Description:BACKGROUND OF THE INVENTION
Busulfan (trade name MYLERAN) chemically known as 1, 4-butanediol dimethane sulfonate is a bifunctional alkylating agent which was first described by Haddow and Timmis (1953). Busulfan has the following chemical structure:

Busulfan is used for the treatment of Chronic Myeloid Leukemia (although it has been largely replaced by newer drugs). It has a role as an insect sterilant, an antineoplastic agent, a teratogenic agent, a carcinogenic agent and an alkylating agent.
Timmis Geoffrey et al. in GB700677A discloses a process for production of Busulfan by reacting butane-1,4-diol with methanesulfonyl chloride in pyridine.

Scheme 1: Process as per GB700677A
The formation of thick precipitate pyridine hydrochloride because of the use of pyridine as solvent makes the process unviable for industrial scale.
Chen Jiange et al. in CN102408363B discloses the process for the preparation of Busulfan by reacting butane-1,4-diol with methanesulfonic anhydride under nitrogen in presence of a base selected from triethylamine, pyridine, diethylisopropylamine or sodium bicarbonate and solvent selected from acetone, tetrahydrofuran, acetonitrile or ether.

Scheme 2: Process as per CN102408363B
The use of methanesulfonic anhydride makes the process less feasible at bulk scale as anhydrides are moisture sensitive and also affected the yield.
Liao Runai et al. in CN105566173A discloses the preparation method of Busulfan by reacting butane-1,4-diol with methane sulfonamide in presence of triethylamine.

Scheme 3: Process as per CN105566173A
The reaction complies in lesser time than the previously known processes but the maximum yield achieved by this process is about 91% which is very less.
Lee Daniel Arnold et al. in WO2015081284A1 discloses the preparation method of Butane-1,4-diyl dimethane sulfonate by reacting butane-1,4-diol with methane sulfonyl chloride in anhydrous DCM and triethylamine base.

Scheme 4: Process as per WO2015081284A1
The process involves the purification of crude by column chromatography which is not applicable at industrial scale and also results in low yield of about 73-74%.
Beatrix Merla et al. in US8178535B2 discloses the process for the preparation of Busulfan used as an intermediate.

Scheme 5: Process as per US8178535B2
The process involves the Busulfan as an intermediate for the preparation of final product i.e. tert - butyl 6- (2- (pyrrolidin-1-yl) ethyl) - 3, 4-dihydropyrrolo [1, 2-a] pyrazine-2(1H)-carboxylate.
In the available literature there is no stable polymorph of Busulfan is reported therefore the present inventors have now developed a Crystalline Busulfan Form - SBU, which is a thermodynamically stable novel polymorph.
Specific polymorphic Form - SBU of Busulfan in the present invention provides advantage in stability and in the drug product manufacturing process.
SUMMARY OF THE INVENTION
Particular aspects of the present invention relates to a process for the preparation of Crystalline Busulfan (I) designated as Form - SBU.
Different aspects of the present application are summarized herein below individually.
In one aspect of the present application, the present invention relates to a process for preparation of Crystalline Busulfan (I) designated as Form - SBU

