FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
"SIBUTRAMINE FREE BASE IN CRYSTALLINE FORM AND ITS
PHARMACEUTICAL USE"
CIPLA LIMITED, an Indian company of 289 Bellasis road, Mumbai Central, Mumbai 400 008, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

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SIBUTRAMINE FREE BASE IN CRYSTALLINE FORM AND ITS PHARMACEUTICAL USE
The present invention is concerned with sibutramine, N-{l-[l-(4-chiorophenyl)cyclobutyl]-3-raethylbutyl}-N,N-dimethyl-amine, compositions containing the same and uses thereof.
Sibutramine has the following structural formula

The synthesis of sibutramine hydrochloride is described in Example 11 of both US 4746680 and US 4806570, wherein crystalline sibutramine hydrochloride is prepared from l-[l-(4-chlorophenyl)cyclobutyl}-3-methylbutyl-amine free base. Sibutramine hydrochloride monohydrate is described in US 4929629, which describes the preparation of sibutramine hydrochloride monohydrate from sibutramine hydrochloride, or from sibutramine free base. Examples 12 and 13 of US 4929629 describe preparation of sibutramine hydrochloride monohydrate from sibutramine free base as the starting material, but no teaching is given in Examples 12 and 13 of US 4929629 as to the crystalline or otherwise amorphous nature of the sibutramine free base starting material.
Sibutramine hydrochloride is a well-known antidepressant drug and is also useful as an anorectic agent, for the treatment of chemical dependencies, anxiety-related disorders and premature ejaculation. Sibutramine hydrochloride is a neuronal monoamine reuptake inhibitor and more particularly inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine, for example as described by Buckett et al,, Prog. Neuro-

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psychopharm. & Biol. Psychiat, 12:575-584,1988; and King et al., J. Clin. Pharm., 26:607-611,1989.
We have now found that sibutramine free base may be obtained as a pure crystalline product, which may easily be handled and conveniently be formulated into tablets and other pharmaceutical forms. Furthermore, it has surprisingly been found that a very good and efficient purification of sibutramine can be obtained during manufacture of sibutramine, for example as the hydrochloride salt, by liberation and crystallisation of sibutramine free base.
There is provided by the present invention, therefore, sibutramine free base, in crystalline form.
There is also provided by the present invention sibutramine free base, in crystalline form having an X-ray diffraction pattern, or substantially the same X-ray diffraction pattern, as shown in Figure 1. More particularly, sibutramine free base, in crystalline form, according to the present invention, can be characterized as having an X-ray diffraction pattern with characteristic peaks (28): 14.1989,14.6800,14.9092,17.3331,20.3059 and 24.2082.
Further characterising data for sibutramine free base, in crystalline form, according to the present invention as obtained by X-ray diffraction is shown in following table 1.
Table 1

Peak No. 29 (deg) d(A) 1/11 FWHM(deg) Intensity (Counts) Integrated (Counts)
1 8.6484 10.21619 14 0.17160 246 2641
2 10.4134 8.48824 9 0.16370 156 1656
3 13.7000 6.45843 3 0.20340 63 1938
4 14.1989 6.23261 97 0.15580 1752 14802
5 14.6800 6.02941 31 0.18120 556 5542
6 14.9092 5.93723 68 0.17170 - 1236 10445
7 15.5000 5.71223 7 0.18760 119 1546

