FORM 2
THE PATENTS ACT, 1970 (39 OF 1970) & THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION "AN IMPROVED PROCESS FOR PREPARING LEVALBUTEROL TARTRATE'

We, CADILA HEALTHCARE LIMITED, of Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Sarkhej-Gandhinagar Highway, Ahmedabad - 380015, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed:


FIELD OF THE INVENTION:
The present invention relates to an improved process for preparing (R)-isomer of Salbutamol i.e. a-[[(l,l-dimethyl-ethyl)amino]methyl]-4-hydroxy-l,3-benzenedimethanol known as Levalbuterol and its pharmaceutically acceptable salts , which is known as Levalbuterol Tartrate of formula (I) as shown below

BACKGROUND OF THE INVENTION:
Activation of p-2-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation.
Albuterol or salbutamol, is a p-2 agonist useful as a bronchodilator. It possesses a high degree of selectivity between [3-1 receptors (which are present in the heart) and (3-2 receptors (which are present in bronchial tissue and elsewhere), for which reason it is widely used in the treatment of asthma, since in therapeutic doses it exhibits fewer cardiac side effects than many other j3 -agonists.
It is known that among many drugs having chiral centers one enantiomer of a racemic pair is often more active than the other in treating a medical condition. Recent data suggest that the levorotatory R-isomer of albuterol i.e Levalbuterol is approximately 80 times more potent than the dextrorotatory S-isomer (Hartley and Middlemis, J. Med. Chem. 14 895-896 (1971)), and preliminary research indicates that administration of the pure R-enantiomer may offer an improved therapeutic ratio.
Levalbuterol relaxes the smooth muscles of the airways from the trachea to the terminal bronchioles. Levalbuterol acts as a functional antagonist to relax the airway

irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.
Levalbuterol is commercially available as a salt, levalbuterol hydrochloride, in a
solution formulation adapted for administration by inhalation using a nebuliser and is sold in
® the United States under the brand name XOPENEX . It has been found that crystals of
levalbuterol hydrochloride obtained by this process are plate-like in shape and possess properties generally undesirable in a product intended for administration using a metered dose inhaler. Further, it was observed that Levalbuterol L-tartrate is a hemitartrate salt of
Levalbuterol that possess particularly advantageous properties. Levalbuterol Tartrate is sold
® in the United States under the brand name XOPENEX HFA . Levalbuterol L-tartrate can be
obtained in the form of needle-like crystals, which have been found to be relatively resistant to agglomeration when micronized and. unlike crystals of the hydrochloride salt, to possess excellent stability, both as bulk drug and in the presence of aerosol formulation components, such as ethanol. They therefore provide a means for delivering effective, reproducible doses of aerosolized levalbuterol from a metered dose or dry powder inhaler into the lungs of patients requiring treatment.
Great Britain patent No. 1298494 discloses the synthesis of levalbuterol for the first time by crystallizing the alkyl acetate of the 4-carboxylate derivative (Formula II)

Formula II
using ditolyltartaric acid [DTTA] and isolating the selected crystalline fraction. Thereafter, the crystal undergoes debenzylation deprotection, followed by ester reduction to yield levalbuterol.
One method of preparing the (R) and (S) isomers of salbutamol in optically pure form is disclosed in U.S. Patent No. 5,545.745. In this method, either of two precursor compounds for salbutamol is resolved using a substituted tartaric acid derivatives chosen from (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl-L-tartaric acid and (+)-di-benzoyl-D-tartaric acid as shown in the below Scheme- 1 and Scheme -2


NH-tBu

Another reference (Hartley et al, Journal of Medicinal Chemistry, 1971, Vol 14, No 9, pp 895-896) describes much the same thing as U.S. Pat. No. 5,545.745: the resolution is performed with either (+) or (-) di-para-toluoyl tartaric acid.
Reference article Enantiomer 2000, 5(3-4), 289-291 discloses the resolution of salbutamol by using di-para-toluoyl tartaric acid and finally breaking the chiral salt to form Levalbuterol Sulphate. The article provides the racemization of (S)-isomer of Levalbuterol Sulphate by using sulphuric acid and final extraction with methyl-tert-butyl ether to isolate the racemic Salmbutamol for the recycling process.
Patent US 6,365,756 describes the resolution of a new ketal derivative of salbutamol (specifically 2-(N-t-butylamino)-l-(+2,2-dimethyl-l,2-benzodioxin-6-yl) ethanol of formula
111).


