# Patent

## Title
Crystalline levosalbutamol sulphate and polymorphic forms thereof

## Abstract

The invention provides three polymorphic forms of crystalline levosalbutamol sulphate designated herein as Forms I, II and III.
Crystalline levosalbutamol sulphate Form I is characterised by a powder XRD pattern with peaks at 10.8, 11.9, 13.0, 18.3, 28.5±0.2 degrees 2 theta.
Crystalline levosalbutamol sulphate Form II is characterised by a powder XRD pattern with peaks at 8.7, 9.6, 15.2, 15.7, 19.1, 27.2, 30.7±0.2 degrees 2 theta.
Crystalline levosalbutamol sulphate Form III is characterised by a powder XRD pattern with peaks at 5.5, 6.9, 7.3, 18.7±0.2 degrees 2 theta.
Processes for making the new polymorphic forms and pharmaceutical compositions comprising them are also provided.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to Indian Patent Application Serial No. 1356/MUM/2004, filed Dec. 17, 2004, and Indian Patent Application Serial No. 40/MUM/2005 entitled, CRYSTALLINE LEVOSALBUTAMOL SULPHATE AND POLYMORPHIC FORMS THEREOF, the disclosures of which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to crystalline levosalbutamol sulphate, polymorphs thereof, processes for making the crystalline material, and compositions thereof.
BACKGROUND OF THE INVENTION
Salbutamol (albuterol) is an antihistaminic compound and is a beta 2-adrenoceptor agonist used as a bronchodilator for the treatment of asthma and as a uterine relaxant for the suspension of premature labour. Salbutamol has been marketed as a racemic mixture, although the beta 2-agonist activity resides almost exclusively in the (R)-enantiomer. The enantioselective disposition of salbutamol and the possibility that (S)-salbutamol has adverse effects have led to the development of an enantiomerically pure (R)-salbutamol formulation known as levosalbutamol (levalbuterol) (Formula I).




A process for the preparation of optically pure salbutamol from mono protected salbutamol precursor is disclosed in U.S. Pat. No. 5,545,745.
US2004114136 and WO2004052835 describe a process for preparing levalbuterol L-tartrate in crystalline form; a pharmaceutical composition comprising levalbuterol L-tartrate, in crystalline form; a metered dose inhaler comprising a canister containing an aerosol formulation of levalbuterol L-tartrate in crystalline form; and a method of affecting bronchodilation in a patient using levalbuterol L-tartrate, including levalbuterol L-tartrate specifically in crystalline form.
Levosalbutamol is prepared by hydrogenating R-benzyl salbutamol in the presence of palladium on carbon.
R-benzyl salbutamol can be prepared by the process described in U.S. Pat. No. 5,545,745.
SUMMARY OF THE INVENTION
The object of the present invention is to provide novel and stable polymorphic forms of levosalbutamol sulphate named herewith as Form I, Form II and Form III.
Another object of the present invention is to provide processes for the preparation of these novel polymorphs of levosalbutamol sulphate.
The invention further provides processes for the inter-conversion of these forms.
There is also provided crystalline levosalbutamol sulphate (Form I) characterised by a powder XRD pattern with peaks at 10.8, 11.9, 13.0, 18.3, 28.5±0.2 degrees 2 theta.
In another aspect, there is provided crystalline levosalbutamol sulphate (Form II) characterised by a powder XRD pattern with peaks at 8.7, 9.6, 15.2, 15.7, 19.1, 27.2, 30.7±0.2 degrees 2 theta.
In a further aspect, there is also provided crystalline levosalbutamol sulphate (Form III) characterised by a powder XRD pattern with peaks at 5.5, 6.9, 7.3, 18.7±0.2 degrees 2 theta.
The invention also provides various processes for making the novel polymorphs.
In one aspect, the invention provides a process for preparing crystalline levosalbutamol sulphate Form I, which process comprises a) preparing levosalbutamol in an organic solvent b) adjusting the pH by addition of sulphuric acid at from 1 to 10° C. c) isolating the product (Form I) at from 0 to 10° C.
There is also provided a process for preparing crystalline levosalbutamol sulphate Form I, which process comprises a) dissolving any form of levosalbutamol sulphate in water b) combining the solution from step a) with a water miscible organic solvent so as to cause precipitation c) isolating Form I thereon.
The invention also provides a process for preparing crystalline levosalbutamol sulphate Form II, which process comprises a) dissolving any form of levosalbutamol sulphate in water b) distilling to residue c) stripping the residue with an organic solvent d) slurrying the solid in an organic solvent e) isolating crystalline Form II.
A further process for preparing Form II comprises jet milling any other form of levosalbutamol sulphate, for example jet milling crystalline Form I.
In another aspect, there is provided a process for preparing crystalline levosalbutamol sulphate Form III, which process comprises a) preparing levosalbutamol in an organic solvent b) adjusting the pH by addition of sulphuric acid at 25 to 30° C. c) isolating the product (Form III) at 25 to 30° C.
In a further aspect, the invention provides a process for preparing Form III which process comprises a) dissolving any form of levosalbutamol sulphate in water b) combining the solution from step a) with a water-miscible organic solvent so as to cause precipitation c) isolating Form III therefrom at ambient temperature (25 to 30° C.).
The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.