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8 15.6881 5.64416 17 0.18070 306 2660
9 16.6520 5.31956 17 0.21280 299 3813
10 17.3331 5.11203 35 0.14540 640 5627
11 18.2171 4.86591 8 0.17140 143 1581
12 20.3059 4.36984 22 0.16730 395 3942
13 20.8115 4,26481 20 0.24190 365 4796
14 21.9821 4.04027 11 0.18920 200 2346
15 22.4770 3.95242 7 , 0.32590 123 2017
16 22.9735 3.86811 12 0.23240 209 2282
17 23.3643 3.80428 16 0.14930 292 2184
18 24.2082 3.67354 100 0.19570 1806 24826
19 24.6600 3.60725 19 0.00000 340 0
20 24.8400 3.58152 18 0.14660 323 3925
21 25.9000 3.43729 11 0.16580 207 2058
22 26.1000 3.41141 10 0.14560 172 1555
23 27.9863 3.18561 5 0.19090 86 1064
24 28.5236 3.12682 15 0.18560 276 2782
25 29.4702 3.02850 3 0.15460 54 783
26 31.6847 2.82170 4 0.18140 77 1322
27 32.3000 2.76934 3 0.21720 54 700
28 32.6210 2.74282 16 0.19070 291 2947
Sibutramine free base, in crystalline form, according to the present invention is preferably more than about 99.5% w/w pure and more preferably more than about 99.8% w/w pure (peak area), Sibutramine free base, in crystalline form, according to the present invention is preferably further characterised as having a melting point in the range of about 52-57°C (DSC; open capsule) and DSC characteristics as shown in Figure 2.
Sibutramine free base, in crystalline form, according to the present invention has therapeutic utility in the inhibition neuronal monoamine reuptake, in particular norepinephrine reuptake and to a lesser extent serotonin and dopamine reuptake. Sibutramine free base, in crystalline

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s
A
form, according to the present invention is suitable for inclusion in pharmaceutical compositions for use in the treatment of disease states prevented, ameliorated or eliminated by administration of a neuronal monoamine reuptake inhibitor and is also suitable for use in methods of treating a patient suffering from or susceptible to disease states prevented, ameliorated or eliminated by administration of a neuronal monoamine reuptake inhibitor. In particular, sibutramine free base, in crystalline form, according to the present invention is useful for treating depression and is also useful as an anorectic agent, for the treatment of chemical dependencies, anxiety-related disorders and premature ejaculation.
The present invention further provides, therefore, a pharmaceutically acceptable composition for administering to a patient, including humans; suffering from, or susceptible to, a disease state prevented, ameliorated or eliminated by the administration of a neuronal monoamine reuptake inhibitor, which composition comprises a therapeutically effective amount of sibutramhie free base, in crystalline form, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
As used herein, the term ''therapeutically effective amount" means an amount of sibutramine free base, in crystalline form, which is capable of preventing, ameliorating or eliminating a disease state for which administration of a neuronal monoamine reuptake inhibitor is indicated.
By "pharmaceutically acceptable composition" it is meant that the carrier, diluent or excipient is compatible with sibutramine free base, in crystalline form, and not deleterious to a recipient thereof. Sibutramine free base, in crystalline form, according to the present invention has been found to be suitable for formulation into stable solid compositions exhibiting good release properties.
The pharmaceutical compositions of the present invention may be administered in any suitable way and in any suitable form, for example orally (preferred) in the form of tablet$, capsules, powders or syrups, or parenterally in the form of conventional sterile solutions for injection.

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The pharmaceutical compositions of the present invention may be prepared by conventional methods known in the art. For example, tablets may be prepared by mixing sibutramine free base, in crystalline form, according to the present invention, with known adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents can comprise corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Other adjuvants or additives such as colourings, aroma enhancers, preservatives and the like may be used provided that they are compatible with sibutramine free base, in crystalline form, as described above.
A pharmaceutically acceptable composition of the present invention comprising of a therapeutically effective amount of sibutramine free base together with a pharmaceutically acceptable carrier, diluent or excipient is found to show surprising property. Therefore, the pharmaceutical composition is synergistic.
Solutions for injections may be prepared according to the present invention by dissolving sibutramine free base, in crystalline form, and possible additives in a part of a solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilization of the solution and filling in suitable ampoules or vials. Any suitable additives conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants and the like.
The particular dosage form of sibutramine free base, in crystalline form, required to treat a disease state prevented, ameliorated or eliminated by the administration of a neuronal monoamine reuptake inhibitor as described herein in a patient, including humans, will depend on the particular disease state or condition, and the symptoms and severity thereof. Dosage, routes of administration, and frequency of dosing are best decided by an attending physician.
Compositions according to the present invention are, however, preferably made so as to be administrable by the oral or parenteral route.
The present invention further provided sibutramine free base, in crystalline form, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a neuronal monoamine reuptake inhibitor as described herein.
The present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of a neuronal monoamine reuptake inhibitor in a patient in need of such treatment, which method comprises administering to the patient a