The resolution is again performed with a chiral tartaric acid derivative, such as (+) or (-) di-para-toluoyl tartaric acid or (+) or (-) di-Obenzoyl tartaric acid. Enantiomers of salbutamol can be produced if desired, via a complicated, multi-stage process involving resolution of the ketal derivative. The disadvantage of the process described is that the enantiomeric excess of the salts obtained is low (based on the values given in the Examples). This requires additional crystallizations, thus lowering the overall yields. Further, two additional synthetic steps of ketalization and hydrolysis further reduces the economic viability of the process.
Patent US 6,995;286 B2 disclsoes the process for making optically pure (R) and (S) salbutamol comprises obtaining the (R) or (S) isomer of either salbutamol or a salbutamol precursor in substantially optically pure form by resolving a racemic or optically impure mixture of enantiomers of salbutamol or of said precursor with either (L) or (D) tartaric acid, and where necessary converting said isomer of said precursor into either (R or (S) salbutamol respectively; then optionally converting said optically pure (R) and/or (S) salbutamol into a pharmaceutical^ acceptable salt as shown in below Scheme -3 and Scheme- 4


Scheme- 4
Patent application US 20060241191 Al discloses the crystalline Form-I, Form-II and Form-Ill of Levalbuterol Sulphate. Patent US 7,256,310 dislcoses Levalbuterol Tartrate in crystalline form and the process for obtaining needle like particles of Levalbuterol Tartrate after micronization.
Chinese patent CN 1,382,685 relates to the process for preparing R-salbutamol tartrate from dl-salbutamol through proportionally mixing L-(+)-tartaric acid with molar ratio of 1 :l-4 with dl-salbutamol and dissolving the mixture in water, alcohol, or ketone or respectively dissolving both, stirring while heating reflux for 10-30 min, cooling to educe out diastereo-isomer and filter to obtain the product.
Patent US 7,049,469 B2 disclsoes the process for preparing levosalbutamol or the pharmacologically acceptable salts thereof starting from prochiral salbutamone as educt, characterized in that salbutamol is subjected to asymmetric hydrogenation in the presence of rhodium and a chiral bidentate phosphine ligand as catalyst system, and the levosalbutamol obtained is optionally converted into a salt with an acid as shown in below Scheme-5.

Patent US 7465831 B2 discloses the process for preparing Levalbuterol Hydrochloride polymorphic Form- A from R-enantiomer of albuterol D-dibenzoyl Tartrate salt. The patent discloses characterization of Form-A by XRPD, DSC and IR and Loss On Drying (L.O.D.) data.

Patent US 7482489 B2 discloses two impurities of Levalbuterol Hydrochloride as a compound namely compound B, (N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(hydroxyrnethyl)phen-l-yl)-ethanamine, having the following structure:

and compound C, (N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(methoxy-methyl)phen-l-yl)-ethanamine. having the following structure:

Patent US 7488758 B2 discloses Levalbuterol Hydrochloride polymorphic Form- B as a compound and being characterized by XRPD peaks at 8.9, 14.5, 19.0 and 19.6 degree two-theta, +/-0.2 degree two-theta.
Chinese patent No. 1,273,966, discloses that the salt of (R)-albuterol D-dibenzoyltartaric acid is treated with potassium carbonate in water and an organic solvent, such as ethylacetate. After phase separation and extraction of the aqueous layer, the collected organic layer is dried and levalbuterol free base crystallizes overnight. The crystalline levalbuterol free base is dissolved in anhydrous alcohol, followed by addition of HC1 to obtain crystalline levalbuterol HC1. Also, levalbuterol HC1 is synthesized by acid displacement from (R)-albuterol D-dibenzoyltartaric acid salt suspended in acetone and the addition of an ether solution of HC1. Despite the many attempts of the prior art to synthesize pure levalbuterol, still novel synthetic processes of preparing polymerically pure levalbuterol are needed to reduce the steps necessary for synthesis.
PCT application WO 2007101872 Al discloses process for preparing acid addition salts like pivalic acid and 3,5-dinitrobenzoic acid of Levalbuterol.
PCT application WO2008015689 Al relates to the use of novel resoluting agent 4-nitro tartranilic acid for the resolution of Salbutamol.
PCT application WO2008070909 Al discloses R- Ibuprofen as the resoluting agent for the preparation of Levalbuterol.
Patent application US 20080132579 Al discloses Levalbuterol hydrochloride characterized by at least one of an enantiomeric excess of at least about 99.8%; having less

.-than about 1700 ppm of residual C1-C4 alcohol; or having a pH of at least about 4.3 in 1% aqueous solution at room temperature.
Patent application US 20080119564 Al discloses Levalbuterol-L-Tartrate, which is a hemitartrate as a compound.
The processes provided for the preparation of Levalbuterol Tartrate in the prior art involves long steps of synthesis with low yield and use of expensive resoluting agents. The art does not disclose any simple process without involving tedious reaction condition for the direct preparation of Levalbuterol Tartrate with better yield and chiral purity. Moreover, the art does not discloses the racemization and recyclability of the recovered S-isomer of Albuterol. Hence, the present invention provides an improved process for preparing Levalbuterol Tartrate which overcomes the drawbacks of prior art process with respect to simple steps, yield and purity of the product and a process for the racemization and recyclability of recovered S-isomer of Albuterol. OBJECTS OF INVENTION:
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative thereof.
Another object of the present invention is to provide an improved process for preparing (R)-isomer of Salbutamol known as Levalbuterol and and its pharmaceutically acceptable salts.
Yet another object of the present invention to provide crystalline form of Levalbuterol p-Di-toluoyl-tartaric acid (In the present invention it is referred as Levalbuterol DTTA).
Further object of the present invention to provide crystalline Form-A (prior art form) of Levalbuterol Hydrochloride.
Yet another object of the present invention to provide crystalline form of Levalbuterol Tartrate.
Yet another object of the present invention to provide one pot process for preparing Levalbuterol Tartrate from Levalbuterol DTTA.
Yet another object of the present invention to provide one pot process for preparing Levalbuterol Tartrate from Levalbuterol Hydrochloride.
It is also an object of the present invention to provide a process of racemization and recyclability of the recovered S-isomer of Albuterol.
Yet another object of the present invnetion is to provide Levalbuterol Tartrate having purity more than 99.5% by area percentage of HPLC.
Still further object of the present invention is to provide Levalbuterol Tartrate having chiral purity more than 99.9%.


