.
v.
VI.
VII.
VIII.
IX.
X.
Dissolving crude 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidinyli dene)-5H-benzo[5,6]cyclo
hepta[l,2-blpyridine in a C1-C4 aliphatic alcohol.
Heating to reflux
Partial recovery of solvent under vacuum
adding C1-C4 aliphatic alcohol
Adding suitable antioxidant 1 stabilizer
Further heating & stirring
Slow addition of an aliphatic ether
cooling of reaction mass & stirring for complete crystallization at 30-35 OC
further cooling to 0-5 OC.
filtration of solid & running washing with aliphatic ether
11
XI. slurry washing of wet cake with a a mixture of C1-C4 aliphatic alcohol, water & a
suitable base.
XII. isolation of wet cake by filtration
XIII. Drying of the wet cake under vacuum at 50-60 "C for 10-12 hours to get pure 8-
Chloro-6,11 -dihydro- 1 1 -(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l,2-
blpyridine
According to one aspect of the present invention, the C1'C4 aliphatic alcohol used in step I, IV &
XI is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol &
diethylene glycol or a mixture thereof.
According to another aspect, the antioxidant used in step V is selected from butylated hydroxy
anisole, butylated hydroxy toluene or propyl gallate.
According to one more aspect of the present invention, the aliphatic ether used in step VII & X
above is selected from diisopropyl ether, diethyl ether, tert-butyl methyl ether or a mixture
thereof.
According yet another aspect of present invention, the base used in step XI can be selected from
either sodium hydroxide or sodium bisulphate.
According to still one more aspect of present invention, the content of polymorphic form I1 is in
excess of 70%.
According to yet another embodiment of current invention, an improved method of analysis is
dirclosed, which is capable of separating all the impurities which may be formed by various
route of synthesis of Loratadine which is starting material for the formation of Desloratadine.
Loratadine formed by different route of synthesis leads to different impurities and side products.
12
Now method of analysis which has been provided in European pharmacopeia is not capable of
separation of all the impurities on single method of analysis whereas the methods disclosed
herein capable to resolving all the below mentioned impurities.
1. DCL-N-Formyl : 4-(8-chloro-5,6-dihydro-l l H-benzo[5,6]cyclohepta[l,2-blpyridin- 1 1 -
y1idene)- 1 -Piperidinecarboxaldehyde (CAS # 1 178 10-6 1-4)
4. Desloratadine : 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidiny1idene)-5Hbenzo[
5,6]cyclohepta[l,2-bl pyridine
6. BHA : Butylated hydroxyl anisole (used as stabilizer)
8. Loratadine : Ethyl 4-(8-chloro-5,6-dihydro- 1 1 H-benzo[5,6]cyclohepta[l,2-
b] pyridin- 1 1 -ylidene)- 1 -piperidinecarboxylate
Method of Analysis - I
Related Substances by HPLC
Reagents
Potassium di hydrogen orthophosphate (HPLC Grade)
Triflouroacetic acid (HPLC Grade)
APR 2011
Triethylamine (HPLC Grade)
Orthophosphoric acid (HPLC Grade)
Tetrahydrofuran (HPLC Grade)
Methanol (HPLC Grade)
Acetonitrile (HPLC Grade)
Milli Q water
Preparation of buffer A: Dissolve 1.36g of Potassium di hydrogen orthophosphate in one liter
water, to this add 1 ml Triflouroacetic acid and 10 ml Triethylamine. Adjust the pH to 3.6 k 0.05
with Orthophosphoric acid. Filter through 0.45 pm or finer porosity membrane filter.
Preparation of buffer B: Dissolve 1.36g of Potassium di hydrogen orthophosphate in one liter
water; to this add 10 ml Triethylamine. Adjust the pH to 2.0 * 0.05 with Orthophosphoric acid.
Filter through 0.45 pm or finer porosity membrane filter.