characterised by X-ray powder diffraction pattern comprising the characteristic diffraction angle peaks at 12.48, 14.18, 15.24, 16.21, 18.79, 21.02, 22.06, 24.13, 25.17, 26.90, 30.84, 33.23 ± 0.2 2?º, IR absorption spectrum having characteristic peaks at 3033, 3020 , 2949 , 2983 , 2965 , 2502 , 2336 , 1649 , 1415 , 1350 , 1320 , 1174 ± 5cm-1, DSC isotherm comprising an endothermic peak ranging between 116 to 122ºC,
comprising the steps of:
a) dissolving the crude or pure Busulfan in a ketone organic solvent;
b) raise the temperature of the reaction mixture upto about 40 to 50ºC;
c) maintaining the temperature for one hour under stirring;
d) charge activated charcoal into the reaction mixture and filter simultaneously;
e) cooling the mixture up to about 0-5ºC and
f) obtaining crystalline Form - SBU of Busulfan.
In another aspect according to the present invention, Thermodynamically stable Crystalline Busulfan (I) Form - SBU is characterised by
i). X-ray powder diffraction pattern comprising the characteristic 2?º peaks of 12.48, 14.18, 15.24, 16.21, 18.79, 21.02, 22.06, 24.13, 25.17, 26.90, 30.84, 33.23 ± 0.2 2?º;
ii). DSC isotherm comprising an endothermic peak ranging between 116 to 122ºC and
iii). IR absorption spectrum having absorption peaks at 3033, 3020, 2949, 2983 ,2965 , 2502 , 2336 , 1649 , 1415 , 1350 , 1320 , 1174 ± 5cm-1.
Further specific aspects of the invention are detailed in the description part of the specification, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: is an illustration of X-ray powder diffraction (XRPD) pattern of Crystalline Busulfan Form - SBU obtained according to the present invention.
FIG. 2: is an illustration of X-ray powder diffraction (XRPD) pattern of Crystalline Busulfan Form - SBU obtained after 24 months stability according to the present invention.
FIG. 3: is an illustration of a differential scanning calorimetric (“DSC”) curve of Crystalline Busulfan Form - SBU obtained according to the present invention.
FIG. 4: is an illustration of an Infrared Spectrometry (“IR”) of Crystalline Busulfan Form - SBU obtained according to the present invention.
FIG. 5: is an illustration of a High performance Liquid Chromatography (“HPLC”) of Crystalline Busulfan Form - SBU obtained according to the present invention.

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention relate to a process for preparation of Crystalline Busulfan (I) Form - SBU. The present invention deals with a simple and industrially amenable process for making the compound of formula (I), which exhibits various advantages over other processes known in the state of arts. The advantages are discussed on the relevant places of further description. Individual embodiments of the present invention are detailed herein below separately.
In one embodiment according to the present application, it provides a process for preparing of Crystalline Busulfan (I) Form - SBU

characterised by X-ray powder diffraction pattern comprising the characteristic diffraction angle peaks at 12.48, 14.18, 15.24, 16.21, 18.79, 21.02, 22.06, 24.13, 25.17, 26.90, 30.84, 33.23 ± 0.2 2?º, IR absorption spectrum having characteristic peaks at 3033, 3020 , 2949 , 2983 , 2965 , 2502 , 2336 , 1649 , 1415 , 1350 , 1320 , 1174 ± 5cm-1, DSC isotherm comprising an endothermic peak ranging between 116 to 122ºC,
comprising the steps of:
a) dissolving the crude or pure Busulfan in a ketone organic solvent;
b) raise the temperature of the reaction mixture upto about 40 to 50ºC;
c) maintaining the temperature for one hour under stirring;
d) charge activated charcoal into the reaction mixture and filter simultaneously;
e) cooling the mixture up to about 0-5ºC and
f) obtaining crystalline Form - SBU of Busulfan.
Individual steps of the embodiment are detailed herein below.
The organic solvent used in step a) for dissolving the crude or pure Busulfan is selected from is a ketone organic solvent selected from acetone, butanone, 1-methyl isobutyl ketone or a mixture thereof and in more preferably it is acetone.
The crude Busulfan used in step a) may be anhydrous or in hydrated form or mixture thereof.
In a particular embodiment, the ratio of organic solvent used for the process for preparation of crystalline Busulfan (I) Form- SBU w.r.t. Busulfan is ranging between 25- 45 : 1 (V/w). Further mixing of the organic solvent in crude or pure Busulfan is at an ambient temperature.
Raise the temperature of the reaction mixture in step b) for a process for preparing of Crystalline Busulfan (I) Form - SBU from ambient temperature to 40-50°C under stirring and more preferably the temperature is maintained in between 45 to 50°C under stirring for the duration of an hour.
In step d) charge the activated charcoal into the reaction mixture for the preparation of crystalline Busulfan (I) Form - SBU wherein the amount of the activated carbon w.r.t Busulfan is ranging between 5-15% (w/w).
Stir the resulting reaction mass for an hour at a temperature ranging between 45 to 50°C.
After completion of stirring (~ one hour) filter the hot reaction mixture through hyflo bed and performed washing 2 to 3 times with acetone and more preferably it is of two times. Distilled the solvent under vacuum at below 50°C.
In step e) obtained the residual reaction mixture after distillation and cooled it under stirring at the temperature ranging between 0-5°C and maintained this temperature for two hours.
In step f) for obtaining the crystalline Form-SBU of Busulfan filter the cooled reaction mixture and washed with chilled acetone (2 to 3 times).