-SUMMARY OF INVENTION:
According to one of the aspects, the present invention provides an improved process for preparing (R)-isomer of Salbutamol known as Levalbuterol and and its pharmaceutically acceptable salts which is simple, cost effective, non-hazardous, easily scalable and industrially viable.
According to one of the aspects, the present invention provides an improved process for preparing Levalbuterol Tartrate from Salbutamol Sulphate. The imoproved process involves the formation of Levalbuterol DTTA salt, further conversion of Levalbuterol DTTA into Levalbuterol HCl and finally one step conversion of Levalbuterol HCl into Levalbuterol Tartrate.
According to one of the aspects, the present invention to provide one pot process for preparing Levalbuterol Tartrate from Levalbuterol DTTA.
According to one of the aspects, the present invention provides a one pot process for preparing Levalbuterol Tartrate from Levalbuterol HCl.
According to one of the aspects, the present invention provides a one pot process for preparing Levalbuterol Tartrate by treating Levalbuterol Hydrochloride with suitable solvents like C1-C4 alochols in presence of base.
According to another aspect, the present invention provides crystalline form of Levalbuterol DTTA.
According to another aspect, the present invention provides process for preparing crystalline form of Levalbuterol DTTA characterized by XRPD, DSC and IR.
According to another aspect, the present invention provides crystalline Form-A of Levalbuterol Hydrochloride.
According to another aspect, the present invention provides process for preparing crystalline Form-A of Levalbuterol Hydrochloride characterized by XRPD, DSC and IR.
According to another aspect, the present inverition provides crystalline form of Levalbuterol Tartrate.
According to another aspect, the present invention provides process for preparing crystalline form of Levalbuterol Tartrate characterized by XRPD, DSC and IR.
According to another aspect, the present invention provides process for preparing crystalline form of Levalbuterol DTTA by treating Levalbuterol DTTA with C1-C4 alcohols like methanol, ethanol or isopropyl alcohol.
According to another aspect, the present invention provides process for preparing crystalline Form-A of Levalbuterol HCl by treating Levalbuterol HCl with C1-C4 alcohols like methanol, ethanol or isopropyl alcohol.

According to another aspect, the present invention provides process for preparing crystalline form of Levalbuterol Tartrate by treating Levalbuterol Tartrate with C1-C4 alcohols like methanol, ethanol or isopropyl alcohol.
According to another aspect, the present invention provides process for racemization of the S-isomer of Albuterol by using suitable acid and organic solvent to form racemic Salbutamol and converting racemic Salbutamol into Salbutamol Sulphate for recycling of the process.
According to another aspect, the present invention provides Levalbuterol Tartrate having purity more than 99.0% by area percentage of HPLC.
According to another aspect, the present invention provides Levalbuterol Tartrate having chiral purity more than 99.9%. BREIF DESCRIPTION OF DRAWINGS
A preferred embodiment of the invention will now be described, by way of example only, with reference to the accompanying figures in which: FIG. 1: X-ray powder diffraction pattern of crystalline Levalbuterol DTTA. FIG. 2: Differential scanning calorimetry of crystalline Levalbuterol DTTA. FIG. 3: IR spectra of crystalline Levalbuterol DTTA.
FIG. 4: X-ray powder diffraction pattern of crystalline Form-A Levalbuterol HC1. FIG. 5: Differential scanning calorimetry of crystalline Form-A Levalbuterol HC1. FIG. 6: IR spectra of crystalline Form- A Levalbuterol HC1. FIG. 7: X-ray powder diffraction pattern of crystalline Levalbuterol Tartrate. FIG. 8: Differential scanning calorimetry of crystalline Levalbuterol Tartrate. FIG. 9: IR spectra of crystalline Levalbuterol Tartrate. DETAILED DESCRIPTION OF INVENTION:
The present invention relates to an improved process for preparing (R)-ct-[[( 1,1-dimethyl-ethyl)amino]methyl]-4-hydroxy-l,3-benzenedirriethanol i.e. Levalbuterol or its pharmaceutically acceptable salt which is known as Levalbuterol Tartrate of formula (1)


