FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(Section 10)
Crystalline form of Telmisartan and the process of
its manufacturing
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT MAHALAXMI
CHAMBERS, 2ND FLOOR, 22, BHULABHAIDESAI ROAD,
MUMBAI 400 026, MAHARASHTRA, INDIA


The following specification particularly describes the nature of the invention and the manner in which it is to be performed

Crystalline form of Telmisartan and the process for its manufacturing.
The present invention relates to a novel crystalline form of 4'-[2-n-propyl-4-methyl~6-( 1 -merhylbenzimid-azole-2-yl)benzimidazole-l -ylmethyI]biphenyl-2-carboxylic acid (Telmisartan ) and its preparation
Background of Invention :
Telmisartan is an angiotensin II -antagonist and useful in regulating hypertension. It is also used in the treatment of diabetic neuropathy & glaucoma. Telmisartan is known to exist in form A,B,C and mixture of A and B forms.
US 2004/0236113A1 describes the preparation of Telmisartan by reacting 2-n-propyl-4-memyl-6-(l'methylbenzmnidazole-2,-yl)benzimidazole (Formula-II) with compound of Formula-Ill. The condensed product of Formula-IV was hydrolyzed to get the Telmisartan as shown in scheme-I

Crude-Telm isartan
(Column Chromatography
Crystallization
Pure-Telmisartan
Scheme-II
EP 0502314 (IE 920373) describes the preparation of Telmisartan by condensing the compound of Formula-V with Formula-VI to get the compound of FormuJa-VJl, which was hydroJyzed to obtain Tehnisartan as per Scheme-II

Wherein Rl = CI to 4 alkyl, cyclo alkyl, fluoromethyl etc..
R2 = C3-C5 alkoxy group substituted in the 3,4,5 position by an Imidazolyl
group or C2-C5 alkoxy group substituted in the 2,3,4,5 position by an
Benzimidazolyl group or tetrahydro benzimidazolyl group or a
benzimidazole —2-yI group optionally substituted in the 1 'position by Cl-
C6 alkyl group.
R3 = H atom or C1-C5 alkyl group
R 4 = Carboxy, alkoxy carbonyl, Cyano, 1H tetrazolyl, 1-Triphenyl methyl
tetrazolyl,C2-C5-(alkoxy carbonyl) etc
Z = Nucleophilic leaving group
In scheme-H the intermediate of Formula-V and VI are condensed at 0 to 100 °C using methylene chloride, fahylether, THF, Dioxane, DMSO,DMF and benzene as solvent and potassium carbonate, sodium carbonate, sodium hydroxide, potassium t-butoxide, triethylamine and pyridine as base to obtain the compound of Formula -VII which on hydrolysis at -10 to 120 C gives crude Telmisartan..
The crude product obtained is purified over silica gel column (particle size: 0.063-0.02 nm) using ethylacetate/ethanol/ammoma-90:10:0.1) and crystallized from acetone. The compound is characterized by melting point and C,H and N analysis. The M.P =261-263 °C. This method is cumbersome as it requires column chromatography and crystallization to obtain pure product.
The US 6410742 Bl discloses that the process disclosed in EP 502314 has proven to be problematic to transfer the method of synthesis to a industrial manufacturing scale . It states in column 2 of this patent
"The corresponding experimental procedure which may be carried out on a laboratory scale can be found in EP502314 Bl.Surprisingly, however, it proved to be problematic to transfer the method of synthesis already known on an industrial scale according to Diagram 1 is obtained after working upon the form of a product which has to be subjected to a further crystallization step to complete the purification. In this obligatory crystallization step the morphology of the end product which crystallize out leads to unforeseen problems. The product which is precipitated as a solid in the form of long needles is difficult to filter, wash and isolate, is ftirther characterized by a very long drying time on account of the presence of solvent and forms -