Any crude Busulfan anhydrous or its hydrate or mixture thereof may be purified by the process of the present invention, which can provide pure crystalline Busulfan Form-SBU.
In a further embodiment of the present application, Thermodynamically stable Crystalline Busulfan (I) Form - SBU is characterised by
i). X-ray powder diffraction pattern comprising of at least seven 2?° peaks selected from the XRPD peak set of 12.48, 14.18, 15.24, 16.21, 18.79, 21.02, 22.06, 24.13, 25.17, 26.90, 30.84, 33.23 ± 0.2 2?º
ii). DSC isotherm comprising at least two endothermic peaks ranging between 116 to 122ºC.
iii). IR absorption spectrum having absorption peaks at 3033, 3020, 2949 , 2983 , 2965 , 2502 , 2336 , 1649, 1415 , 1350 , 1320 , 1174 ± 5cm-1.
Crystalline Form SBU of Busulfan exists in the pure form with purity exceeding 99.8% (% w/w by HPLC)
In order to check the thermodynamic stability inventors of the present application performed 24 months stability in the following storage conditions:
S. No. Temperature Relative Humidity
1. 30ºC ± 2ºC 65%±5%
The below mentioned table shows the thermodynamic stability nature of the Crystalline Busulfan Form-SBU and the HPLC purity indicates to retain pure form nature with purity exceeding 99.8% (% w/w by HPLC).
Limits Initial 6M 24M
Assay (by HPLC; on anhydrous basis) Between 99.0% to 100.5%w/w 100.00 % w/w 100.16 % w/w 100.26 % w/w
Related Substances (1, 4 Butanediol) Not more than 0.15%w/w Not detected Not detected 0.006%w/w
MSA content (By HPLC) Not more than 0.15% w/w 0.002%w/w Not detected Not detected
XRPD peaks Initial peaks:
12.48, 14.18, 15.24, 16.21, 18.79, 21.02, 22.06, 24.13, 25.17, 26.90, 30.84, 33.23 ± 0.2 ?º

± 0.2 ?º After 24 months at 30ºC/65±5% condition
12.57, 14.32, 15.39, 16.39, 18.96, 21.23, 22.22, 24.29, 25.26, 27.01, 30.97, 33.00 ± 0.2 ?º

FIG. 1 and FIG. 2 illustrate the of X-ray powder diffraction (XRPD) pattern of Crystalline Busulfan Form- SBU obtained in the initial stage and after 24 months stability respectively.
The characteristic 2?° peaks and their d spacing values, for the novel crystalline Form-SBU are tabulated in the Table-1.
TABLE 1
Characteristic XRPD Peaks of Crystalline Form-SBU
S. No. Angle d Spacing Value
(2?°) ± 0.20 (A°)
1. 12.48 7.089
2. 13.72 6.448
3. 14.18 6.242
4. 15.24 5.808
5. 16.21 5.463
6. 18.79 4.718
7. 19.92 4.453
8. 21.02 4.221
9. 22.06 4.026
10. 22.65 3.923
11. 24.13 3.686
12. 25.17 3.535
13. 26.90 3.313
14. 28.04 3.180
15. 28.64 3.114
16. 29.34 3.042
17. 30.41 2.937
18. 30.84 2.897
19. 32.18 2.779
20. 32.80 2.728
21. 33.23 2.694
22. 33.62 2.663
23. 34.59 2.591
24. 35.39 2.534
25. 35.66 2.515
26. 37.67 2.386
27. 38.20 2.355
28. 38.99 2.308