Mobile phase A: Buffer A
Mobile phase B: To 300 ml buffer B add 700 ml Acetonitrile and 50 ml Tetrahydrofuran
Preparation of Diluent
Buffer B: Acetonitrile: Methanol (800: 100: 100)
Chromatographic Parameters
Use a suitable High Performance Liquid Chromatograph (HPLC) with following parameters.
Column Hypersil BDS C-8 (250mmx4.6rnrn) 5p or Equivalent
Flow rate 1.0 mllmin
Detector UV at h=275 nm
Injection volume : 30 pl
Run time 60 min
Delay Time 10 min
Column Temperature : 25OC
Gradient Programme :
Note: Equilibrate the HPLC with 50:50 (Mobile phase A: Mobile phase B) ratio for 15-20
min before starting gradient Programme.
Preparation of Blank
Use diluent as blank
RT Check / System Suitability Solution Preparation
Accurately weigh and transfer about 25 mg Desloratadine sample containing Imp-B and
5.0 mg each of DCL-Flouro, Loratadine (L-10) and B.H.A, then add 2.5mg of DCL-Chloro to a
50ml volumetric flask. Dissolve in diluent by sonication if necessary and dilute to volume with
the diluent.
Sample Solution Preparation
Accurately weigh and transfer about 25 mg of sample to a 50 ml volumetric flask.
Dissolve in diluent by sonication if necessary and dilute to volume with diluent.
Diluted Standard Solution Preparation
Accurately dilute1 ml of Sample solution to 100 ml with diluent
Then further dilute 1 ml of this solution to 10 ml with diluent
Procedure
Equilibrate the column and instrument until base line stabilizes then Inject one injection of blank
(diluent), RT check 1 System suitability solution, two replicate injections of diluted standard
solution.
Evaluation of System Suitability
The chromatographic system is suitable for analysis if and only if
The resolution between DCL and IMP-A is NLT 4.0
The % RSD for two replicate injections of Desloratadine peak area in Diluted Standard Solution
Preparation is NMT 10.0
If the system suitability passes inject sample solution and record the chromatograms
Retention time of Desloratadine is about 18.0 min
Approximate RT & RRT'S of Desloratadine Impurities w.r.t Desloratadine
Sr.No Impurity RT RRT
1. Impurity-B 1 Endocyclic -1 7.7 -0.97
2. Desloratadine -18.1 1 .OO
3. DCL-Chloro -20.7 -1.14
4. Impurity-A 1 DCL-Flouro -2 1.7 -1.19
5. Loratadine -37.9 -2.09
6. B.H.A * -54.7 -3.02
*B.H.A = Butylated Hydroxyanisole
Note: Integrate the peaks with percentage area more than 0.05 and report the
chromatogram.
Calculations for impurities
AT
% Impurity = ------ X 0.10
AS
Where,
A'I' = Area of individual impurity in test.
AS = Average area of Desloratadine peak in Diluted Standard Solution Preparation
Method of analysis 11:
Related Substances by HPLC
Reagents
Trifluoroacetic acid (HPLC Grade)
Sodium dodecyl sulfate (HPLC Grade)
Potassium Dihydrogen Phosphate (HPLC Grade)
Triethylamine (HPLC Grade)
Ortho phosphoric acid (HPLC Grade)
Acetonitrile (HPLC Grade)
Milli Q water
Preparation of Mobile phase A: Dissolve 0.8658 Sodium dodecyl sulfate in water, add 0.5 ml
of Trifluoroacetic acid and dilute to 1000 ml with water. Mix 57 volumes of this solution with 43
volumes of Acetonitrile, Filter through 0.45 pm or finer porosity membrane filter.
Preparation of Mobile phase B: Dissolve 0.68 g Potassium Dihydrogen Phosphate in water,
add 5.0 ml of Triethylamine and adjusted pH to 2.0 with diluted ortho phosphoric acid and dilute
to 500 ml with water. Mix 50 volumes of this solution with 50 volumes of Acetonitrile, Filter
through 0.45 pm or finer porosity membrane filter.