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therapeutically effective amount of sibutramine free base, in crystalline form, substantially as hereinbefore described.
Sibutramine free base, in crystalline form, according to the present invention, is also useful as an intermediate in the preparation of pharmaceutically acceptable salts of sibutramine. The present invention, therefore, further provides use of sibutramine free base, in crystalline form, as an intermediate for the preparation of pharmaceutically acceptable salts of sibutramine.
The present invention also provides a process of preparing a pharmaceutically acceptable salt of sibutramine, preferably the hydrochloride salt, wherein sibutramine free base, in crystalline form, is converted to a pharmaceutically acceptable salt of sibutramine.
The present invention further provides a sibutramine salt, preferably the hydrochloride salt of sibutramine, prepared by a process according to the present invention substantially as hereinbefore described.
The pharmaceutically acceptable salts of sibutramine, such as the hydrochloride, may be prepared according to the present invention from sibutramine free base, in crystalline form, by methods known in the art. More particularly, sibutramine free base, in crystalline form, may be reacted with an appropriate amount of acid in a water miscible solvent, such as acetone, ethanol or the like, with subsequent isolation of the salt by concentration and cooling; alternatively, sibutramine free base, in crystalline form, may be reacted with an excess of an acid in a water immiscible solvent, such as ethylether, ethylacetate, dichloromethane or the like, with the salt separating spontaneously. Sibutramine hydrochloride thus obtained by a process according to the present invention has a very high purity, preferably a purity of more than about 99.8% w/w, and more preferably more than about 99.9% w/w. Other salts of sibutramine, for example sibutramine oxalate, may also be obtained in a very pure form according to the present invention.
The present invention also provides a process of preparing sibutramine free base in crystalline form, which process comprises dissolving a sibutramine salt in a first organic

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solvent medium, adding thereto a base, separating therefrom sibutramine free base and crystallising sibutramine free base from a second organic solvent medium.
The salt of sibutramine from which sibutramine free base, in crystalline form, according to the present invention is prepared (hereinafter generally referred to as the sibutramine crude salt) may be any convenient salt, such as the hydrochloride, sulphate, oxalate, phosphate, or any other convenient salt Preferably the hydrochloride salt is employed. Other suitable salts are salts of organic acids.
The sibutramine crude salt, and also mixtures containing the same, may include impurities, which will need to be removed or which it is desired to remove. The sibutramine crude salt may be a salt separated directly from a preparatory reaction mixture, or it may have been subjected to some initial or simultaneous purification, for example re-crystallisation, treatment with activated carbon or silica gel or the like. The sibutramine crude salt may be prepared by any of the above-mentioned processes or processes known in the art. The sibutramine crude salt may be isolated by precipitation or it may exist in a solvent, for example in a mixture resulting directly from the synthesis thereof. Similarly a crude mixture comprising sibutramine free base may be obtained directly from the synthesis thereof according to any of the above mentioned processes or it may be subjected to initial or simultaneous purification, for example re-crystallisation, treatment with activated carbon or silica gel or the like.
Sibutramine free base may be liberated from a sibutramine crude salt by dissolving the crude salt in a first organic solvent medium, adding a base, followed by purification and extraction. Alternatively it may be isolated from a crude mixture of the base by purification and extraction. The first organic solvent medium may comprise toluene, ethyl acetate or any other suitable solvent and the base may be any conventional base, preferably sodium hydroxide or ammonia. Sibutramine free base is collected by separation of the organic phase, evaporation of the solvent in order to obtain the base (typically in the form of an oil) and then crystallisation of sibutramine free base from a second suitable solvent medium, such as an alkane, including n-heptane, hexane, isooctane and the like, and CM alcohols, such as methanol, ethanol, isopropanol and the like.

