An improved process for the preparation of telmisartan, its salts, hydrates
and polymorphs thereof
FIELD OF INVENTION
The present invention provides an improved process for the preparation of salts of telmisartan with
high yield, high degree of purity with fewer impurities, which is economically viable on
commercial scale. Specifically, the invention provides an improved process for the preparation of
sodium salt of telmisartan, which may further be used for the preparation of telmisartan. Moreover,
the invention also provides a novel polymorphic form T of telmisartan sodium and process for
preparation thereof. Also provided are the pharmaceutical composition of said polymorphic form
T of telmisartan sodium and method of treatment of a mammal using the same. Further the
invention also provides amorphous form of telmisartan sodium and process for the preparation
thereof.
BACKGROUND OF THE INVENTION
Telmisartan i.e. 4'-[2-n-propyl-4-methyl-6-(l-methylbenzimid-azol-2-yl)benzimidazoI-lylmethyl]
biphenyl-2-carboxylic acid is represented by Formula I.
Telmisartan is a non-peptide angiotensin II receptor (type ATI) antagonist. It has been approved
for the treatment of hypertension. It may be used alone or in combination with other
antihypertensive agents, diuretic such as hydrochlorothiazide. Boehringer Ingelheim markets
telmisartan under the trade name Micardis(R).
US 5,591,762 discloses telmisartan and its pharmaceutical^ acceptable salts, along with its
pharmaceutical compositions.
US 6,358,986 discloses polymorphic forms of telmisartan, specifically, polymorphic form B and
mixture of the polymorphic forms A and B are disclosed. It also discloses the process for preparing
telmisartan form B and the use thereof for preparing pharmaceutical compositions.
US 6,737,432 discloses a crystalline sodium salt of telmisartan, characterized by x-ray powder
diffraction peaks at 4.21, 4.98, 6.32 and 6.48 degrees two-theta±0.2 degrees two-theta, having a
melting point of 245±5°C.
US 2006/111417 relates to an amorphous form of telmisartan and a process for the preparation
thereof. It also discloses the combination of amorphous form of telmisartan with one or more
pharmaceutical carrier.
US 2006/293377 is directed to amorphous telmisartan sodium and processes for preparing such
amorphous form of telmisartan sodium. The invention is also directed to polymorphic crystal
structures of telmisartan sodium and to processes for preparing polymorphic crystal structures of
telmisartan sodium. The invention is also directed to pharmaceutical compositions comprising
polymorphic crystal structures and an amorphous form of telmisartan sodium. Specifically, it
provided the amorphous form of telmisartan sodium and the preparation thereof. Also provided
are the telmisartan sodium polymorph crystal Forms 0 to XIII and XV to XX and preparations
thereof. Also provided are pharmaceutical composition of amorphous and polymorphic forms of
telmisartan sodium or mixtures thereof, and methods of treatment of a mammal in need thereof.
US 2009/0012140 relates to the novel salts of telmisartan, novel polymorphic form thereof and
processes for their preparation and to pharmaceutical compositions containing them. New alkali
and alkaline earth metal salts of telmisartan in amorphous form and a new crystalline sodium salt
of telmisartan have been prepared by preparing a solution despite low solubility of telmisartan and
rapidly vacuum evaporating to dryness.
It is known that different polymorphic forms of the same drug may have substantial differences in
certain pharmaceutically important properties. Polymorphism is often characterized as the ability
of a drug substance to exist as two or more crystalline phases that have different arrangements
and/or conformations of the molecules in the crystalline lattice.
The present invention relates to the solid state physical properties of telmisartan sodium. These
properties can be influenced by controlling the conditions under which telmisartan sodium is
obtained in solid form. Solid state physical properties affect the ease with which the material is
handled during processing into a pharmaceutical product such as a tablet or capsule formulation.
The physical properties impact the sort of excipients, for instance, to add to a telmisartan sodium
formulation. Furthermore, the solid state physical property of a pharmaceutical compound is
important to its dissolution in aqueous fluid or even in a patient's stomach fluid, which have
therapeutic consequences. The rate of dissolution is also a consideration in liquid forms of
medicine as well. The solid state form of a compound may also affect its storage conditions. These
practical physical characteristics are influenced by the particular polymorphic form of a substance.
One polymorphic form may give rise to thermal behavior different from that of the amorphous
material or other polymorphic forms.