BRIEF DESCRIPTION OF THE DRAWINGS
The novel compounds, and compositions thereof, are also provided for use as medicaments, particularly in the treatment of respiratory disorders and related conditions.
FIG. 1 shows the X-ray powder diffraction pattern of levosalbutamol sulphate Form I.
FIG. 2 shows an IR spectrum of levosalbutamol sulphate Form I.
FIG. 3 shows the X-ray powder diffraction pattern of levosalbutamol sulphate Form II.
FIG. 4 shows an IR spectrum of levosalbutamol sulphate Form II.
FIG. 5 shows the X-ray powder diffraction pattern of levosalbutamol sulphate Form III.
FIG. 6 shows an IR spectrum of levosalbutamol sulphate Form III.



Table 1 gives the numerical XRD data for FIG. 1 (Form I).
Table 2 gives the numerical XRD data for FIG. 3 (Form II).
Table 3 gives the numerical XRD data for FIG. 5 (Form III).
The present invention provides a novel crystalline form of levosalbutamol sulphate which is designated as Form I. Levosalbutamol sulphate crystalline Form I is characterized by an X-ray powder diffraction pattern having significant reflections expressed as 2 theta values at about 10.781, 11.941, 13.002, 18.341, 28.541±0.2 degrees, as will be clear from Table 1.
The X-ray powder diffractogram of levosalbutamol sulphate crystalline Form I is shown in FIG. 1. The major peaks and their intensities of X-ray powder diffractogram are shown in Table 1. The intensities of the reflections are also expressed as percent of most intense reflection.
Other preferred significant reflections for Form I expressed as 2 theta values include 12.66, 15.819, 17.4, 20.939, 21.72, 22.5, 23.14, 24.341, 26.12, 31.28, 31.93±0.2 degrees. The X-ray powder diffractograms for all the polymorphic Forms disclosed herein were collected on Rigaku d-max 2200 model X-ray diffractometer using Cu K α radiation (λ=1.5405 A°).
Levosalbutamol sulphate crystalline Form I is also characterised by an IR spectrum with peaks at 3568, 3307, 2980, 2799, 2561, 2458, 1615, 1508, 1440, 1380, 1342, 1258, 1200, 1112, 1082, 1029, 976, 915, 836, 793, 775, 752, 648, 617, 535, 497, 453 cm−1.
FIG. 2 shows the IR spectrum for Form I. The IR spectra for all the polymorphic Forms disclosed herein were collected using the Spectrum-1 make of Perkin Elmer Sample and analysed as KBr pellets in the region of 4000-400 cm−1.
In the preparation of levosalbutamol sulphate crystalline Form I, preferably R-benzyl salbutamol is hydrogenated using a catalyst, preferably a palladium on carbon catalyst, in a large volume of a suitable organic solvent. Preferably an alcoholic solvent is used, more preferably ethyl alcohol. Suitably the process is performed under hydrogen pressure, preferably at 30 psi. The catalyst is preferably then filtered and the pH of the filtrate is adjusted, preferably to 5-5.5 and preferably at 0-10° C. with sulfuric acid, suitably concentrated sulphuric acid, to provide crystals, which are filtered and dried to afford levosalbutamol sulphate Form I. The product (Form I) may be obtained by isolating at 0-10° C.
The present invention also provides another novel crystalline form of levosalbutamol sulphate, which is designated as Form II. Levosalbutamol sulphate crystalline Form II is characterized by an X-ray powder diffraction pattern having significant reflections expressed as 2 theta values at about 8.701, 9.636, 15.180, 15.657, 19.139, 27.199, 30.702±0.2 degrees, as will be clear from Table 2.
The X-ray powder diffractogram of levosalbutamol sulphate Form II is shown in FIG. 3. The major peaks and their intensities of X-ray powder diffractogram are shown in Table 2. The intensities of the peaks are expressed as percent of most intense reflection.
Other preferred significant reflections for Form II expressed as 2 theta values include peaks at about 8.701, 9.636, 15.180, 18.657, 17.44, 19.139, 21.699, 22.201, 22.837, 23.339, 23.76, 24.361, 25.022, 25.399, 26.059, 26.321, 27.199, 30.702±0.2 degrees.
Levosalbutamol sulphate crystalline Form II is also characterised by an IR spectrum with peaks at 3393, 3026, 2982, 2822, 2463, 1630, 1614, 1513, 1484, 1448, 1380, 1321, 1279, 1258, 1235, 1204, 1155, 1093, 1066, 1036, 1023, 919, 900, 838, 829, 818, 808, 788, 618, 596, 540, 493, 453, 440 cm−1.
FIG. 4 shows the IR spectrum for Form II.