Preparation of Diluent
Use Mobile phase A as diluent
Chromatographic Parameters
Use a suitable High Performance Liquid Chromatograph (HPLC) with following parameters.
Column : YMC J'spere ODs-MSO, 250mm x 4.6 mm, 4micron packing
Flow rate : 1.0 mllmin
Detector : UV at h=280 nrn
Injection volume : 100 pl
Run time : 50 min
Column Temperature : 35OC
(Slight adjustment in chromatographic parameters is allowed for required system suitability)
Gradient Programme :
Preparation of Blank
Use diluent as blank
Impurity RT Check Solution Preparation
Ascurately weigh and transfer about 4.0 mg each of DCL-Endocyclic, DCL-Chloro, DCLFluoro,
DCL-N-Oxide, DCL-N-Formyl, BHA and Loratadine to a individual 50ml volumetric
flask and make upto mark with diluent.
Then weigh 8.0 mg Desloratadine in 100 ml volumetric flask dissolve in diluent and add 2 ml
each of DCL-Chloro, DCL-Fluoro, DCL-N-Formyl and Loratadine and 3 ml each of DCLEndocyclic,
DCL-N-Oxide and BHA from above preparation and dilute to 100 ml with diluent.
Sample Solution Preparation
Accurately weigh and transfer about 20mg of sample to a 25 ml diluent. Dilute 5.0 ml of this
solution to 50 ml with diluent
Diluted Standard Solution Preparation
Dilute1 .O ml of sample solution to 100 ml with diluent and further dilute 1.0 ml of this solution
to 10.0 ml with diluent
Procedure
Equilibrate the column and instrument until base line stabilizes then Inject one injection of blank
(diluent), Impurity RT check solution, two replicate injections of diluted standard solution.
Evaluation of System Suitability
The clu-omatographic system is suitable for analysis if and only if
The resolution between DCL-Endocyclic and DCL is NLT 2.0
The % RSD for two replicate injections of Desloratadine peak area in Diluted Standard Solution
Preparation is NMT 10.0
If the system suitability passes inject two different preparations of sample solution and record
the chromatograms
Retention time of Desloratadine is about 23.0 min
Approximate RT & RRT'S of Desloratadine Impurities w.r.t Desloratadine
Sr.No Impurity RT RRT
1. DCL-N-Formy1 -1 1.2 -0.48
2. DCL-Fluoro -1 8.2 -0.78
3. DCL-Endocyclic -21.2 -0.9 1
4. Desloratadine -23.3 1 .OO
5. DCL-N-Oxide -25.3 -1.09
6. BHA -28.0 -1.20
7. DCL-Chloro -29.7 -1.27
8. Loratadine -31.1 -1.33
Note: Integrate the peaks with percentage area more than 0.05 and report the
chromatogram.
Note: Correction factor for Impurities DCL-Flouro and DCL-Endocyclic is 1.6 as per EP
Monograph
Calculations for impurities
AT
?G Inlpurity = ------ X 0.08
AS
Where,
AT = Area of individual impurity in test.
AS = Average area of Desloratadine peak in Diluted Standard Solution Preparation
The above mentioned invention is supported by the following non limiting examples.
EXAMPLES:
Example 1:
To a mixture of water (400 ml), methanol (1 00 ml) & acetone (100 ml), sodium bisulphite (0.2 g)
is charged followed by charging of crude Desloratadine (100 g). The resulting mixture is heated
and stirred at 40-45 OC for 1.0 hour. The resulting solid is filtered & provided running washing
with diisopropyl ether (50 ml) followed by slurry washing with a mixture of water (400 ml),
methanol (100 ml) & sodium bisulphite (0.2 g) at 40-45 "C & stirred for 30 minutes. This wet
cake is given running washing with water (500 ml). The wet cake is dried at 50-60 OC under
vacuum for 10-12 hours to get pure Desloratadine as white solid.