SUMMARY OF THE INVENTION
An embodiment of the present invention provides an improved process for the preparation of salt
oftelmisartan.
Yet another embodiment of the present invention provides an improved process for the preparation
of alkali or alkaline earth metal salt oftelmisartan.
Yet another embodiment of the present invention provides an improved process for the preparation
of sodium salt oftelmisartan.
Yet another embodiment of the invention provides sodium salt oftelmisartan having purity of
more than 99%, preferably more than 99.5 and more preferably more than 99.7%.
Yet another embodiment of the invention provides crystalline form 'J' oftelmisartan sodium.
Yet another embodiment of the invention provides crystalline form 'J' oftelmisartan sodium.
*
Yet another embodiment of the invention provides amorphous form of telmisartan monosodium
salt.
Yet another aspect of the invention provides an improved process for the preparation of sodium
salt of telmisartan with high yield, high degree of purity and less number of impurities.
In yet another aspect, the invention provides a process for the preparation of sodium salt of
telmisartan comprising the steps of:
i) providing a solution of telmisartan in suitable solvent;
ii) adding suitable sodium salt to the reaction mixture obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline monosodium salt of telmisartan from reaction mass.
In further aspect, the invention provides a process for the preparation of salt of telmisartan
comprising the steps of:
(i) providing a solution of telmisartan in a suitable solvent;
(ii) adding hydroxide, carbonate, bicarbonate or alkoxide of alkali or alkaline earth metals
to the reaction mixture obtained in step (i)
(iii) optionally heating the reaction mixture and
(iv) isolating the salt of telmisartan from reaction mass.
In further aspect, the invention provides a process for the preparation of sodium salt of telmisartan
o) (Scheme 1) comprising the steps of:
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ss i) providing a solution of telmisartan in a suitable solvent;
*^ ii) adding aqueous solution of hydroxide, carbonate, bicarbonate or alkoxide of sodium
£ metal to the reaction mixture obtained in step (i)
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In further aspect, the invention provides a process for the preparation of sodium salt of telmisartan
comprising the steps of:
i) providing a solution of telmisartan in a suitable solvent;
ii) adding aqueous solution of hydroxide, carbonate, bicarbonate or alkoxide of sodium
metal to the reaction mixture obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the monosodium salt of telmisartan from reaction mass.
In further aspect, the invention provides a process for the preparation of sodium salt of telmisartan
comprising the steps of:
i) providing a solution of telmisartan in a suitable solvent;
ii) adding aqueous solution of hydroxide, carbonate, bicarbonate or alkoxide of sodium
metal to the reaction mixture obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline monosodium salt of telmisartan from reaction mass.
In further aspect, the invention provides a process for the preparation of sodium salt of telmisartan
comprising the steps of:
i) providing a solution of telmisartan in a suitable solvent;
ii) adding aqueous solution of sodium hydroxide to the reaction mixture obtained in step
0)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline monosodium salt of telmisartan from reaction mass.
In yet another aspect, the invention provides a process for the preparation of sodium salt of
telmisartan comprising the steps of:
i) providing a solution of telmisartan in toluene;
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ii) adding alcoholic aqueous solution of sodium hydroxide to the reaction mixture
obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline monosodium salt of telmisartan from reaction mass.
In yet another aspect, the invention provides a process for the preparation of sodium salt of
telmisartan comprising the steps of:
i) providing a solution of telmisartan in toluene;
ii) adding ethanolic aqueous solution of sodium hydroxide to the reaction mixture
obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline monosodium salt of telmisartan from reaction mass.
In yet another aspect, the invention provides a process for the preparation of crystalline form 'J'
of monosodium salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan in toluene;
ii) adding ethanolic aqueous solution of sodium hydroxide to the reaction mixture
obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline form 'J' of monosodium salt of telmisartan from reaction
mass.
2 In yet another aspect, the invention provides a process for the preparation of crystalline form 'J'
of the sodium salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan sodium in a solvent or mixture of solvents wherein
S in case of solvents mixture solvents can be added in a single step or one by one;
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ii) optionally heating the reaction mixture and
iii) isolating the crystalline form 'J' of monosodium salt of telmisartan from reaction
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In yet another aspect, the invention provides a process for the preparation of crystalline form 'J'
of the sodium salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan sodium in toluene;
ii) Adding ethanolic aqueous solution to the reaction mixture obtained in step (i)
Mi) optionally heating the reaction mixture and
iv) isolating the crystalline form 'J' of monosodium salt of telmisartan.