Figures 1 and 2 also reveal that the crystalline nature of the material remain same and having the thermodynamic stability.
Therefore specific polymorphic Form - SBU of Busulfan in the present invention provides advantage in the stability and in the drug product manufacturing process.
Minor variations in the observed 2?° angles values may be expected based on the analyst, the specific XRPD diffractometer employed and the sample preparation technique. Further possible variations may also be expected for the relative peak intensities, which may be largely affected by the non-uniformity of the particle size of the sample. The 2 theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the X-ray powder diffraction pattern. D-spacing values are calculated with observed 2 theta angles and copper K a wavelength using the Bragg equation well known to those of having skill in the art of XRPD diffractometry science.
In view of possibility of marginal error in the assigning 2 theta angles and d-spacing, the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown form over the X-ray powder diffraction pattern of a known form. For example, one skilled in the art can overlay an X-ray powder diffraction pattern of an unidentified crystalline form of Busulfan over FIG. 1 and readily determine whether the X-ray diffraction pattern of the unidentified form is the same or different w.r.t. the X-ray powder diffraction pattern of the crystalline form SBU of this invention.
The product obtained by the present invention is free of process related impurities, including unreacted reactants (key starting material), side products, degradation products and other medium dependent impurities. The Crystalline Busulfan - Form SBU obtained by the process according to the present invention is highly pure having a purity of greater than 99.8% by HPLC (%w/w).
Busulfan crystalline Form SBU” obtained by the process of present application is characterized by its X-ray powder diffraction (“XRPD”) pattern, differential scanning calorimetry (“DSC”) curve, and Infrared Spectrophotometer (IR) data.
The crystalline Form-SBU described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis. The samples of crystalline Form-SBU of Busulfan were analyzed by XRPD on a Bruker AXS D2 Advance Diffractometer using X-ray source—Cu Ka radiation using the wavelength 1.5406 Å and lynx Eye detector. DSC was done on a Discovery series 25.0 instrument.
Crystalline Busulfan (Assay) can be analysed by HPLC method, using High Perform Liquid chromatograph make Shimadzu equipped with UV Detector operated at 280 nm and 4MC Pack, ODS-A (150x4.6) 3 µm, particle size column. Analyses were performed using the following mobile phase, at flow rate of 1.0 ml/minute for 20 minutes column over temperature 20° C.±2°C.
Mobile phase: water: ACN: THF (30:65:05) %v/v/v
Diluent: water: ACN: THF (30:50:20) %v/v/v
Other related substance Methane Sulphonic Acid (MSA) content is also detected by HPLC – RID method having Column-Welch Utisil HILIC Amide (250x 4.6) mm 5 µm or equivalent flow rate -1.0ml/minute.
Injection Volume-200µL
Detector-RID
Column oven temperature- 40°C
Sample cooler temperature-15°C
Run time -20mins
Buffer-Ammonium acetate (7.7g) 1000mlwater Milli Q
pH- 4.50±0.05 using glacial acetic acid
Mobile phase A- Buffer (100%)
B- ACN (100%)
Diluent ACN- 100%
Another related substance 1, 4-butanediol content is detected By Gas Chromatography (GC) with the following details:
Column- HP-1 (30mxo.5mm) 2.65µm or equivalent
Carrier gas: Nitrogen
Flow: 3.5ml/minute
Split ratio: 1:5
Detector- Flame ionization detector
Column Initial temperature: 50°C
Initial time: 2 minutes
Injector Temp: 200°C
Detector Temp: 250°C
Injection Volume: 1.0µL
Hydrogen Flow: 30ml/min
Air flow: 300ml/min
Run time: 22 minutes
Illustrative examples of analytical data for the crystalline Busulfan ‘Form-SBU’ obtained in the Examples are set forth in the FIGS. 1-5.
A polymorphic form may be described by reference to patterns, spectra, or other graphical data as shown or depicted in a figure, or by one or more data points. It will be appreciated that patterns, spectra, and other graphical data may be slightly shifted in their positions, relative intensities, or other values due to various factors known to the person skilled in the art. For example, in the crystallographic and powder X-ray diffraction science, shifts in peak positions or the relative intensities of one or more peaks of a pattern can occur because of, the equipment used, protocol of the sample preparation, preferred packing and orientations, the radiation source, operator's minor operational error, method and length of data collection, and the like. However, those of ordinary skill in the art will be able to compare the figures herein with patterns, etc. generated for an unknown form of, in this case, Crystalline Busulfan Form- SBU, and confirms its identity with the form disclosed herein. The same holds true for other techniques which may be reported herein.