A further aspect of the present invention provides a process for the preparation of levosalbutamol sulphate crystalline Form II. The process comprises dissolving any form of levosalbutamol sulphate in water and distilling it to residue. The residue is further stripped with an organic solvent, which is preferably water miscible and is preferably acetone, and the solid further slurried in a solvent, preferably the same solvent, and isolating the solid, preferably by filtering the solid and drying under vacuum to give levosalbutamol sulphate Form II.
The present invention also provides another novel crystalline form of levosalbutamol sulphate, which is designated as Form III. Levosalbutamol sulphate crystalline Form III is characterized by an X-ray powder diffraction pattern having significant reflections expressed as 2 theta values at about 5.496, 6.901, 7.340, 18.660±0.2 degrees, as will be clear from Table 3.
The X-ray powder diffractogram of levosalbutamol sulphate Form III is shown in FIG. 5. The major peaks and their intensities of X-ray powder diffractogram are shown in Table 3. The intensities of the peaks are also expressed as a percent of the most intense reflection.
Other preferred significant reflections for Form III expressed as 2 theta values include peaks at about 5.496, 6.901, 7.340, 8.18, 8.399, 10.978, 11.758, 14.298, 16.321, 17.98, 18.18, 18.660, 18.86, 19.189, 20.179, 20.72, 20.019, 22.219, 23.121, 23.64, 23.858, 24.638, 25.339, 27.62, 28.79, 29.319, 30.80, 32.341, 33.218, 33.781, 34.181±0.2 degrees.
Levosalbutamol sulphate crystalline Form III is also characterised by an IR spectrum with peaks at 3533, 3412, 3086, 2979, 2823, 2799, 1613, 1547, 1505, 1437, 1397, 1380, 1365, 1353, 1303, 1256, 1243, 1198, 1110, 1133, 1086, 1075, 1055, 1029, 990, 949, 919, 838, 792, 737, 723, 640, 618, 563, 536, 480, 442, 425 cm−1.
FIG. 6 shows the IR spectrum for Form III.
A further aspect of the present invention provides a process for the preparation of levosalbutamol sulphate crystalline Form III. Preferably R-benzyl salbutamol is hydrogenated using a catalyst, preferably a palladium on carbon catalyst in a suitable organic solvent, preferably an alcoholic solvent, more preferably ethyl alcohol. Preferably this is done under hydrogen pressure, preferably at about 30 psi. Form III can be isolated by adjusting the pH by addition of sulphuric acid at ambient temperature (25 to 30° C.) and isolating the product at ambient temperature (25 to 30° C.). Preferably, these steps are done by filtering the catalyst and washing, for example with denatured alcohol. The pH of the filtrate is preferably adjusted to 5-5.5 at ambient temperature (25 to 30° C.) with sulfuric acid, preferably in concentrated form, to give crystals, which are filtered and dried to afford levosalbutamol sulphate Form III. The product (Form III) may be obtained by isolating at 25 to 30° C.
A further aspect of the present invention provides a process for the preparation of levosalbutamol sulphate crystalline Form II by jet milling levosalbutamol sulphate. For example, crystalline levosalbutamol Form I may be jet milled so as to give Form II.
It will be understood that crystalline levosalbutamol sulphate and the polymorphic Forms thereof disclosed herein may be formulated with conventional excipients, auxiliaries and carriers into a wide variety of pharmaceutical compositions, including but not limited to tablets, capsules, pellets, caplets, MDI, DPI, and Respule formulations, and oral liquids such as syrups. Where appropriate plain or sustained release formulations may be provided. Those skilled in the art of pharmaceutical formulation will be aware of the conventional ingredients which may be employed to formulate the above compositions. Such formulations may be made in accordance with conventional manufacturing procedures.
In particular, the compounds of the present invention may be combined with one or more other pharmaceutically active compounds, as will be clear to those skilled in the art. Any suitable combination of active materials is envisaged, provided the combination is acceptable from a pharmaceutical and regulatory standpoint. The compounds of the invention may, for example be combined with corticosteroids such as fluticasone, beclomethasone or budesonide; anticholinergic agents such as ipratropium, tiotropium or atropine; mucolytic agents such as ambroxol; xanthine derivatives such as theophylline; antihistamines; analgesics, and bronchodilators. As will be clear, the additional active or actives may be provided in any suitable form, including the pharmaceutically acceptable derivatives thereof, including salts, esters, polymorphs, and the optically active forms as well as the racemates.