In further aspect, the invention provides a process for the preparation of amorphous form of sodium
salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan in a suitable solvent;
ii) adding aqueous solution of hydroxide, carbonate, bicarbonate or alkoxide of sodium
metal to the reaction mixture obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the amorphous form of sodium salt of telmisartan from reaction mass.
In yet another aspect, the invention provides a process for the preparation of amorphous form of
monosodium salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan in toluene;
ii) adding ethanolic aqueous solution of sodium hydroxide to the reaction mixture
obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the amorphous form of monosodium salt of telmisartan from reaction mass.
In yet another aspect, the invention provides a process for the preparation of amorphous form of
the sodium salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan sodium in toluene;
ii) adding ethanolic aqueous solution to the reaction mixture obtained in step (i)
iii) optionally heating the reaction mixture and
8
iv) isolating the amorphous form of sodium salt of telmisartan.
In yet another aspect, the invention provides a process for the preparation of amorphous form of
the sodium salt of telmisartan comprising the steps of:
i) providing Form J of telmisartan sodium;
ii) heating the Form J of telmisartan sodium and
iii) isolating the amorphous form of sodium salt of telmisartan.
In another aspect, the invention provides a process for the preparation of telmisartan comprising:
(i) providing a solution of telmisartan in a suitable solvent;
(ii) adding hydroxide, carbonate or bicarbonate of alkali or alkaline earth metals to the
reaction mixture obtained in step (i);
(iii) optionally heating the reaction mixture;
(iv) isolating the salt of telmisartan from reaction mass;
(v) optionally purifying the salt of telmisartan and
(vi) obtaining telmisartan from the salt of step (v) or (iv).
In yet another aspect, the invention provides a process for the preparation of salt of telmisartan
comprising the steps of:
i) providing a solution of telmisartan alkyl ester in a suitable solvent;
ii) adding a suitable salt of alkali or alkaline earth metal to the reaction mixture obtained
in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the salt of telmisartan from reaction mass.
In yet another aspect, the invention provides a process for the preparation of sodium salt of
telmisartan comprising the steps of:
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) providing a solution of telmisartan alkyl ester in a suitable solvent;
i) adding a suitable sodium salt to the reaction mixture obtained in step (i)
ii) optionally heating the reaction mixture and
v) isolating the crystalline monosodium salt of telmisartan from reaction mass.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates the X-ray powder diffractogram (XRPD) of Form J telmisartan sodium.
FIG. 2 illustrates the Differential scanning calorimetry (DSC) of Form J telmisartan sodium.
FIG. 3 illustrates the Thermogravimetric Analysis (TGA) of Form J telmisartan sodium.
FIG. 4 illustrates the Infrared spectroscopy (IR) of Form J telmisartan sodium.
FIG. 5 illustrates the X-ray powder diffractogram (XRPD) of amorphous form of telmisartan
sodium.
FIG. 6 illustrates the Differential scanning calorimetry (DSC) of amorphous form of telmisartan
sodium.
FIG. 7 illustrates the Thermogravimetric Analysis (TGA) of amorphous form of telmisartan
sodium.
FIG. 8 illustrates the Infrared spectroscopy (IR) of amorphous form of telmisartan sodium.
DETAILED DESCRIPTION OF THE INVENTION
Present invention discloses sodium salts of telmisartan and novel polymorphic form 'J' of
telmisartan sodium. The object of the present invention are also processes for their preparation and
a. pharmaceutical compositions containing them. The substances in accordance with our invention
provide advantageous dissolution properties. The polymorphic form T of present invention is
advantageous, CN as it has better dissolution properties in comparison to telmisartan.
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?5 The present invention also comprises the solvates and hydrates of the above-described crystalline
CN
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The starting material used to prepare the crystalline telmisartan sodium according to the invention
may be the free acid of telmisartan or an alkyl ester of telmisartan which may be obtained by
methods known in the art e.g. according to US 5,591,762
An aspect, the invention is to provide a process for the preparation of salt of telmisartan comprising
the steps of:
(i) providing a solution of telmisartan in a suitable solvent;
(ii) adding hydroxide, carbonate bicarbonate or alkoxide of alkali or alkaline earth metals
to the reaction mixture obtained in step (i);
(iii) optionally heating the reaction mixture and
(iv) isolating the salt of telmisartan from reaction mass.
