Claims:1. A process for preparation of salbutamol sulphate, which process comprises;
a) hydrogenating 2-(tert. Butyl amino)-1-(4-Benzyloxy-3-hydroxymethyl phenyl) ethanol in methanol in presence of Pd/C under 35-45 psi hydrogen pressure in a solvent at temperature of 30°- 50°C to obtain crude salbutamol base in filtrate;
b) converting the salbutamol base insitu obtained in step a) into salbutamol sulphate by treating with sulphuric acid under cold condition;
c) purifying the salbutamol sulphate obtained in step c) by treatment with ammonia gas and methanol to precipitate out insoluble salt followed by isolation of Salbutamol base;
d) treating the Salbutamol base thus obtained in step c) with methanol at a low temperature; and
e) reacting the Salbutamol base obtained in in step d) with sulphuric acid at 5°-10°C in a solvent by adjusting the pH between 4-5 to precipitate highly pure Salbutamol Sulphate with a purity of greater than 99%.
2. The process as claimed in claim 1, wherein, the hydrogenation is conducted at a temperature range of 35°- 40°C.
3. The process as claimed in claim 1 c), wherein, the process is a non-aqueous process.
4. The process as claimed in claim 1, wherein, the salbutamol sulphate thus obtained with a purity greater than 99% and with individual unknown impurity less than 0.1%.
, Description:Technical filed:
This invention relates to a simple process for preparation of salbutamol sulphate with greater purity & yield and with individual unknown impurity less than 0.1%.

Background and prior art:
Salbutamol, also referred to as a-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol or Albuterol or, is a ß-2 agonist useful as a bronchodilator. Salbutamol is a selective ß2-agonist bronchodilator which provides short acting bronchodilation in reversible airways obstruction. Salbutamol is used to rapidly treat asthma, bronchospasm and reversible airways obstruction by widening the airways of the lungs. It possesses a high degree of selectivity between ß-1 receptors (which are present in the heart) and ß-2 receptors (which are present in bronchial tissue and elsewhere), for which reason it is widely used in the treatment of asthma.

US5399765A discloses a method for producing albuterol by the resolution of a mixture of enantiomers of 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate using ditoluoyltartaric acid.

US7247750B2 describes a process for preparing levosalbutamol or a pharmacologically acceptable salt thereof from prochiral salbutamone, comprising subjecting the salbutamone to asymmetric hydrogenation in the presence of rhodium and a chiral bidentate phosphine ligand as catalyst system and in the presence of a solvent comprising a protic or aprotic solvent, to obtain levosalbutamol, and optionally converting the resulting levosalbutamol into a salt with an acid.

WO2008015689A1 describes a process for the preparation of optically pure R (-) salbutamol of formula (6) and its pharmaceutically acceptable salts by using a (+) 4-nitro tartranilic acid as the resolving agent and a binary solvent system comprising alkyl acetate and C1 to C4 branched or normal chain alcohol for dissolution of the racemic mixture and resolving agent and purification of the 4-nitro tartranilic acid salt of R (-) salbutamol. 4-nitro tartranilic acid salt of R (-) salbutamol is converted into formic acid salt of R(-) 4-benzyl salbutamol followed by basification and debenzylation to form optically pure R(-) salbutamol.

As is evident from above, the prior art fails to address the process impurities/related substances associated with the manufacture of salbutamol sulfate.

In Salbutamol Sulphate any individual unknown impurity should be less than 0.1% to meet the pharmacopeial grade.

There are several process impurities/related substances associated with the manufacture of salbutamol sulfate. Different process related impurities have been observed with various synthetic routes and/or manufacturing processes. Ten of the known salbutamol related substances have been mentioned in Europian Pharmacopoeia; however, all these impurities are never present together, as they are originated from different processes.

Moreover, while, the Europian Pharmacopoeia specifies that individual impurity is not more than 0.3% and total impurity is not more than 1.0%; the British Pharmacopoeia specifies that the related impurities which is determined by TLC, to be maximum of 0.5%. Further, the United States pharmacopoeia requires that the sum of the impurities in salbutamol sulphate should not be greater than 2.0%. However, all the impurities at the level of >0.1% must identify and be characterized to comply with regulatory authorities.

Therefore, it is important that any individual unknown impurity should be less than 0.1% to meet the requirement of pharmacopeial grade Salbutamol suphate.

In the light of there being no satisfactory process for preparation of salbutamol sulphate that addressed controlling process impurities/related substances associated with the manufacture of salbutamol sulfate, the objective of the present invention is to provide a process for preparation of salbutamol sulphate with high purity with individual unknown impurity content less than 0.1%.