Levalbuterol Tartrate according to the present invention is prepared by an improved process which comprises of the following steps:
a) treating Salbutamol Sulphate in sutaible organic solvent in presence of a base;
b) isolating Salbutamol free base;
c) Resoluting Salbutamol free base with (+)-di-toluoyl-D-tartaric acid monohydrate in the presence of sutaible organic solvent;
d) isolating Levalbuterol DTTA salt;
e) treating Levalbuterol DTTA salt with suitable organic solvent and hydrochloric acid;
f) purification with suitable organic solvent to isolate Levalbuterol HCl
g) treating Levalbuterol HCl salt in suitable organic solvent and adding L-(+)-Tartaric acid in presence of base at elevated temperature:
h) isolating Levalbuterol Tartrate salt.
In the preferred embodiment of the present invention, for the formation of Salbutamol free base the suitalble organic solvents for step (a) is selected from C1-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol or mixtures thereof. The preferred organic solvent is methanol.
The suitable base for the step (a) is selected from alkali metal hyroxides and carbonates such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate and like. The preferred base is sodium bicarbonate.
In the preferred embodiment of the present invention, the resolution of Salbutamol free base with (+)-di-toluoyl-D-tartaric acid in step (c) the suitable solvent is selected from mixture of C1-C4 alcohols with water like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol and like. The preferred organic solvent is mixture of methanol and water.
In the preferred embodiment of the present invention, for the formation of Levalbuterol HCl as in step (e), the suitable organic solvent is selected from the mixture of solvents such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, C1-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, acetone, acetonitrile, benzonitrile, phenylacetonitrile and like.The preferred organic solvent is mixture of ethyl acetate and methanol.
The suitable organic solvent for the purification of Levalbuterol HCl in step (f) is selected from the mixture of solvents selected from methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, C1-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol. The preferred organic solvent is mixture of ethyl acetate and methanol.

In the preferred embodiment of the present invention, the suitable solvent for the formation of Levalbuterol Tartrate in step (g) is selected from C1-C4 alcohols like methanol, ethanol. propanol, isopropyl alcohol, butanol. isobutyl alcohol or mixtures thereof. The preferred organic solvent is ethanol.
The suitable base for the step (g) is selected from organic and inorganic bases such as
monomethy] amine, diethyl amine, triethyl amine, pyridine, piperidine, N-methyJ pyrrolidine,
dimethyl amino pyridine, alkali and alkaline metal carbonates such as sodium carbonate,
potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate,
potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate and like. The preferred
base is potassium bicarbonate. '
The term elevated temperature for the step (g) is referred for the temperature in the range from 45 to 65°C. The more preferable range is from 50 to 53°C and the most preferred range of elevated temperature for step (g) is 60 to 65°C.
The improved process for preparing Levalbuterol Tartrate as per the present invention is shown in below Scheme -6


According to another embodiment, the present invention provides the racemization of S-isomer for Albuterol and its conversion into racemic Salbutamol Sulphate for the further


HO'
XJ
Racemic Salbutamol Sulphate
Scheme -7
The process for racemization of S-isomer of Albuterol into racemic Salbutamol Sulphate comprises of steps;
a) treating S-isomer of Albuterol with sulfuric acid in presence of suitable solvent;
b) isolating Salbutamol free base;
c) treating Salbutamol free base with sulfuric acid in presence of suitable solvent;
d) isolating Salbutamol Sulphate
The suitable organic solvent in step (a) for the conversion of S-isomer of Albuterol into Salbutamol free base is selected from diisopropyl ether, diethyl ether, methyl tert-butyl ether, methyl acetate, ethylacatate and mixtures thereof. The preferred solvent is methyl tert-butyl ether.
The suitable organic solvent in step (c) for the formation of Salbutamol Sulphate is selected from acetone, n-butanone, methanol, ethanol, propanol, isopropyl alcohol, butanol and mixtures thereof. The preferred solvent is mixture of methanol and acetone.
According to the another embodiment, the present invention provides the one pot process for the preparation of Levalbuterol Tartrate from Levalbuterol DTTA. The one pot process for the preparation of Levalbuterol Tartrate comprises of following steps:
a) treating Levalbuterol DTTA salt with suitable organic solvent and hydrochloric acid;
b) adding suitable organic solvent and L-(+)-Tartaric acid in presence of base at elevated temperature;
c) isolating Levalbuterol Tartrate salt.
In the preferred embodiment of the present invention, for the formation of Levalbuterol Tartrate from Levalbuterol DTTA as in step (a), the suitable organic solvent is