Scheme 1
COOR
CH3
CH-, N*
(3)
Ester of telmisartan
Base
CH3
N /=<
(D
Telmisartan
CH3
Salt of
COOH sodium
Salt of
sodium
CH3 cxxh CH;,
(2)
Telmisartan sodium
11
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The solvents used in the above aspect can be independently selected from the group comprising of
nitriles, alcohols, ketones, esters, halogenated hydrocarbons, ethers, amides, dialkylsulfoxides,
hydrocarbons, organic acids, water or the mixtures thereof. Nitriles are selected from the group
comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Alcohols are
selected from the group comprising of methanol, ethanol, w-propanol, isopropanol, w-butanol and
the like, preferably ethanol. Ketones are selected from the group comprising of acetone, methyl
ethyl ketone, methyl isobutyl ketone and the like. Esters are selected from the group comprising of
ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like. Halogenated
hydrocarbons are selected from the group comprising of dichloromethane (DCM), chloroform,
dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of
diethyl ether, methyl tert-buty\ ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane
and the like. Amides are selected from the group comprising of N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA), N-methylformamide, N-methylpyrrolidone and the like. Dialkyl
sulfoxides can be selected from the group comprising of dimethylsulfoxide, diethylsulfoxide,
dibutylsulfoxide and the like. Aliphatic hydrocarbons are selected from the group comprising of
alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and
the like. Aromatic hydrocarbons are selected from the group comprising of toluene, xylene and the
like, preferably toluene. Organic acids are selected from the group comprising of acetic acid, formic
acid, propionic acid and the like.
Carbonates as described herein are selected from the group comprising of K2CO3, CS2CO3 and
Na2C03 etc. Bicarbonates are selected from the group comprising of NaHCCh, KHCO3 etc.
Hydroxides are selected from the group comprising of NaOH, KOH, LiOH, CsOH etc, preferabely
-3T NaOH.
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o> Suitable sodium as referred above may be selected from but not limited to sodium hydroxide,
sodium hydride, sodium carbonate, sodium hydrogen carbonate or sodium alkoxides. Sodium
alkoxides are the sodium salts which are formed with alcohols, preferably with lower alcohols
?5 selected from among methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec.-butanol,
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£2 isobutanol, n-butanol and tert.-amyl alcohol. The preferable sodium salts are sodium hydroxide,
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^ sodium hydride, sodium ethoxide or sodium methoxide; more preferable are sodium hydroxide
° and sodium methoxide.
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The hydroxide, carbonate or bicarbonate of alkali or alkaline earth metals added to the reaction
mixture obtained in step (i) may be may be added to the reaction mixture as solids or in solution
form. Sodium hydroxide may be added with a solvent or mixture of solvents as referred above,
preferably added in the form of aqueous solutions or mixture of sodium hydroxide with an alcohol
and water wherein preferable alcohol is ethanol.
In yet another aspect, the invention provides a process for the preparation of crystalline form 'J'
of monosodium salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan in toluene;
ii) adding ethanolic aqueous solution of sodium hydroxide to the reaction mixture
obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline form 'J' of monosodium salt of telmisartan from reaction
mass.
In yet another aspect, the invention provides a process for the preparation of crystalline form 'J'
of the sodium salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan sodium in a solvent or mixture of solvents wherein
in case of solvents mixture solvents can be added in a single step or one by one;
ii) optionally heating the reaction mixture and
iii) isolating the crystalline form 'J' of monosodium salt of telmisartan from reaction
mass.
In yet another aspect, the invention provides a process for the preparation of crystalline form 'J'
of the sodium salt of telmisartan comprising the steps of:
To i) providing a solution of telmisartan sodium in toluene;
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£2 ii) Adding ethanolic aqueous solution to the reaction mixture obtained in step (i)
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^ iii) optionally heating the reaction mixture and
^ iv) isolating the crystalline form T of monosodium salt of telmisartan.