In another embodiment, the Busulfan crystalline Form - SBU obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Busulfan of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions derived from Busilfan of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the below examples, which are provided by way for illustration purpose only and should not be construed as limiting the scope of the invention in any manner.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the present invention.
Examples:
Example 1- Process for the preparation of the Crude Busulfan:
Charged acetonitrile (520 ml), 1, 4 butane diol (100 gm), triethylamine (467 ml) in above round bottom flask at 25-30°C under nitrogen atmosphere. Stirred the reaction mass for 10 minutes at 25-30°C under nitrogen atmosphere. Cool the reaction mass to 0-5°C under nitrogen atmosphere. Add methane sulfonyl chloride (215 ml) slowly through addition funnel in 3 to 4 hours at temperature below 30°C. Raised the temperature of the reaction mass to 30 - 35°C and continue stirring for 30 minutes. Checked 1, 4 butane diol content by GC until the required range is not achieved. Raised the temperature of the reaction mass 55 - 60ºC and stirred for 10 minutes. Cool the reaction mass 0 - 5°C under stirring. Add DM water (1500 ml) slowly into the reaction mass at 0 to 5°C. Stirred the reaction mass for 1 hour at 0 - 5°C. Filtered the reaction mass through Buchner funnel and washed with DM water (two times 400 ml and 300 ml respectively) and suck dry well. Washed the solid with chilled acetone 2 x 83.5 ml and suck dry well. Dry the material under vacuum at 35 - 40°C for 6 hour.
Yield: Dry wt: = 206.67 gm
Example 2- Process for the preparation of Crystalline Busulfan Form- SBU: (using Ketone Solvent as Methyl Ethyl ketone-MEK)
Arrange 3.0L glass RBF with condenser, addition funnel and water bath etc. Charged Busulfan crude (50 gm) and Methyl Ethyl ketone (2000 ml) into the reaction flask under stirring. Raised the temperature of reaction mixture 40 - 50ºC under stirring until the dissolution. Stirred the reaction mass for 1 hour at 45 to 50ºC. Charged activated charcoal (5 gm) into the reaction mixture. Stirred the reaction mass for 1 hour at 40 to 50ºC. Filter the hot reaction mixture through hyflo bed and washed with Methyl Ethyl ketone (50 ml). Charged the filtrate into another reaction flask and distilled the solvent under vacuum keeping approx. 200 ml to 250 ml inside reaction flask at temperature below 50ºC. Cool the reaction mixture to 0 - 5ºC under stirring. Stirred the reaction mixture at 0 - 5ºC for 120 minutes. Filtered and washed the reaction mass with chilled Methyl Ethyl ketone (50 ml) & Suck dry well. Unload and dry the material under vacuum at 40 - 45ºC.
Yield: Dry wt: 44.15 gm
Example 3- Process for the preparation of Crystalline Busulfan Form- SBU: (using Ketone Solvent as Acetone)
Arrange 5.0L glass RBF with condenser, addition funnel and water bath etc. Charged Busulfan crude (100 gm) and acetone (4000 ml) into the reaction flask under stirring. Raised the temperature of reaction mixture 40 - 50ºC under stirring until the dissolution. Stirred the reaction mass for 1 hour at 45 to 50ºC. Charged activated charcoal (10 gm) into the reaction mixture. Stirred the reaction mass for 1 hour at 40 to 50ºC. Filter the hot reaction mixture through hyflo bed and washed with acetone (100 ml). Charged the filtrate into another reaction flask and distilled the solvent under vacuum keeping approx. 400 ml to 500 ml inside reaction flask at temperature below 50ºC. Cool the reaction mixture to 0 - 5ºC under stirring. Stirred the reaction mixture at 0 - 5ºC for 120 minutes. Filtered and washed the reaction mass with chilled acetone (100 ml) & Suck dry well. Unload and dry the material under vacuum at 40 - 45ºC.
Yield: Dry wt: 91.36 gm
HPLC purity: 100.00% (% w/w by HPLC)
X-ray powder diffraction pattern peaks at 12.48, 14.18, 15.24, 16.21, 18.79, 21.02, 22.06, 24.13, 25.17, 26.90, 30.84, 33.23 ± 0.2 2?º.
DSC isotherm endothermic peak: 117.76
IR absorption spectrum peaks at 3033, 3020, 2949, 2983, 2965, 2502, 2336, 1649, 1415, 1350, 1320, 1174 ± 5cm-1.
Example 4-
In order to check the thermodynamic stability inventors of the present application performed 24 months stability in the following storage conditions:
S. No. Temperature Relative Humidity
1. 30ºC ± 2ºC 65%±5%