-selected from acetone, acetonitrile, benzonitrile, phenylacetonitrile and like. The preferred organic solvent is acetonitrile.
Jn the preferred embodiment of the present invention, the suitable solvent for the formation of Levalbuterol Tartrate in step (b) is selected from C1-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol or mixtures thereof. The preferred organic solvent is ethanol
The suitable base for the step (b) is selected from monomethyl amine, diethyl amine, triethyl amine, pyridine, piperidine, N-methyl pyrrolidine, dimethyl amino pyridine and like. The preferred base is triethyl amine.
The term elevated temperature for the step (b) is referred for the temperature in the range from 45 to 65 C. The more preferable range is from 50 to 53°C and the most preferred range of elevated temperature for step (c) is 60 to 65°C.
According to the another embodiment, the present invention provides the one pot process for the preparation of Levalbuterol Tartrate from Levalbuterol HC1. The one pot process for the preparation of Levalbuterol Tartrate comprises of following steps:
a) treating Levalbuterol HC1 salt in suitable organic solvent and adding L-(+)-Tartaric acid in presence of base at elevated temperature;
b) isolating Levalbuterol Tartrate salt.
In the preferred embodiment of the present invention, the suitable solvent for the formation of Levalbuterol Tartrate in step (a) is selected from C1-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol or mixtures thereof. The preferred organic solvent is ethanol.
The suitable base for the step (a) is selected from organic and inorganic bases such as monomethyl amine, diethyl amine, triethyl amine, pyridine, piperidine, N-methyl pyrrolidine, dimethyl amino pyridine, alkali and alkaline metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate and like. The preferred base is potassium bicarbonate.
The term elevated temperature for the step (a) is referred for the temperature in the range from 45 to 65°C. The more preferable range is from 50 to 53°C and the most preferred range of elevated temperature for step (a) is 60 to 65°C.
According to another embodiment, the present invention provides crystalline form of
Levalbuterol DTTA.

The crystalline form of Levalbuterol DTTA is characterized by X-ray diffraction peaks at 5.6, 8.1, 11.9, 12.7, 15.2, 16.8, 18.5, 19.0, 19.8, 21.2, 22.8, 24.3, 25.9, 27.2, 29.0, 30.7 and 32.2 degree two-theta, ±0.2 two-theta.
The crystalline form of Levalbuterol DTTA is characterized by Differential scanning calorimetry having a melting endotherm at 147°C.
Alternatively, the crystalline form of Levalbuterol DTTA is characterized by IR peaks at 3666, 3518, 3066, 3028, 3005, 2939, 2883, 2659, 2515, 2355, 2339, 2328, 1820, 1807,
1768, 1643, 1566, 1556, 1487, 1371, 1213, 1076, 1018, 893, 823, 680, 657, 553 and 453 cm
-i
According to another embodiment, the present invention provides the process for preparing crystalline form of Levalbuterol DTTA, comprising following steps of;
a) suspending or forming a slurry of Levalbuterol DTTA in suitable organic solvent
b) isolating crystalline Levalbuterol DTTA
The suitable organic solvent for step (a), is selected from mixture of C1-C4 alcohols with water like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol and like. The preferred organic solvent is mixture of methanol and water.
According to another embodiment, the present invention provides crystalline Form-A of Levalbuterol HC1.
The crystalline Form -A of Levalbuterol HC1 is characterized by X-ray diffraction peaks at 6.9, 10.7, 15.3, 15.6, 19.1, 20.7, 27.4, 23.9 and 32.4 degree two-theta, ±0.2 two-theta.
The crystalline Form-A of Levalbuterol HC1 is characterized by Differential scanning calorimetry having an endotherm at about 185°C to 196°C.
Alternatively, the crystalline Form- A of Levalbuterol HC1 is characterized by IR peaks at 3534, 3414, 3087, 2979, 2797, 1613, 1547, 1505, 1481,1437, 1397, 1365, 1325, 1304, 1243, 1199, 1152, 1109, 1087, 1076, 1056, 1030, 990, 920, 839, 792 and 640 cm "' .
According to another embodiment, the present invention provides the process for preparing crystalline Form- A of Levalbuterol HC1, comprising following steps of;
c) suspending or forming a slurry of Levalbuterol HC1 in suitable organic solvent
d) isolating crystalline Form-A of Levalbuterol HC1
The suitable organic solvent in step (a) is selected from ethylacetate, acetone, tetrahydrofuran, dimethyl carbonate, acetonitrile, toluene, xylene, methanol, ethanol, isopropanol, dimethylsulfoxide or dimethyl formamide. The preferred organic solvent is mixture of ethyl acetate and methanol.