The invention thus provides a pharmaceutical composition comprising crystalline levosalbutamol sulphate, particularly Form I or Form II or Form III thereof, in combination with one or more pharmaceutically active compounds and, optionally, a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
The following specific examples illustrate the best mode of carrying out the process of the present invention. The invention is not limited to the particular embodiments illustrated herein but includes permutations, which are obvious as set forth in the description.
EXAMPLES
Example 1
R-benzyl salbutamol (20.0 kg.), methanol ( 61.0 ltr.), denatured alcohol (72 ltrs.) was charged in an autoclave, palladium (5%) on charcoal (1.30 kg) was charged and stirred under 30 psi hydrogen pressure. After completion of reaction the catalyst was filtered and washed with methanol (60 lts.) and denatured alcohol (60 ltrs.). The pH of the clear filtrate was adjusted with sulphuric acid to 5-5.5 pH at 0-10° C. and the resulting solid was stirred at 0-10° C. for 1 hr., filtered and washed with methanol (20 ltrs.). The product was dried under vacuum at 30° C. for 1 hr. and further at 50-60° C. for additional 1 hr. to give R-salbutamol Form I ( 19.0 kg.).
Example 2
R-benzyl salbutamol (10.0 kg.), methanol ( 30.0 ltr.), denatured alcohol (36 ltrs.) was charged in an autoclave, wet palladium (5%) on charcoal (0.65 kg) was charged and stirred under 30 psi hydrogen pressure. After completion of reaction the catalyst was filtered and washed with denatured alcohol (25 ltrs.). The pH of the clear filtrate was adjusted with sulphuric acid to 5-5.5 pH at ambient temperature (25 to 30° C.) and the resulting solid was filtered and washed with methanol (10 ltrs.) at 25 to 30° C. The product was dried under vacuum at 50-60° C. temp to give R-salbutamol sulphate Form III ( 19.0 kg.).
Example 3
R-salbutamol sulphate (14.80 Kg) was dissolved in water (60.0 ltrs.) and filtered to get a clear solution. The filtrate was distilled under vacuum below 60° C. to residue. The residue was stripped with acetone (74.0 ltrs.) twice, further acetone (148.0 lts.) was added and the resulting slurry was stirred for 2 hrs. The slurry was filtered and dried under vacuum at 60° C. for 10-12 hrs to give R-salbutamol sulphate Form II (11.1 kg.)
Example 4
R-salbutamol sulphate (10 Kg) was dissolved in water (30.0 ltrs.) and stirred for 10-15 min. The resulting clear solution was filtered. Methanol (150 ltrs.) was added slowly to the clear filtrate at room temperature and stirred for 30 mins. and further chilled to 0-5° C. The resulting solid was filtered and washed with methanol. The product was dried under vacuum at 60° C. for 3-4 hrs to give R-salbutamol sulphate Form I (8 kg.)
Example 5
R-salbutamol sulphate (20 Kg) was dissolved in water (60.0 ltrs.) and filtered to get a clear solution, charge 300 ltr acetone slowly at 25-30° C. and the resulting mixture was stirred for 2 hrs at room temp. The resulting slurry was filtered and dried under vacuum at 80° C. for 10-12 hrs to give R-salbutamol sulphate Form III (17 kg.)
Example 6
R-salbutamol sulphate (10 gms) was dissolved in water (30 ml). Methanol (150 ml) was charged at 25-30° C. and Isopropyl alcohol (75ml) was added and the mixture was cooled to 5-10° C. for 2 hrs. filtered and dried at 80° C. under vacuum for 15-20 hrs. to give Form II.
Example 7
R-salbutamol sulphate was dissolved in methanol at reflux temperature. The reaction mass was then cooled to room temperature and further chilled to 5-10° C. The resulting solid was filtered and dried at 80° C. to give R-salbutamol sulphate Form II
Example 8
R-salbutamol sulphate Form I was subjected to jet milling to get R-salbutamol sulphate Form II having a particle size of 90% less than 5 micron and 100% below 12.5 micron.
Note that in Examples 3 to 7 any form of R-salbutamol sulphate may be used as the stating material.