large, very hard fragments during the drying process. Grinding these fragments produces a dry powder which exhibit a strong tendency to electrostatic charging and is virtually impossible to pour."
A publication in Journal Of Pharmaceutical Science , Vol.89, No. 11, November 2000, describes three crystalline forms of Telmisartan A,B and C and gives the X-ray powder diffractogram (XRPD) of Form A and B, Differential scanning Calorimetry (DSC) and Infrared (IR) data of Form A, B and C (Figure I to IV).
US 6410742 Bl describes manufacturing process of Telmisartan Form-B and mixture of two polymorphic crystalline Form A and B in various ratios. This patent also provides the information on IR and DSC of Form A, B and the mixtures there of. The process for the preparation of Form-A involves dissolution of Telmisartan recrystallized from dimethylformamide or dimethyl acetamide in a mixture of ammonia & ethanol at 70-80 C, followed by neutralization with acetic acid at 70-80 °C and filtration at 0-10 °C.
US 6,358,986 discloses the preparation of Telmisartan Form-B in a mixture of formic acid, water and solvent like either tetrahydrofuran, ethylacetate or methyl ethyl ketone. It further states that
" A sample taken directly after cenrrifuging and dried in a thin layer in circulating air dryer in the laboratory typically shows a content of 95-99% Form -B. After centrifuging, the product begins to change partially into form- A, depending on the temperature, pH, retention time, and water content, towards the end of the drying."
CN 1344712 describes the preparation of Telmisartan by condensing the compound of Formula-V with methyl or ethyl ester of Formula-VI at 20 to 100 C using chloroform as solvent and sodium alcoholate, tributyl amine, tripropylamine, potassium hydroxide, Cesium and Barium hydroxide as base during condensation to get the compound of Formula-VII, which was hydrolyzed with acid such as HBr and acetic acid at RT to reflux or with base in C 1-5 alcohol -water at 20 -160 °C for 1-10 hours.

Summary of the Invention :
The main object of the invention is to provide a novel and stable crystalline polymorph that can be prepared by an industrially feasible process for the preparation of 4'-[2-n-propyl-4-methyl-6-(l -methylbenzimid-azole-2-yl)benzimidazole-l-ylmethyl]biphenyl-2-carboxylic acid (Telmisartan)
It is an another object of the invention is to provide a process for preparation of Telmisartan avoiding the use of Column chromatography by controlling the impurities at Telmisartan t-butyl ester & hydrolysis stage.
It is an another object of the invention to provide a process for crystallization in a mixture of solvents selected from methylene chloride, ethylene dichloride, ethylacetate, toluene, methanol, ethanol, isopropyl alcohol, acetone, Tetrahydrofiiran, Dioxane in the ratio of 0-100 %.
It is an another object of the invention to provide a process of crystallization without the problems in filtration & drying of the material by controlling the pH, water content in the process and drying time.
It is yet another object of the invention is to avoid formation of hard materials.during drying.
It is yet another object of the invention is to provide insitu purification to avoid the isolation of solid Crude Telmisartan to achieve easy scale up of the process.
It is yet another object of the invention is to provide XRD and DSC
characterization of crystalline 4'-[2-n-propyl-4-methyl-6-(l-
methylbenzimid-azole-2-yl)benzimidazole-l-ylmethyl]biphenyl-2-carboxylic acid (Telmisartan )
Description of the figures :
Figure-I shows the Infrared (IR) spectrum of crystalline form A, B and
C. of Telmisartan shown in the figure as graph a), b) and c) as reported in
J.of Pharm. Sc.vol 89 (11) 2000.
Figure-II shows the Diffrential scanning calorimertry chart (DSC)
of crystalline Form- A,B and C of Telmisartan shown in the figure as
graph a), b) and c) as reported in J.of Pharm. Sc.vol 89 (11) 2000.