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In further aspect, the invention provides a process for the preparation of amorphous form of sodium
salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan in a suitable solvent;
ii) adding aqueous solution of hydroxide, carbonate, bicarbonate or alkoxide of sodium
metal to the reaction mixture obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the amorphous form of sodium salt of telmisartan from reaction mass.
In yet another aspect, the invention provides a process for the preparation of amorphous form of
monosodium salt of telmisartan comprising the steps of:
v) providing a solution of telmisartan in toluene;
vi) adding ethanolic aqueous solution of sodium hydroxide to the reaction mixture
obtained in step (i)
vii) optionally heating the reaction mixture and
viii) isolating the amorphous form of monosodium salt of telmisartan from reaction mass.
In yet another aspect, the invention provides a process for the preparation of amorphous form of
the sodium salt of telmisartan comprising the steps of:
v) providing a solution of telmisartan sodium in toluene;
vi) adding ethanolic aqueous solution to the reaction mixture obtained in step (i)
vii) optionally heating the reaction mixture and
viii) isolating the amorphous form of sodium salt of telmisartan.
In yet another aspect, the invention provides a process for the preparation of amorphous form of
the sodium salt of telmisartan comprising the steps of:
iv) providing Form J of telmisartan sodium;
v) heating the Form J of telmisartan sodium and
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vi) isolating the amorphous form of sodium salt of telmisartan.
In yet another aspect, the invention provides a process for the preparation of telmisartan
comprising:
(i) providing a solution of telmisartan in a suitable solvent;
(ii) adding hydroxide, carbonate, bicarbonate or alkoxide of alkali or alkaline earth metals
to the reaction mixture obtained in step (i);
(iii) optionally heating the reaction mixture;
(iv) isolating the salt of telmisartan from reaction mass;
(v) optionally purifying the salt of telmisartan and
(vi) obtaining telmisartan from the salt of step (v) or (iv).
In yet another aspect, the invention provides a process for the preparation of sodium salt of
telmisartan comprising the steps of:
i) providing a solution of telmisartan alkyl ester in a suitable solvent;
ii) adding a suitable salt of alkali or alkaline earth metal to the reaction mixture obtained
in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline monosodium salt of telmisartan from reaction mass.
In yet another aspect, the invention provides a process for the preparation of sodium salt of
telmisartan comprising the steps of:
i) providing a solution of telmisartan alkyl ester in a suitable solvent;
ST ii) adding a suitable sodium salt to the reaction mixture obtained in step (i)
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o iii) optionally heating the reaction mixture and
S iv) isolating the crystalline monosodium salt of telmisartan from reaction mass.
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The amount of sodium salt to be used depends on the starting material used for the preparation i.e.
free acid telmisartan or an ester of telmisartan. Naturally the amount of sodium salt used in case
of an ester of telmisartan will be approximately double vis-a-vis used for free acid i.e. telmisartan.
At least 1 mole of sodium salt has to be added per mole of telmisartan. However, it is also possible
according to the invention to add an excess of sodium salt.
The novel crystalline monosodium salt of telmisartan is characterized by its X-ray powder
diffraction ("XRPD") pattern and differential scanning calorimeter (DSC) thermogram. The
crystalline form of monosodium salt of deferasirox is designated hereinafter as "crystalline Form
J". It is characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 1.
Crystalline Form J of telmisartan sodium salt is characterized by characteristic differential
scanning calorimeter (DSC) thermogram, substantially as depicted in Fig, 2.
Crystalline Form J of telmisartan sodium salt is characterized by Thermo Gravimetric Analysis
(TGA) as depicted in Fig, 3.
Crystalline Form J of telmisartan sodium salt is characterized by an infrared absorption spectrum
of Fig. 4.
Amorphous form of telmisartan sodium salt is characterized by (i) XRPD pattern substantially in
accordance with Fig. 5 or (ii) differential scanning calorimeter (DSC) thermogram, in accordance
-JT with Fig, 6.
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_2 Amorphous telmisartan sodium salt is characterized by Thermo Gravimetric Analysis (TGA) as
jz depicted in Fig, 7.
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Accordingly, telmisartan sodium obtained according to the instant invention possess the relative
particle size distribution wherein the 10th volume percentile particle size D(0.1) is less than about
100 p.m and/or the 50th volume percentile particle size D(0.5) is less than about 200 (xm and/or the
90th volume percentile particle size D(0.9) is less than about 500 urn, or any combination thereof.