TABLE 1







LEVOSALBUTAMOL S04 - Form I












Peak No.
2θ (deg)
d (A)
Height
Height %
FWHM















1
10.781
8.1998
10389
59.5
0.237


2
11.941
7.4053
2043
11.7
0.237


3
12.660
6.9865
1090
6.2
0.232


4
13.005
6.8036
1080
6.2
0.167


5
15.819
5.5975
1576
9.0
0.266


6
17.400
5.0924
2170
12.4
0.236


7
18.341
4.8332
2847
16.3
0.268


8
19.019
4.6624
621
3.6
0.271


9
20.939
4.2390
2564
14.7
0.265


10
21.720
4.0883
3195
18.3
0.282


11
22.500
3.9482
2001
11.5
0.202


12
23.140
3.8406
17446
100.0
0.234


13
24.341
3.6537
1870
10.7
0.243


14
26.120
3.4087
1108
6.4
0.285


15
28.541
3.1249
1379
7.9
0.281


16
31.280
2.8572
914
5.2
0.378


17
31.939
2.7997
955
5.5
0.451


18
33.980
2.6361
686
3.9
0.361


19
34.279
2.6138
419
2.4
0.350


20
35.739
2.51036
712
4.1
0.329


21
36.340
2.4702
635
3.6
0.391
















TABLE 2







LEVOSALBUTAMOL S04 - Form II












Peak No.
2θ (deg)
d (A)
Height
Height %
FWHM















1
8.701
10.1542
8249
100.0
0.205


2
9.636
9.1706
2610
31.6
0.195


3
13.422
6.5914
365
4.4
0.184


4
15.180
5.8318
6090
73.8
0.213


5
15.657
5.6550
2247
27.2
0.201


6
17.440
5.0809
2091
25.3
0.193


7
19.139
4.6335
1416
17.2
0.272


8
19.360
4.5811
900
10.9
0.385


9
19.583
4.5294
666
8.1
0.376


10
20.221
4.3879
462
5.6
0.156


11
21.439
4.1413
7819
94.8
0.256


12
21.699
4.0921
3525
42.7
0.356


13
22.201
4.0008
2317
28.1
0.128


14
22.837
3.8907
1299
15.7
0.091


15
23.339
3.8083
4096
49.7
0.308


16
23.760
3.7417
2345
28.4
0.236


17
24.361
3.6508
1107
13.4
0.165


18
25.022
3.5558
829
10.0
0.080


19
25.399
3.5038
1127
13.7
0.176


20
26.059
3.4166
1162
14.1
0.271


21
26.321
3.3832
1437
17.4
0.256


22
27.199
3.2759
2718
32.9
0.255


23
28.740
3.1037
622
7.5
0.193


24
29.263
3.0493
356
4.3
0.628


25
30.077
2.9687
721
8.7
0.162


26
30.702
2.9097
1586
19.2
0.211


27
31.640
2.8255
631
7.6
0.351


28
32.001
2.7944
700
8.5
0.464


29
32.319
2.7677
680
8.2
0.354


30
33.859
2.6452
368
4.5
0.382


31
34.242
2.6165
730
8.8
0.315


32
35.002
2.5615
424
5.1
0.244


33
35.299
2.5406
316
3.8
0.542


34
35.838
2.5036
376
4.6
0.239


35
36.238
2.4769
427
5.2
0.232


36
36.737
2.443
254
3.1
0.313


37
37.999
2.3660
297
3.6
0.245


38
38.265
2.3502
319
3.9
0.658


39
38.777
2.3203
491
6.0
0.380
















TABLE 3







LEVOSALBUTAMOL S04 - Form III












Peak No.
2θ (deg)
d (A)
Height
Height %
FWHM















1
5.496
16.0657
2337
41.8
0.206


2
6.901
12.799
320
5.7
0.295


3
7.340
12.034
1938
34.6
0.217


4
8.181
10.7983
2348
42.0
0.645


5
8.399
10.5187
5559
99.4
0.251


6
10.978
8.0527
577
10.3
0.190


7
11.758
7.5203
978
17.5
0.178


8
12.778
6.9221
365
6.5
0.186


9
14.298
6.1895
565
10.1
0.233


10
14.701
6.0206
428
7.7
0.165