Figure-Ill shows the X-ray powder diflfractogram (XRPD) of crystalline Form- A of Telmisartan as reported in J.of Pharm. Sc.vol 89 (II) 2000. Figure-IV shows the XRPD of crystalline Form- B of Telmisartan as reported in J.of Pharm. Sc.vol 89 (11) 2000.
Figure- V shows the Infrared spectra of the Telmisartan of this invention. Figure-VI shows the DSC of crystalline Telmisartan of this, invention. Figure-VII shows the XRPD of crystalline Telmisartan of this invention.
Figure-VIII shows the slow scan XRPD between 20° value of 4 to 15 of crystalline Telmisartan of this invention.
Figure-IX shows the expanded scan XRPD between 26° value of 16 to 26 of crystalline Telmisartan of this invention
Table-I shows the 20° and I/IO values for crystalline Telmisartan of this invention
Deatailed description of Invention.
The process for preparing 4'-[2-n-propyl-4-methyl-6-(l-methylbenzimid-
azoIe-2~yl)benzimidazole-l -ylmethyl]biphenyl-2-carboxylic acid
(Telmisartan ) comprises steps,
a) Reaction of 4-Memyl-6-(l-memylbenzimidazole-2-yl)-2-propyl beimmidazole with tert-Butyl-2-(4-Bromomethyl phenyl)benzoate in water miscible polar solvents using suitable base.
b) Quenching of the reaction in water, filtration & washing of the obtained Telmisartan -tert. Butyl ester.
c) Dissolution of the Telmisartan-tert-butyl ester in methylene chloride and washing with dilute hydrochloric acid to remove the basic impurities without the use of column chromatography
d) Hydrolysis of 4'-[2-n-propyl-4-methyl-6-(l-methylbenzimid-azole-2-yl)benzimidazole-l -ylmerhyl]biphenyl-2-carboxylic acid tert.-butyl ester using TFA in MDC, separation of organic layer containing the product and no isolation of crude Telmisartan.

e) Washing of organic layer at pH 7.5-8 with water and dilute ammonia to reduce the impurity level further. Optional washing of organic layer with water followed by drying.
f) Mixing of dried organic layer with water miscible solvent followed by charcolization of solution to further reduce the impurity level; Crystallization of product by distillation of solvent mixture up to 75-80 % by volume
g) Cooling of the crystallized mass to 5-10 °C.
h) Filtration of product, washing with chilled methanol and drying at 70-
75 °C.
The crystalline Telmisartan obtained after step h) having moisture content < 1% is stable polymorph and does not change to other form during filtration and drying. It does not form hard lumps during drying process & no milling of product was required. It is characterized by XRPD and DSC as shown in Figure-V to IX.
The crystalline Telmisartan of present invention exhibits endotherm 271 -274° C in DSC. and characteristic 28 peak at 6.7, and 23 75. It is stable, does not face problem in crystallization, filtration and drying when it is scaled up at industrial scale.
The following non limiting examples illustrate the invention.
Example-1: 4'-12-n-propvl-4-methvl-6-fl-methvlbenzimid-azoIe-2-
yl)benzimidazole-l-yImethyl]biphenyI-2-carboxylk acid.
30 gms 4-Metliyl-6-(l-methylbenzimidazol-2-yl)-2-propyl benzimidazole and 13.4 gms potassium tert-butoxide is added in 150 ml dimethyl sulfoxide and is slowly heated to 60-65°C. To this mixture 37.6 gms tert-Butyl 2-(4-bromomethylphenyl)benzoate is added & the reaction temperature is maintained for two hours. It is monitored by HPLC and quenched in 750 ml water. The precipitated product is filtered and washed with 50 ml water. The wet cake is dissolved in 300 ml methylene dichloride and washed with 5 % dilute hydrochloric acid to remove the basic impurities.