Summary of the invention:
In line with the above objective, the present invention provides a process for preparation of salbutamol sulphate, which process comprises;
a) hydrogenating 2-(tert. Butyl amino)-1-(4-Benzyloxy-3-hydroxymethyl phenyl) ethanol in methanol in presence of Pd/C under 35-45 psi hydrogen pressure at temperature of 30°- 50°C to obtain crude salbutamol base in filtrate;
b) converting the salbutamol base insitu obtained in step a) into salbutamol sulphate by treating with sulphuric acid under cold condition;
c) purifying the salbutamol sulphate obtained in step b) by treatment with ammonia gas and methanol to precipitate out insoluble salt followed by isolation of Salbutamol base;
d) treating the Salbutamol base obtained in step c) with methanol at a low temperature; and
e) reacting the Salbutamol base obtained in step d) with sulphuric acid at 5°-10°C by adjusting the pH between 4-5 to precipitate highly pure salbutamol sulphate with a purity of greater than 99%.

Description of drawings:
Figure 1 depicts HPLC chromatogram of the salbutamol base isolated from methanol, as per example 1.
Figure 2 depicts HPLC chromatogram of the salbutamol base isolated from ethylacetate, as per example 2.
Figure 3 depicts HPLC chromatogram of the salbutamol sulphate prepared as per example 3.
Detailed description:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, the present invention provides a process for preparation of salbutamol sulphate, which process comprises;
a) hydrogenating 2-(tert. Butyl amino)-1-(4-Benzyloxy-3-hydroxymethyl phenyl) ethanol in methanol in presence of Pd/C under 35-45 psi hydrogen pressure at temperature of 30°- 50°C to obtain crude salbutamol base in filtrate ;
b) converting the salbutamol base insitu obtained in step a) into salbutamol sulphate by treating with sulphuric acid under cold condition;
c) purifying the salbutamol sulphate obtained in step c) by treatment with ammonia gas and methanol to precipitate out insoluble salt followed by isolation of Salbutamol base;
d) treating the Salbutamol base thus obtained in step c) with methanol at a low temperature; and
e) reacting the salbutamol base obtained in step d) with sulphuric acid at 5°-10°C by adjusting the pH between 4-5 to precipitate highly pure salbutamol sulphate with a purity of greater than 99%.

In an embodiment, 2-(tert Butyl amino)-1-(4-Benzyloxy-3-hydroxymethyl phenyl) ethanol i.e. Benzyl Salbutamol was charged in Methanol. Then charged 5% Palladium on carbon and maintained the reaction mixture under 35-45 psi hydrogen pressure at 35°- 40°C for 1-2 hrs. After the completion of reaction (monitored on TLC), the catalyst was filtered and washed with Methanol. Methanol was distilled out completely under vacuum from the combined filtrate and methanol washings to obtain a crude salbutamol. The salbutamol thus obtained was crystallized by charging Methanol to the crude and stirred for 30 min at 15°-20°C. Salbutamol base thus obtained was filtered and washed with chilled Methanol. Then the product was dried to obtain Salbutamol Base with a purity of greater than 99% and any impurity less than 0.1%.

In an alternate embodiment, the crude salbutamol was crystallised from most commonly used solvent, i.e., ethyl acetate, to assess the significance of ethylacetate role in crystallization of salbutamol with reasonable purity. Accordingly, in this embodiment, 2-(tert Butyl amino)-1-(4-Benzyloxy-3-hydroxymethyl phenyl) ethanol i.e. Benzyl Salbutamol was charged in Methanol. Then 5% Palladium on carbon was charged and maintained the reaction mixture under 35-45 psi hydrogen pressure at 35°- 40°C for 1-2 hrs. After the completion of the reaction, the catalyst was filtered and washed with Methanol. The filtrate and methanol washings were combined and Methanol was distilled out completely under vacuum to obtain crude salbutamol. To this crude, Ethylacetate was charged and stirred for 30 min at 15°-20°C. Salbutamol base thus obtained was filtered and washed with chilled Ethylacetate. Then the product was dried to obtain Salbutamol Base with a purity of less than 99% and any impurity more than 0.1%.
The above process specifically underlines the fact that use of methanol for debenzylation and for crystallization of salbutamol is required to keep the impurity levels less than 0.1%.

In yet another embodiment, the salbutamol free base thus obtained was treated with sulphuric acid in methanol to obtain crude salbutamol sulphate. It has been observed that unknown impurities are increased i.e., above 0.1% during the treatment of Salbutamol free base with sulphuric acid, which may be attributed to thermal shock at point of contact of salbutamol base with sulphuric acid.

In yet another embodiment, the salbutamol sulphate thus obtained was purified under non aqueous conditions by treating with ammonia gas and methanol to liberate salbutamol followed by treating the salbutamol with sulphuric acid. Accordingly, the crude Salbutamol Sulphate obtained in the previous embodiment was charged in Methanol, to this Ammonia gas was purged at 15°-20°C till to achieve the pH 9-10. Then the reaction mass was stirred for 30 min at 15°-20° and filtered the insoluble ammonium sulphate salt. Further, Methanol was distilled out from the filtrate to obtain crude salbutamol. To this, Methanol was charged and stirred for 30 min at 15°-20°C. Salbutamol free base thus obtained was filtered and washed with Methanol. The Salbutamol base thus obtained was dissolved in Methanol and Conc. Sulphuric Acid was added at 5°-10°C to adjust the pH in the range of 4-5. The reaction mass was further stirred for 30 min at 15°-20°C; the product thus obtained was filtered and washed with chilled Methanol. Then the product was dried to obtain pure Salbutamol Sulfate with a purity of greater than 99% and individual impurity less than 0.1%.