Yield = 88.0 g
Purity by HPLC = 99.74 %
Desloratadine isomer = 0.26 %
Assay by HPLC = 98.67 %
Desloratadine form I content by IR = 79.91 %.
Example 2:
In a clean reactor containing ethyl acetate (9 liter) is charged followed by charging of crude
Desloratadine (1.0 Kg) & stirring. The temperature of reaction mass is raised to reflux under
stirring to get clear reaction mass, followed by its fine filtration through hyflow bed followed by
addition of butylated hydroxyanisole (1.0 g). Then the filtrate is recovered so as to be left with
only 3 times of initial volume. The resulting solution is cooled to 0-5 O C followed by stirring at
this temperature for 2-3 hours. The resulting material is filtered and given slurry washing with
diisopropyl ether (2.0 Liter) and butylated hydroxyanisole (0.8 g) mixture twice. The wet cake is
dried at 50-60 "C for 10-12 hours to get pure Desloratadine as white solid.
Yield = 77.0 g
Purity by HPLC = 99.95 %
Desloratadine isomer = 0.05 %
Assay by HPLC = 98.80 %
Desloratadine form I content by IR = 93.15 %.
Example 3:
In a clean reactor containing ethyl acetate (9 liter) is charged followed by charging of crude
Desloratadine (1.0 Kg) & stirring. The temperature of reaction mass is raised to reflux under
stirring to get clear reaction mass, followed by its fine filtration through hyflow bed followed by
addition of butylated hydroxyanisole (1.0 g). Then the filtrate is recovered so as to be left with
only 3 times of initial volume. The resulting solution is cooled to 0-5 "C followed by stirring at
this teinperature for 2-3 hours. The resulting material is given running washing with ethyl acetate
(0.50 Liter) followed by slurry washing with diisopropyl ether (2.0 Liter) and butylated
hydroxyanisole (0.8 g) mixture. The wet cake thus obtained in again given slurry washing with a
mixture of methanol (0.5 Liter), water (5.0 Liter) & sodium bisulphite (2.0 g) by stirring for 30
2 1
minute at 25-35 "C. The wet cake is dried at 50-60 "C for 10-12 hours to get pure
Desloratadine as white solid.
Yield = 84.0 g
Purity by HPLC = 99.87 %
Desloratadine isomer = 0.13 %
Assay by HPLC = 99.49 %
Desloratadine form I content by IR = 85.74 %.
Example 4:
In a clean reactor containing ethyl acetate (9 liter) is charged followed by charging of crude
Desloratadine (1.0 Kg) & stirring. The temperature of reaction mass is raised to reflux under
stirring to get clear reaction mass, followed by its fine filtration through hyflow bed followed by
addition of butylated hydroxyanisole (1.0 g). Then the filtrate is recovered so as to be left with
only 3 times of initial volume. The resulting solution is cooled to 0-5 O C followed by stirring at
this temperature for 2-3 hours. The resulting material is given running washing with ethyl acetate
(0.50 Liter) followed by slurry washing with diisopropyl ether (2.0 Liter) and butylated
hydroxyanisole (0.8 g) mixture. The wet cake thus obtained in again given slurry washing with a
mixture of methanol (0.5 Liter), water (5.0 Liter) & sodium hydroxide (50.0 g) by stirring for 30
minuteat 25-35 "C. The wet cake is dried at 50-60 "C for 10-12 hours to get pure
Desloratadine as white solid.
Yield = 83.0 g
Purity by HPLC = 99.88 %
Desloratadine isomer = 0.12 %
Assay by HPLC = 98.91 %
APR 2014
Desloratadine form I1 content by IR = 84.36 %.