To the organic layer containing tert-Butyl 4"-[(l ,4'-dimethyl-2'-propyl [2,6'-bi-l H-benzimidazol]-1 '-yl)methyl]-[ 1,1 '-biphenyl]-2-carboxylate (Telmisartan t-butyl ester ) 120 ml.trifluoro acetic acid is added and stirred at 35-40 0C for 6-8 hours. The reaction mixture is quenched in 10 % sodium dithionate solution and further successively washed three times with dilute ammonia solution at pH 7.5-8 to reduce the impurities. To the organic layer 200 ml methanol is added and is treated with activated carbon. The carbon was filtered and the mother liquor is concentrated to 80 %of the initial volume. It is then cooled to 5 °C and filtered. The product is washed with chilled methanol and dried at 70-75 °C for 12 hours. Yields 18 gms Purity by HPLC = 98.5% Moisture content = 0.56 %
Example-2: 4,-[2-n-propyI-4-methyl-6-(l-methyIbenzimid-a2oIe-2-
yl)ben2imidazole-l-ylmethyl]biphenyl-2-carboxylic acid.
30 Kg 4-Memyl-6-(l-memylberjzimidazol-2-yl)-2-propyl benzimidazole and 13.4 kgs potassium teit-butoxide is added in 150 lit dimethyl sulfoxide and is slowly heated to 60-65°C. To this mixture 37.6 kgs tert-Butyl 2-(4-bromomethylphenyl)benzoate is added & the reaction temperature is maintained for two hours. It is monitored by HPLC and quenched in 750 lit. water. The precipitated product is filtered and washed with 50 lit water. The wet cake is dissolved in 300 lit methylene dichloride and washed with 5 % dilute hydrochloric acid to remove the basic impurities.
To the organic layer containing tert-Butyl 4'-[(l,4'-dimemyI-2'-propyl [2,6'-bi-l //-benzimidazol]-l '-yOmethylH 1,1 }-biphenylJ-2-carboxylate (Telmisartan t-butyl ester ) 120 litrrifluoro acetic acid is added and stirred at 35-40 0C for 6-8 hours. The reaction mixture is quenched in 10 % sodium dithionate solution & further successively washed three times with dilute ammonia solution at pH 7.5-8 to reduce the impurities. To the organic layer 200 lit methanol is added & is treated with activated carbon. The carbon was filtered and the mother liquor is concentrated to 80 %of the initial volume. It is then cooled to 5 °C and filtered. The product is washed with chilled methanol and dried at 70-75 °C for 12 hours.
Yield = 20 kgs
Purity by HPLC = 99.5%
Moisture content = 0.31 %

Example-3.: 4'-(2-n-propyl-4-methyI-6-(l-methyIbenzimid-azole-2-
yI)benzimidazole-l-yImethyI|biphenyl-2-carboxylic acid.
30 gms 4-Methyl-6-(l-methylbenzimidazol-2-yl)-2-propyl benzimidazole and 13.4 gms potassium tert-butoxide is added in 150 ml dimethyl sulfoxide and is slowly heated to 60-65°C. To this mixture 37.6 gms tert-Butyl 2-(4-bromometliylphenyl)benzoate is added & the reaction temperature is maintained for two hours. It is monitored by HPLC and quenched in 750 ml water. The precipitated product is filtered and washed with 50 ml water. The wet cake is dissolved in 300 ml methylene chchloride and washed with 5 % dilute hydrochloric acid to remove the basic impurities.
To the organic layer containing tert-Butyl 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-l/f-benzimidazol]-l '-yl)methyl]-[l ,F-biphenyl]-2-carboxylate (Telmisartan t-butyl ester ) 120 ml.trifluoro acetic acid is added and stirred at 35-40 OC for 6-8 hours. The reaction mixture is quenched in 10 % sodium dithionate solution and further successively washed three times with dilute ammonia solution at pH 7.5-8 to reduce the impurities. To the organic layer 200 ml tetrahydofuran is added and is treated with activated carbon. The carbon was filtered and the mother liquor is concentrated to 80 %of the initial volume. It is then cooled to 5 °C and filtered. The product is washed with chilled tetrahydrofuran and dried at 70-75 °C for 12 hours.
Yield =16 gms
Purity by HPLC = 98.17 %
Moisture content = 0.78 %
Example-4: _4?-[2-n-propyl-4-methyI-6-(l-methyIben2;imid-azoIe-2-
yl)benzimidazole^l-ylmethyllbiphenyl-2-carboxyIic acid.
5 jmis 4-Methyl-6-(l-metliylbenzimidazol-2-yl)-2-propyl benzimidazole and 2.21 gms potassium tert-butoxide is added in 25 ml dimethyl formamide and is slowly heated to 60-65°C. To this mixture 6.27 gms tert-Butyl 2-(4-bromomethylphenyl)benzoate is added & the reaction temperature is maintained for two hours. It is monitored by HPLC and quenched in 125 ml water. The precipitated product is filtered and washed with 15 ml water. The wet cake is dissolved in 50 ml methylene dichloride and washed with 5 % dilute hydrochloric acid to remove the basic impurities.