The below mentioned table shows the thermodynamic stability nature of the Crystalline Busulfan Form-SBU and the HPLC purity which indicates to retain pure crystalline form nature with purity exceeding 99.8% (% w/w by HPLC).

Limits Initial 6M 24M
Assay (by HPLC; on anhydrous basis) Between 99.0% to 100.5%w/w 100.00 % w/w 100.16 % w/w 100.26 % w/w
Related Substances (1, 4 Butanediol) Not more than 0.15%w/w Not detected Not detected 0.006%w/w
MSA content (By HPLC) Not more than 0.15% w/w 0.002%w/w Not detected Not detected
XRPD peaks Initial peaks:
12.48, 14.18, 15.24, 16.21, 18.79, 21.02, 22.06, 24.13, 25.17, 26.90, 30.84, 33.23 ± 0.2 ?º After 24 months at 30ºC/65±5% condition
12.57, 14.32, 15.39, 16.39, 18.96, 21.23, 22.22, 24.29, 25.26, 27.01, 30.97, 33.00 ± 0.2 ?º

FIG. 1 and FIG. 2 illustrate the of X-ray powder diffraction (XRPD) pattern of Crystalline Busulfan Form- SBU obtained in the initial stage and after 24 months stability respectively.
The above mentioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities use etc.

Claims:

We Claim:
1. A process for the preparation of crystalline Busulfan (I) Form- SBU

characterised by X-ray powder diffraction pattern comprising the characteristic diffraction angle peaks at 12.48, 14.18, 15.24, 16.21, 18.79, 21.02, 22.06, 24.13, 25.17, 26.90, 30.84, 33.23 ± 0.2 2?º, IR absorption spectrum having characteristic peaks at 3033, 3020 , 2949 , 2983 , 2965 , 2502 , 2336 , 1649 , 1415 , 1350 , 1320 , 1174 ± 5cm-1, DSC isotherm comprising an endothermic peak ranging between 116 to 122ºC,
comprising the steps of:
a) dissolving the crude or pure Busulfan in a ketone organic solvent;
b) raise the temperature of the reaction mixture upto about 40 to 50ºC;
c) maintaining the temperature for one hour under stiring;
d) charge activated charcoal into the reaction mixture and filter simultaneously;
e) cooling the mixture up to about 0-5ºC and
f) obtaining crystalline Form - SBU of Busulfan.
2. A process for preparing Busulfan (I) Crystalline Form - SBU as claimed in claim 1, wherein a ketone organic solvent is selected from acetone, butanone, 1-methyl isobutyl ketone or a mixture thereof and more preferably it is acetone.
3. A process for preparation of Crystalline Busulfan (I) Form - SBU as claimed in claim 1, wherein ratio of organic solvent w.r.t. Busulfan is ranging between 25- 45 : 1 (V/w).
4. A process for preparation of Crystalline Busulfan (I) Form - SBU as claimed in claim 1, wherein the amount of the activated carbon w.r.t Busulfan is ranging between 5-15% (w/w).
5. Thermodynamically stable Crystalline Busulfan (I) Form - SBU is characterised by
i). X-ray powder diffraction pattern comprising the characteristic 2?º peaks of 12.48, 14.18, 15.24, 16.21, 18.79, 21.02, 22.06, 24.13, 25.17, 26.90, 30.84, 33.23 ± 0.2 2?º;
ii). DSC isotherm comprising an endothermic peak ranging between 116 to 122ºC and
iii). IR absorption spectrum having absorption peaks at 3033, 3020, 2949, 2983 , 2965 , 2502 , 2336 , 1649 , 1415 , 1350 , 1320 , 1174 ± 5cm-1.
6. A pharmaceutical composition comprising Crystalline Form-SBU of Busulfan along with at least one or more pharmaceutically acceptable excipients.
,