According to another embodiment, the present invention provides crystalline form of Levalbuterol Tartrate.
The crystalline form of Levalbuterol Tartrate is characterized by X-ray diffraction peaks at 5.7, 11.0, 11.3, 12.3, 13.8, 14.6, 16.7, 17.8, 18.2, 18.9, 20.0, 22.1, 22.6, 23.5, 24.7, 26.1, 26.8, 27.6, 28.9, 29.2, 31.3 and 33.1 degree two-theta, ±0.2 two-theta.
The crystalline form of LevaJbuferoJ Tartrate is characterized by Differential scanning calorimetry having an endotherm at 195°C -205°C.
Alternatively, the crystalline form of Levalbuterol Tartrate is characterized by IR peaks at 3541, 3518, 3269, 3165, 3082, 3020, 2978, 2953, 2862, 2785, 2682, 2640, 2544, 2503,2447,2351,2318,2235,2067, 1568, 1487, 1361, 1338, 1298, 1234, 1207, 1153, 1114, 1099, 1055, 1033, 948, 912, 887, 792, 777, 746, 713, 688, 594, 563 and 459 cm "' .
According to another embodiment, the present invention provides the process for preparing crystalline form of Levalbuterol Tartrate , comprising following steps of;
a) suspending or forming a slurry of Levalbuterol Tartrate in suitable organic solvent at elevated temperature;
b) isolating crystalline Levalbuterol Tartrate
In the preferred embodiment of the present invention, the suitable solvent for the formation of Levalbuterol Tartrate in step (a) is selected from C1-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol or mixtures thereof. The preferred organic solvent is ethanol.
The term elevated temperature for the step (a) is referred for the temperature in the range from 45 to 65T. The more preferable range is from 50 to 53°C and the most preferred range of elevated temperature for step (a) is 60 to 65°C.
Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art wbuld appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. Working Examples: 1) Preparation of Salbutamol Free base
Salbutamol Sulphate (100 g, 0.293 mole), sodium bicarbonate (40 g, 0.4761) and methanol (100 mL) was added to a four-neck two litre round bottom flask. The reaction

mass was stirred for 6 hours at 25 to 35°C. The reaction mass was filtered and washed with methanol (50 mL). The filtrate was distilled to afford the title compound as Salbutamol free base.
2) Preparation of Levalbuterol DTTA
Salbutamol free base (80 g) and mixture of methanol-water (800 mL) was added to a four-neck two Utoe round bottom flask and stirred for 15 minutes at 25 to 35°C. Further, Di-p-toluoyl-(D)-Tartaric acid (130 g, 0.3214) was added and heated to get reflux temperature of 70 to 75°C. The reaction mass was stirred for 15 minutes. Further, the reaction mass was slowly cooled to 25 to 35°C and stirred for one hour. The reaction mass filtered and washed with mixture of methanol-water (50 mL + 50 mL) to afford the title compound as Levalbuterol DTTA which was further purified with water-methanol mixture (50 mL + 50 mL) to obtain pure Levalbuterol DTTA.
3) Preparation of Levalbuterol HCI
Levalbuterol DTTA (100 g, 0.1598 mole) and ethyl acetate (1000 mL) and methanol (60 mL) was added to a four-neck two litre round bottom flask. The reaction mass was cooled to 0 to +/- 2°C and stirred for 5 minutes. Further, Cone. HCI (16 mL) was added at 0 to +/- 2°C and stirred for 1 hour at the same temperature. The reaction mass was filtetered and washed with chilled ethyl acetate (2 x 50 mL). Further, to the obtained wet cake mixture of ethyl acetate (240 mL) and methanol (25 mL) was added at 30 to 35 C. The reaction mass was cooled to 20 to 25 C and stirred for 4 hours at the same temperature. The reaction mass was filtered and washed with ethyl acetate (2 x 50 mL). The product was dried at 50 to 55°C for 8-10 hours to afford the title compound as Levalbuterol HO.
4) Preparation of Levalbuterol Tartrate [One pot process]
Levalbuterol HCI (100 g, 0.3625 mole) and potassium bicarbonate (58 g, 0.579 mole) were addeel with ethanol (1000 mL) to a four-neck two litre round bottom flask. The reaction mass was refluxed for 30 minutes at 25 to 35°C. To the reaction mass L-(+)-Tartaric acid (27 g. 0.179 mole) was added at 60 to 65°C and stirred for one hour. Further, the reaction mass was cooled to 25 to 35°C within 1 to 2 hours. The reaction was further cooled to 0 to 10°C and stirred for 5 to 6 hours at 0 to 10°C. The product was filtered and washed with chilled ethanol (70 mL) and dried at 50 to 55°C for 8-10 hours to afford the title compound as Levalbuterol Tartrate.
5) Preparation of Levalbuterol Tartrate from Levalbuterol DTTA [One pot process]
Levalbuterol DTTA (100 g, 0.1598 mole) and acetonitrile (1160 mL) was added to a four-neck two litre round bottom flask. The reaction mass was cooled to 0 to +/- 2°C and