In another aspect there is provided a pharmaceutical composition that includes a therapeutically
effective amount of telmisartan sodium according to the process of the present invention and one
or more pharmaceutical^ acceptable carriers, excipients or diluents.
In another aspect, in view of the pharmaceutical activity of the crystalline telmisartan sodium salt
according to the invention, the present invention relates to the use thereof for preparing a
pharmaceutical composition, particularly for preparing a pharmaceutical composition for the
prevention or treatment of diseases wherein the administration of therapeutically effective doses of
one or more angiotensin-II-antagonists may provide a therapeutic benefit. Preferably, the present
invention relates to the use of crystalline telmisartan-sodium salt for preparing a pharmaceutical
composition for the prevention or treatment of diseases selected from among hypertension, cardiac
insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), the
progression of cardiac insufficiency after myocardial infarct, diabetic neuropathy, glaucoma,
gastrointestinal diseases and bladder diseases, the prevention or treatment of hypertension being
particularly preferred.
The details of the process of the invention are provided 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
m invention.
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EXAMPLES
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£ Example-1: Preparation of Telmisartan Sodium:
Charged toluene (100 mL) & Telmisartan (50.0 g) into glass reactor at room temperature (25-
30°C).Stirred for 10-15 min at 25-30°C. o Heat reaction mixture to 80 - 85°C. Added NaOH solution
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in reaction mass at 80-85°C in 15 — 30 min. [Prepare NaOH solution by mixing NaOH (4.04 g)
dissolved in water (5.0 mL) with ethanol (30.0 mL]..Stirred for 90 min. Filtered the mass through
hyflo bed followed by micron filter and washed with mixture of toluenel. Take filtrate & heat the
mass to 80 - 85°C and stirred for 10 min. Slowly cooled the mass to 25-30°C in 2-3h.Stirred for
60 min. Cooled the mass to 15-20°C.Maintained for lh .Filtered the solid and washed with toluene
(10 mL) . Suck dried the wet cake .Dried the wet material for l-2h at 25-30°C under vacuum &
raised the temp, to 55-60°C & dried for 10-12 h under vacuum.
Weight 28-32g; HPLC purity NLT 99.5%
Example 2: Preparation of Telmisartan Sodium form J:
Charged toluene (100 mL) & Telmisartan (50.0 g) into glass reactor at room temperature (25-
30°C).Stirred for 10-15 min at 25-30°C.added NaOH solution in reaction mass at 25-30°C in 15 -
30 min. [Prepare NaOH solution by mixing NaOH (4.04 g) dissolved in water (5.0 mL) with
ethanol (30.0 mL].Heat reaction mixture to 80 - 85°C.Stirred for 90 min. Slowly cooled the mass
to 55-65°C.Filtered the mass through hyflo bed followed by micron filter and washed with mixture
of toluene/ethanol. Take filtrate & heat the mass to 80 - 85°C and stirred for 10 min. Slowly
cooled the mass to 25-30°C in 2-3h.Stirred for 60 min. Cooled the mass to 15-20°C.Maintained
for lh .Filtered the solid and washed with toluene (10 mL) . Suck dried the wet cake .Dried the
wet material for l-2h at 25-30°C under vacuum & raised the temp, to 55-60°C & dried for 10-12 h
under vacuum.
Weight 28-32g; HPLC purity NLT 99.5%
Example 3: Preparation of Amorphous Telmisartan Sodium:
Charged toluene (100 mL) & Telmisartan (50.0 g) into glass reactor at room temperature (25-
Sj 30°C).Stirred for 10-15 min at 25-30°C.added NaOH solution in reaction mass at 25-30°C in 15 -
©
^ 30 min. [Prepare NaOH solution by mixing NaOH (4.04 g) dissolved in water (5.0 mL) with
ethanol (30.0 mL]. Heat reaction,mixture to o 80 - 85°C.Stirred for 90 min. Slowly cooled the mass
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to 55-65°C.Filtered the mass through hyflo bed followed by micron filter and washed with mixture
of toluene/ethanol. Take filtrate & heat the mass to 80 - 85°C and stirred for 10 min. Slowly
cooled the mass to 25-30°C in 2-3h.Stirred for 60 min. Cooled the mass to 15-20°C.Maintained
for lh .Filtered the solid and washed with toluene (10 mL) . Suck dried the wet cake. Dried the
wet material for l-2h at 25-30°C under vacuum & raised the temp, to 100-110°C & dried for 14-
18 h under vacuum.