The organic layer containing tert-Butyl 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-1 H-benzimidazol]-1 '-yl)methy l]-[ 1,1 '-bipheny l]-2-carboxylate (Telmisartan t-butyl ester ) is evaporated under vacuum at 35-40 °C to dryness. To the residue 50 ml methylene chloride and 20 ml.trifluoro acetic acid is added and stirred at 25-30 °C for 6-8 hours. The reaction mixture is quenched in 50 ml 10 % sodium dithionate solution and organic layer is washed with 10 ml dilute ammonia solution at pH 7.5-8 to reduce the impurities. To the organic layer 30 ml methanol is added and is treated with 0.5 gms activated carbon. The carbon was filtered and the mother liquor is concentrated to 80 %of the initial volume. It is then cooled to 5 °C and filtered. The product is washed with chilled methanol and dried at 70-75 °C for 12 hours. Yield = 3.25 gms Purity by HPLC = 98.96 % Moisture content = 0.87 %
Example-5: 4'-{2-n-propyl-4-methyl-6-(l-methylbeiizimid-azole-2-
yl)benzimidazole-l-ylmethyl]biphenyl-2-carboxylicacid.
5 gms 4-Memyl-6-(l-memylbenzimidazol-2-yl)-2-propyl benzirmdazole and 2.21 gms potassium tert-butoxide is added in 25 ml N-Methylpyrrolidinone and is slowly heated to 60-65°C. To this mixture 6.27 gms tert-Butyl 2-(4-bromomethylphenyl)benzoate is added & the reaction temperature is maintained for two hours. It is monitored by HPLC and quenched in 125 ml water. The precipitated product is filtered and washed with 15 ml water. The wet cake is dissolved in 50 ml methylene dichloride and washed with 5 % dilute hydrochloric acid to remove the basic impurities.
The organic layer containing tert-Butyl 4'-[(l,4'~dimethyl-2'-propyl [2,6'-bi-l#-benzimidazol]-l '-yl)methyl]-[l,l '-biphenyl]-2-carboxylate (Telmisartan t-butyl ester ) is evaporated under vacuum at 35-40 °C to dryness. To the residue 50 ml methylene chloride and 20 ml.trifluoro acetic acid is added and stirred at 25-30 °C for 6-8 hours. The reaction mixture is quenched in 50 ml 10 % sodium dithionate solution and organic layer is washed with 10 ml dilute ammonia solution at pH 7.5-8 to reduce the impurities. To the organic layer 30 ml methanol is added and is treated with 0.5 gms activated carbon. The carbon was filtered and the mother liquor is concentrated to 80 %of the initial volume. It is then cooled to 5 °C and

filtered. The product is washed with chilled methanol and dried at 70-75 °C
for 12 hours.
Yield = 3.1 gms
Purity by HPLC = 99.46%
Moisture content = 0.35 %