stirred for 5 minutes. Further, Cone. HC1 (16 mL) was added at 0 to +/- 2 C and stirred for 1 hour at the same temperature. The temperature was raised to 25 to 35°C. To the reaction mass triethyl amine (7 g, 0.69 mole) was added at 25 to 35°C. The reaction mass was heated at 60 to 65°C. To the reaction mass Tartaric acid (11.8 g, 0.079 mole) was added at 60 to 65°C and stirred for 1 hour. The reaction mass was cooled to 25 to 35°C and further cooled to 0 to J 0°C and maintained for 5 hours atOto 10°C. The poduxt was filtered and washed with chilled ethanol (50 mL) and dried at 50 to 55°C for 8-10 hours to afford the title compound as Levalbuterol Tartrate.
6) Racemization of S-isomer of Albuterol
Distil out mother liquor and add 0.8 M sulphuric acid (500 mL) into the obtained residue. Extract the Di-p-toluoyl-(D)-Tartaric acid with methyl tert-butyl ether (2 x 250 mL). The aqueous solution was vacuum dried and again dissolved in 600 mL of 0.1 M sulphuric acid. The reactio mass was refluxed for 24 hours and water was evaporated to afford Salbutamol Sulphate which was crystallized with acetone and methanol mixture. Advantages of the invention:
i) The present invention provides the eco-friendly, cost-effective and industrially viable process for preparing Levalbuterol Tartrate with high yield and purity.
ii) The present invention provides one pot process for preparing Levalbuterol Tartrate from Levalbuterol DTTA.
iii) The present invention provides one pot process for preparing Levalbuterol Tartrate from Levalbuterol HC1.
iv) The present invention provides the racemization of S-isomer of Albuterol and formation of racemjc Salbutamol Sulphate for the re-cydabi lity of the process.
v) The present invention provides the crystalline form of Levalbuterol DTTA.
vi) The present invention provides the crystalline Form- A of Levalbuterol HC1.
vii) The present invention provides the crystalline Form of Levalbuterol Tartrate.

We claim:
An improved process for preparing Levalbuterol Tartrate of formula (I) which comprises of the following steps:


2
a) treating Salbutamol Sulphate in sutaible organic solvent in presence of a base;
b) isolating Salbutamol free base;
c) resoluting Salbutamol free base with (+)-di-toluoyl-D-tartaric acid monohydrate in the presence of sutaible organic solvent;
d) isolating Levalbuterol DTTA salt;
e) treating Levalbuterol DTTA salt with suitable organic solvent and hydrochloric acid;
f) purification with suitable organic solvent to isolate Levalbuterol HC1
g) treating Levalbuterol HC1 salt in suitable organic solvent and adding L-(+)-Tartaric acid in presence of base at elevated temperature;
h) isolating Levalbuterol Tartrate salt.
2. An improved process for preparing Levalbuterol Tartrate as claimed in claim 1 wherein in step (a) the organic solvent is selected from C1-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol or mixtures thereof, preferably methanol.
3. An improved process for preparing Levalbuterol Tartrate as claimed in claim 1 wherein in step (a) said base is selected from alkali metal hyroxides and carbonates such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate and like, preferably sodium bicarbonate.
4. An improved process for preparing Levalbuterol Tartrate as claimed in claim 1 wherein in step (c)the suitable solvent is selected from mixture of C1-C4 alcohols with water like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol and like, preferably mixture of methanol and water.
5. An improved process for preparing Levalbuterol Tartrate as claimed in claim 1 wherein in step (e) said suitable organic solvent is selected from acetone, acetonitrile, benzonitrile. phenylacetonitrile and like, preferably acetonitrile.
6. An improved process for preparing Levalbuterol Tartrate as claimed in claim 1 wherein in step (f) said organic solvent is selected from methyl acetate, ethyl acetate, isopropyl

acetate, butyl acetate, C1-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol or a mixture thereof, preferably mixture of ethyl acetate and methanol.
7. An improved process for preparing Levalbuterol Tartrate as claimed in claim 1 wherein in step (g) said organic solvent is selected from C1-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol or mixtures thereof, preferably ethanol.
8. An improved process for preparing Levalbuterol Tartrate as claimed in claim 1 wherein in
step (g) said base is selected from organic and inorganic bases such as monomethyl amine, diethyl amine, triethyl amine, pyridine, piperidine, N-methyl pyrrolidine, dimethyl amino pyridine, alkali and alkaline metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate and like, preferably potassium bicarbonate.
9. An improved process for preparing Levalbuterol Tartrate as claimed in claim 1 wherein in
steP (g) said elevated temperature is in the range of from 45 to 65°C, preferably, in the
range of from 50 to 53°C and the more preferably in he range of from 60 to 65°C.
10. One pot process for the preparation of Levalbuterol Tartrate comprising of
a) treating Levalbuterol DTTA salt with suitable organic solvent and hydrochloric acid;
b) adding suitable organic solvent and L-(+)-Tartaric acid in presence of base at elevated
temperature:
c) isolating Levalbuterol Tartrate salt.
11. One pot process as claimed in claimlO(a), wherein organic solvent is selected from acetone, acetonitrile, benzonitrile, phenylacetonitrile and like, preferably acetonitrile.
12. One pot process as claimed in claimlO wherin in step (b) said solvent is selected from Cl-C4 alcohols like methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol or mixtures thereof, preferably ethanol.
13. One pot process as claimed in claim 10 wherein in step (b) said base is selected from organic and inorganic bases such as monomethyl amine, diethyl amine, triethyl amine, pyridine, piperidine, N-methyl pyrrolidine, dimethyl a.mino pyridine, alkali and alkaline metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate and like, preferably potassium bicarbonate.
14. One pot process as claimed in claimlO wherein in stej) (b) the elevated temperature is in the range from 45 to 65°C, preferably from 50 to 53°C and more preferrably 60 to 65°C.