11
16.321
5.4266
4839
86.5
0.292


12
16.981
5.2172
498
8.9
0.134


13
17.980
4.9293
1110
19.8
0.319


14
18.180
4.8758
1421
25.4
0.532


15
18.660
4.7512
4455
79.6
0.432


16
18.860
4.7013
3247
58.0
0.243


17
19.189
4.6215
636
11.4
0.100


18
20.179
4.3969
797
14.2
0.529


19
20.720
4.2833
2355
42.1
0.315


20
22.019
4.0335
5594
100.0
0.306


21
22.219
3.9976
2598
46.4
0.595


22
23.121
3.8436
761
13.6
0.563


23
23.640
3.7604
2729
48.8
0.460


24
23.858
3.7265
2189
39.1
0.547


25
24.638
3.6103
654
11.7
0.168


26
25.339
3.5120
1235
22.1
0.276


27
25.721
3.4607
445
8.0
0.215


28
26.299
3.3859
414
7.4
0.352


29
26.518
3.3585
550
9.8
0.354


30
26.879
3.3142
493
8.8
0.249


31
27.620
3.2270
1316
23.5
0.274


32
28.799
3.0974
719
12.9
0.655


33
29.319
3.0437
827
14.8
0.654


34
30.800
2.9006
565
10.1
0.319


35
31.242
2.8606
430
7.7
0.207


36
32.341
2.7659
867
15.5
0.232


37
33.218
2.6948
719
12.9
0.313


38
33.781
2.6512
565
10.1
0.245


39
34.181
2.6211
1029
18.4
0.267


40
36.646
2.4502
325
5.8
0.557


41
37.140
2.4187
376
6.7
0.252


42
37.522
2.3950
478
8.5
0.306


43
39.397
2.2852
356
6.4
0.427

## Claims

1. Crystalline levosalbutamol sulphate (Form I) characterised by a powder XRD pattern with peaks at 10.8, 11.9, 13.0, 18.3, 28.5±0.2 degrees 2 theta.

2. The Crystalline levosalbutamol sulphate according to claim 1 characterised by a powder XRD pattern as shown in FIG. 1.

3. The Crystalline levosalbutamol sulphate according to claim 1 further characterised by having an IR spectrum as shown in FIG. 2.

4. The Crystalline levosalbutamol sulphate according to claim 1 characterised by a powder XRD pattern with peaks as shown in Table 1.

5. A Crystalline levosalbutamol sulphate (Form II) characterised by a powder XRD pattern with peaks at 8.7, 9.6, 15.2, 15.7, 19.1, 27.2, 30.7±0.2 degrees 2 theta.

6. The Crystalline levosalbutamol sulphate according to claim 5 characterised by a powder XRD pattern as shown in FIG. 3.

7. The Crystalline levosalbutamol sulphate according to claim 5 further characterised by having an IR spectrum as shown in FIG. 4.

8. The Crystalline levosalbutamol sulphate according to claim 5 characterised by a powder XRD pattern with peaks as shown in Table 2.

9. Crystalline levosalbutamol sulphate (Form III) characterised by a powder XRD pattern with peaks at 5.5, 6.9, 7.3, 18.7±0.2 degrees 2 theta.

10. The Crystalline levosalbutamol sulphate according to claim 9 as shown in FIG. 5.

11. The Crystalline levosalbutamol sulphate according to claim 9 further characterised by having an IR spectrum, as shown in FIG. 6.

12. The Crystalline levosalbutamol sulphate according to claim 9 characterised by a powder XRD pattern with peaks as shown in Table 3.