Example 5:
Desbratadine (1.0 Kg) is dissolved in methanol (2.0 Liter) in a round bottom flask followed by
its heating at 50-60 "C and stirring to get complete dissolution. Now the hot filtrate is fine
filtered through hyflow bed followed by running washing with methanol (1.0 Liter). Now the
complete recovery of methanol is done under vacuum to get crude material at 50-60 "C. Now this
crude material is re-dissolved in methanol (0.75 Liter) followed by addition of butylated
hydroxyanisole (1.0 g) & charging of diisopropyl ether (5.0 Ltr) under stirring at 50-60 "C. The
reaction mass is then stirred for complete crystallization for 8 hours at 25-35 OC. The reaction
mass is further cooled to 0-5 OC for its filtration. The reaction mass is then filtered and provided
running washing with diisopropyl ether (0.2 Liter). The wet cake thus obtained is again given
slurry washing with Water (5.0 liter), methanol (0.5 liter) & Sodium bisulphite (2.0 g) mixture
and filtered. The wet cake obtained is filtered and dried under vacuum for 10-12 hours at 50-60
"C.
Yield = 17.6 g
Purity by HPLC = 99.92 %
Desloratadine isomer = 0.08 %
Assay by HPLC = 99.77 %
Desloratadine form I1 content by IR = 75.27%.
Example 6:
Desloratadine (1.0 Kg) is dissolved in methanol (2.0 Liter) in a round bottom flask followed by
its heating at 50-60 "C and stirring to get complete dissolution. Now the hot filtrate is fine
filtered through hyflow bed followed by running washing with methanol (1.0 Liter). Now the
complete recovery of methanol is done under vacuum to get crude material at 50-60 "C. Now this
crude material is re-dissolved in methanol (0.75 Liter) followed by addition of butylated
hydroxyanisole (1.0 g) & charging of diisopropyl ether (10.0 Ltr) under stirring at 50-60 "C. The
reaction mass is then stirred for complete crystallization for 8 hours at 25-35 "C. The reaction
mass is further cooled to 0-5 OC for its filtration. The reaction mass is then filtered and provided
running washing with diisopropyl ether (0.2 Liter). The wet cake thus obtained is again given
slurry washing with Water (5.0 liter), methanol (0.5 liter) & Sodium bisulphite (2.0 g) mixture
and filtered. The wet cake obtained'is filtered and dried under vacuum for 10-12 hours at 50-60
"C.
Yield = 21.9 g
Purity by HPLC = 99.75 %
Desloratadine isomer = 0.25 %
Assay by HPLC = 99.01 %
Dt;slosatadine form I1 content by IR = 54.29 %.

We claim:
1. An improved process for preparation of highly pure, stable white Desloratadine or 8-
Chloro-6,11 -dihydro- 1 1 -(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine which
comprises
a) Stirring of a suspension of crude 8-Chloro-6,ll -dihydro- 1 1 -(4-piperidiny1idene)-5Hbenzo[
5,6]cyclo hepta[l,2-blpyridine in C1-C4 aliphatic alcohol and water
b) Adding an aliphatic ketone and stirring
c) Adding a suitable base
d) Heating of reaction mass
e) Stirring for 1 hour
f) Filtration of resulting solid
g) Slurry washing of resulting wet cake of step (f) in a mixture of water, aliphatic alcohol &
a suitable base
h) Heating the reaction mass.
i) Stirring of the reaction mass for 30 minutes.
j) Isolation of product as wet cake by filtration .
k) Drying of the wet cake under vacuum at 50-60 "C for 10-12 hours to get stable white
Desloratadine or 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l,2-
blpyridine..
2. The process as claimed in claim 1 wherein the temperature in step (d) and (h) is 30-60 "C,
more preferably 35-50 "C and most preferably 40-45 "C.
3. The process as claimed in claim 1 wherein aliphatic ketone used in step (b) can be selected
from acetone, methyl ethyl ketone, 2-butanone, methyl isobutyl ketone, diethyl ketone,
diisopropyl ketone, dibutyl ketone or a mixture thereof.