15. One pot process for the preparation of Levalbuterol Tartrate comprising of;
a) treating Levalbuterol HCl salt in suitable organic solvent and adding L-(+)-Tartaric acid in the presence of a base at elevated temperature;
b) isolating Levalbuterol Tartrate salt.

16. A process as claimed in claiml5 wherein in step (a) said solvent is selected from C1-C4 ai'coiiors like nietfianof, ethano/, propane/, isopropyr. alcohol, butanol, isobutyl alcohol or mixtures thereof, preferably, ethanol.
17. A process as claimed in claim 15 wherein in step (a) said base is selected from organic and inorganic bases such as monomethyl amine, diethyl amine, triethyl amine; pyridine, piperidine, N-methyl pyrrolidine, dimethyl amino pyridine, alkali and alkaline metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate and like, preferably potassium bicarbonate.
18. A process as claimed in claiml5 wherein in step (a) said elevated temperature is in the range from 45 to 65°C, preferably 50 to 53°C and the more preferrably 60 to 65°C.
19. Crystalline Levalbuterol DTTA characterized by X-ray diffraction peaks at 5.6, 8.1, 11.9, 12.7, 15.2, 16.8, 18.5, 19.0, 19.8, 21.2, 22.8, 24.3, 25.9, 27.2, 29.0, 30.7 and 32.2 degree two-theta, ±0.2 two-theta., having a melting endotherm at 147 C characterized by DSC and having IR psaks at 3666, 3518, 3066, 3028, 3005, 2939, 2883, 2659, 2515, 2355, 2339, 2328, 1820, 1807, 1768, 1643, 1566, 1556, 1487, 1371, 1213, 1076, 1018, 893, 823, 680, 657, 553 and 453 cm "' .
20. Crystalline Levalbuterol Hydrochloride Form-A characterized by X-ray diffraction peaks at 6.9, 10.7, 15.3; 15.6, 19.1, 20.7, 27.4, 23.9 and 32.4 degree two-theta, ±0.2 two-theta, having an melting endotherm at about 185°C to I96°C characterized by DSC and having IR peaks at 3534, 3414, 3087, 2979, 2797, 1613, 1547, 1505, 1481,1437, 1397, 1365, 1325, 1304, 1243, 1199, 1152, 1109, 1087, 1076, 1056, 1030, 990, 920, 839, 792 and 640 cm "' .
21. Crystalline Levalbuterol Tartrate characterized by X-ray diffraction peaks at 5.7, 11.0, 11.3, 12.3, 13.8, 14.6, 16.7, 17.8, 18.2, 18.9,20.0,22.1,22.6,23.5,24.7,26.1,26.8,27.6, 28.9, 29.2, 31.3 and 33.1 degree two-theta, ±0.2 two-theta, having an melting endotherm at 195°C -205°C and IR peaks at 3541, 3518, 3269, 3165, 3082, 3020, 2978, 2953, 2862, 2785, 2682, 2640, 2544, 2503, 2447, 2351, 2318, 2235, 2067, 1568, 1487, 1361, 1338, 1298, 1234, 1207, 1153, 1114, 1099, 1055, 1033,948,912,887,792,777,746,713,688, 594, 563 and 459cm "'

22. An improved process of racemizatioa of S-isomer for Albuterol and its conversion into
racemic Salbutamol Sulphate which comprises of a}' treating S-isomer of Albuterol with sulfuric acid in presence of suitable solvent;
b) isolating Salbutamol free base;
c) treating Salbutamol free base with sulfuric acid in presence of suitable solvent;
d) isolating Salbutamol Sulphate
23. A process as claimed in claim 22 wherein in step (a) said solvent is selected from
diisopropyl ether, diethyl ether, methyl tert-butyl ether, methyl acetate, ethylacatate and
mixtures thereof, preferably methyl tert-butyl ether.
24. A process as claimed in claim 22 wherein in step (c) said solvent is selected from acetone,
■ n-butanone^methanol, ethanol, propanol, isopropyl alcohol, butanol and mixtures thereof,
preferably mixture of methanol and acetone.
25. An improved process of preparing Levalbuterol Tartrate as claimed in claim 1, said
Levalbuterol Tartrate having purity greater than 99.5% and having chiral purity more
than 99.9%(ee).
26. An improved process of preparing Levalbuterol Tartrate as claimed in claim 1, said Levalbuterol Tartrate having aieast 90% of the particles of Levalbuterol Tatrate have a volume diameter less than 5 microns.
27. An improved process of preparing Levalbuterol Tartrate as claimed in claim 1, said Levalbuterol Tartrate having aieast 50%> of the particles of Levalbuterol Tatrate have a volume diameter less than 3.5 microns.
28. An improved process of preparing Levalbuterol Tartrate as herein described with
reference, to the foregoing examples and accompanying drawings.
Dated this the 20th day of April 2009
H.SUBRAMANIM of SUBRAMANIM NATARAJ & ASSOCIATES ATTORNEY FOR THE APPLICANTS