Weight 28-32g; HPLC purity NLT 99.5%

Claims:
1. A process for the preparation of amorphous form of monosodium salt of telmisartan
comprising the steps of:
i) providing a solution of telmisartan in a suitable solvent;
ii) adding aqueous solution of hydroxide, carbonate, bicarbonate or alkoxide of sodium
metal to the reaction mixture obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the amorphous form of sodium salt of telmisartan from reaction mass or
i) providing a solution of telmisartan in toluene;
ii) adding ethanolic aqueous solution of sodium hydroxide to the reaction mixture
obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the amorphous form of monosodium salt of telmisartan from reaction mass
or
i) providing a solution of telmisartan sodium in toluene;
ii) Adding ethanolic aqueous solution to the reaction mixture obtained in step
iii) optionally heating the reaction mixture and
iv) isolating the amorphous form of sodium salt of telmisartan or
i) providing Form J of telmisartan sodium;
ii) heating the Form J of telmisartan sodium and
iii) isolating the amorphous form of sodium salt of telmisartan.
2. Amorphous form of telmisartan sodium as defined in claim 1 characterized by
i) X-ray diffraction pattern as depicted in Fig. 5 or
ii) DSC as depicted in Fig 6.
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3. A process for the preparation of Crystalline form 'J' of telmisartan sodium according to claim
1 comprising the steps of:
i) providing a solution of telmisartan in suitable solvent;
i) adding suitable sodium salt to the reaction mixture obtained in step (i)
ii) optionally heating the reaction mixture and
iv) isolating the crystalline monosodium salt of telmisartan from reaction mass.
wherein sodium salt is a salt selected from hydroxide, carbonate, bicarbonate or alkoxide of
sodium.
4. A process for the preparation of Crystalline form T of telmisartan sodium according to claim
1 comprising the steps of:
i) providing a solution of telmisartan sodium in toluene;
ii) Adding aqueous ethanolic solution to the reaction mixture obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline form CJ5 of monosodium salt of telmisartan.
5. A process for the preparation of sodium salt of telmisartan comprising the steps of:
i) providing a solution of telmisartan in toluene;
ii) adding alcoholic aqueous solution of sodium hydroxide to the reaction mixture
obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the monosodium salt of telmisartan from reaction mass or
Q- i) providing a solution of telmisartan alkyl ester in a suitable solvent;
£ ii) adding a suitable sodium salt to the reaction mixture obtained in step (i)
iii) optionally heating the reaction mixture and
iv) isolating the crystalline monosodium salt of telmisartan from reaction mass.
°. 6. A process for the preparation of telmisartan comprising:
° (i) providing a solution of telmisartan in a suitable solvent;
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(ii) adding hydroxide, carbonate, bicarbonate or alkoxide of alkali or alkaline earth
metals to the reaction mixture obtained in step (i);
(iii) optionally heating the reaction mixture;
(iv) isolating the salt of telmisartan from reaction mass;
(v) optionally purifying the salt of telmisartan and
(vi) obtaining telmisartan from the salt of step (v) or (iv).
7. A process according to any of the preceding claims wherein suitable solvents is selected from
the group comprising of nitriles, alcohols, ketones, esters, halogenated hydrocarbons, ethers,
amides, dialkylsulfoxides, hydrocarbons, organic acids, water or the mixtures thereof;
carbonate is selected from the group comprising of K2CO3, CS2CO3 and NaaCCh; bicarbonate
is selected from the group comprising of NaHC03, KHCO3; hydroxide is selected from the
group comprising of NaOH, KOH, LiOH, CsOH.
8. Crystalline form 'J5 of telmisartan sodium characterized by DSC as depicted in Fig. 2.
9. Crystalline form T of telmisartan sodium characterized by X-ray diffraction pattern as
depicted in Fig. 1.
10. Crystalline form T of telmisartan sodium characterized by the relative particle size
distribution wherein the 10th volume percentile particle size D(0.1) is less than about 100
jxm and/or the 50th volume percentile particle size D(0.5) is less than about 200 |im and/or
the 90th volume percentile particle size D(0.9) is less than about 500 jam, or any
combination thereof.