4. An improved process for preparation of highly pure, stable white Desloratadine or 8-
Chloro-6,11 -dihydro- 1 1 -(4-piperidinyli dene)-5H-benzo[5,6]cyclohepta[l,2-b] pyridine
which comprises
a) Dissolving crude 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidinyli dene)-5Hbenzo[
5,6]cyclohepta[l,2-blpyridine in an aliphatic ester
b) Heating to reflux
c) Adding suitable antioxidant / stabilizer
d) Partial recovery of solvent under vacuum
e) Cooling of reaction mass & stirring for 2-3 hours.
f) Further cooling to 0-5 OC
g) Filtration of solid to get wet cake
h) Washing of wet cake of step (g) with a mixture of an aliphatic ether & antioxidants /
stabilizer.
i) Slurry washing of wet cake with a mixture of CI-C4 aliphatic alcohol, water & a suitable
base
j) Isolation of product as wet cake by filtration
APR 2011
k) Drying of the wet cake under vacuum at 50-60 "C for 10- 12 hours to get stable white
Desloratadine or 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidiny1idene)-5Hbenzo[
5,6]cyclohepta[l,2-blpyridine.
5. The process as claimed in claim 4 wherein aliphatic ester used in step (a) is C1'C3 aliphatic
esters like ethyl acetate, propyl acetate, butyl acetate or a mixture thereof.
6. An improved process for preparation of highly pure, stable white Desloratadine or 8-
Chloro-6,11 -dihydro-1 1 -(4-piperidinyli dene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine
which comprises
Dissolving crude 8-Chloro-6,11 -dihydro- 1 1 -(4-piperidinyli dene)-5H-benzo[5,6]cyclo
hepta[l,2-blpyridine in a CI-C4 aliphatic alcohol.
Heating to reflux
Partial recovery of solvent under vacuum
adding C1-C4 aliphatic alcohol
Adding suitable antioxidant 1 stabilizer
Further heating & stirring
Slow addition of an aliphatic ether
Cooling of reaction mass & stirring for complete crystallization at 30-35 "C
Further cooling to 0-5 "C.
Filtration of solid to get wet cake
2 1 APR 20W
k) Slurry washing of wet cake of step (f) with a mixture of C1-C4 aliphatic alcohol, water &
a suitable base.
1) isolation of wet cake by filtration
m) Drying of the wet cake under vacuum at 50-60 "C for 10-12 hours to get stable white
Desloratadine i.e. 8-Chloro-6,ll -dihydro- 1 1 -(4-piperidiny1idene)-5Hbenzo
[5,6]cyclohepta[1,2-blpyridine
7. The process as claimed in claims 1, 4 and 6 wherein C1-C4 aliphatic alcohol used in step
(a) and (g) of claim 1, step (i) of claim 4, step (a), (d) and (k) of claim 6 is selected from
methanol, ethanol, 1-propanol, 2-propanol, butanol, etc or a mixture thereof.
8. The process as claimed in claims 4 and 6 wherein the antioxidant/ stablizer used in step (c),
(h) of claim 4 and step (e) of claim 6 is selected from butylated hydroxy anisole, butylated
hydroxy toluene, propyl gallate or a mixture thereof.
9. The process as claimed in claim 4 and 6 wherein the aliphatic ether used in step (h) of
claim 4 and step (g) and step (j) of claim 6, is selected from diisopropyl ether, diethyl
ether, tert-butyl methyl ether or a mixture thereof.
10. The process as claimed in claim 1,4 and 6 wherein base used in step (c) and (g) of claim 1,
step (i) of claim 4 and step (k) of claim 6 might be selected from sodium hydroxide,
sodium bisulphate etc or a mixture thereof.
b
2 \ APR 2014
11. The process as claimed in claim 1, 4 and 6 which gives Deesloratadine polymorphic form
I1 content L 70% by IR Method.
12. Novel HPLC Method I and I1 for the analysis of Desloratadine which are capable of
separating all potential impurities of Desloratadine.