The inventive step of the present invention not only lies in the use of methanol as a preferred solvent throughout the process of the present invention viz., debenzylation of Benzyl Salbutamol; crystallization of salbutamol and preparation of salbutamol sulphate but also lies in the use of non-aqueous condition for liberating salbutamol and subsequent treatment with sulphuric acid to obtain salbutamol sulphate with greater purity with individual impurity less than 0.1%.
The present invention is exemplified by the following examples which are provided for illustration only and, should not be construed to limit the scope of the invention.

Examples:
Example-1: Preparation Salbutamol Base and crystallisation from Methanol
100 gm (0.3039 mol) of 2-(tert. Butyl amino)-1-(4-Benzyloxy-3-hydroxymethyl phenyl) ethanol i.e. Benzyl Salbutamol was charged in 850 ml Methanol. Then 2.8 gm of 5% Palladium on carbon was charged and maintained the reaction mixture under 35-45 psi hydrogen pressure at 35°- 40°C for 1-2 hrs. Completion of reaction was monitored on TLC; after the completion, the catalyst was filtered and washed with 50 ml Methanol. Filtrate and methanol washings were combined and Methanol was distilled out completely under vacuum to obtain residue. 100 ml Methanol was charged to this residue and stirred for 30 min at 15°-20°C. Salbutamol base thus obtained was filtered and washed with 50 ml chilled Methanol. Then the product was dried to get Salbutamol Base with a purity of greater than 99%.
Yield: 58gm

Reaction Scheme:

Benzyl Salbutamol Salbutamol Base

Example-2: Preparation Salbutamol Base and crystallisation from Ethylacetate
100 gm (0.3039 mol) of 2-(tert. Butyl amino)-1-(4-Benzyloxy-3-hydroxymethyl phenyl) ethanol i.e. Benzyl Salbutamol was charged in 850 ml Methanol. Then 2.8 gm of 5% Palladium on carbon was charged and maintained the reaction mixture under 35-45 psi hydrogen pressure at 35°- 40°C for 1-2 hrs. The catalyst was filtered and washed with 50 ml Methanol. The Filtrate and the methanol washings were combined and Methanol was distilled out completely under vacuum to obtain a residue. 200 ml Ethylacetate was charged to this residue and stirred for 30 min at 15°-20°C. Salbutamol base thus obtained was filtered and washed with 50 ml chilled Ethylacetate. Then the product was dried to obtain 65 to 70 gm of the Salbutamol Base with a purity of less than 99% and with individual unknown impurity more than 0.1%.
Yield: 68gms

Reaction Scheme:

Benzyl Salbutamol Salbutamol Base

Example -3: Preparation of salbutamol sulphate
100 gm (0.3039 mol) of 2-(tert. Butyl amino)-1-(4-Benzyloxy-3-hydroxymethyl phenyl) ethanol i.e. Benzyl Salbutamol was charged in 850 ml Methanol. Then 2.8 gm of 5% Palladium on carbon was charged and maintained the reaction mixture under 35-45 psi hydrogen pressure at 35°- 40°C for 1-2 hrs. Completion of reaction was monitored on TLC; after the completion, the catalyst was filtered and washed with 50 ml Methanol. Filtrate and methanol washings were combined and 10 ml (0.188 mol) of Sulphuric Acid was added at 5°-10°C to adjust the pH between 4-5. The reaction mass was stirred for 30 min at 15°-20°C. The product thus obtained was filtered and washed with 100 ml chilled Methanol. Then the product was dried to obtain 65 to 71 gm of the Salbutamol Sulphate.
Yield: 68 gm

Reaction Scheme:

Benzyl Salbutamol Salbutamol Sulphate

Example-4: Purification of Salbutamol Sulphate
100 gm (0.347 mol) of impure Salbutamol Sulfate was charged in 1000 ml Methanol, to this Ammonia gas was purged at 15°-20°C to get pH 9-10. The reaction mass was stirred for 30 min at 15°-20°C and filtered the insoluble salt. Methanol was distilled out from the filtrate under vacuum to obtain residue. 100 ml Methanol was charged to this residue and stirred for 30 min at lower temperature of about 10°C. Salbutamol base thus obtained was filtered and washed with 10 ml chilled Methanol. The Salbutamol base obtained was dissolved in 1000 ml Methanol and 10 ml (0.188 mol) of Conc. Sulphuric Acid was added at 5°-10°C to adjust the pH between 4-5. The reaction mass was stirred for 30 min at 15°-20°C. The product thus obtained was filtered and washed with 100 ml chilled Methanol. Then the product was dried to obtain pure Salbutamol Sulphate with a purity of greater than 99% and with individual unknown impurity less than 0.1%.
Yield: 75gms

Salbutamol Sulphate