The present invention will now be further illustrated by the following Figures and Examples, which do not limit the scope of the invention in any way.
Figure 1: X-ray diffraction pattern of sibutramine free base, in crystalline form, according to the present invention. The X-ray diffraction pattern was obtained using a Shimadzu XRD-600Q spectrometer. CuKa (1.54060A) 30kV, 30mA; Slits: DS: 1.00 deg, SS: 1.00 deg, RS: 0.15mm; cont scan 2^0 deg/min.
Figure 2: DSC trace showing the melting point of sibutramine free base, in crystalline
form, according to the present invention being in the range of 52-57DC. Method: 30.0 -250.0°C 10°C/min; N2, 50.0ml/min; integral--441.60mJ, onset 51.96°C Peak 54.49°C, Endset 56.33°C.
Example 1
Crystallisation of Sibutramine free base
N- {1 -[ l-(4-Chlorophenyl)cyclobutyl]-3-methylbutyl} -N.N-dimethyl-amine hydrochloride (101 grams, 0.25 mole) was suspended in water (500 ml) and toluene (500 ml). NaOH (60 ml. 5 N (aq)) was added and the mixture (pH>10) was stirred for 15 minutes before the phases were separated. The organic phase was washed with water (2x100 ml) and filtered through a pad of filter help. The volatiles were removed in vacuo and the title compound was obtained as an oil. n-Heptane (400 ml) was added and the mixture was heated to 70°C. On cooling crystals formed The white crystals of the title compound were filtered off and dried at ambient temperature over night in vacuo. Yield: 75.4 grams (93%). DSC (onset, open capsule): 52-57°C. Purity: (>99.8% (peak area)).
Example 2
Crystallisation of Sibutramine free base
N-{l-[l-(4-ChJorophenyl)cyclobutyl]-3-methylbutyl}-N3N-dimethyl-amine) as a
hydrochloride was suspended in water (500 ml) and ethylacetate (500 ml). NaOH (60 ml, 5N (aq)) was added and the mixture (pH>10) was stirred for 15 minutes before the phases were separated. The organic phase was washed with water (2x100 ml) and filtered through a pad of filter help. The volatiles were removed in vacuo and the title compound was obtained as an oil. N-hexane (150 ml) was added and the mixture was heated to 50°C. On cooling

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crystals formed. The white crystals of the title compound were filtered off and dried at ambient temperature over night in vacuo. Yield: 68 grams (93%). DSC (onset, open capsule): 52-57°C Purity: (>99.8% (peak area)).
Example 3
Crystallisation of Sibutramine free base
N-{l-[l-(4-Chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethyl-amine) as a
hydrochloride was suspended in water (500 ml) and ethylacetate (500 ml). NaOH (60 ml, 5 N (aq)) was added and the mixture (pH>10) was stirred for 15 minutes before the phases were separated. The organic phase was washed with water (2x100 ml) and filtered through a pad of filter help. The volatiles were removed in vacuo and the title compound was obtained as an oil. Methanol (100 ml) was added and the mixture was heated to 50°C. On cooling crystals formed. The white crystals of the title compound were filtered off and dried at ambient temperature over night in vacuo. Yield: 68 grams (93%). DSC (onset, open capsule): 52-57°C. Purity: (>99.8% (peak area)).
Example 4 Tablet Preparation
This Example refers to wet granulation and preparation of tablets of sibutramine free base.
The batch size was 200 g and the granulation was performed in a small-scale laboratory high shear mixer (Micromixer).
Sibutramine free base was sieved through a sieve aperture of 0.3 mm. The ingredients of the intragranular phase were mixed at 600 rpm. 25 ml of purified water was added in 30 seconds and the granulation terminated after a total processing time of 3 minutes. The granulate was wet sieved through a 0.7 mm sieve aperture and dried at 40°C in 30 minutes to equilibrium relative humidity of 32%. The dried granulate was finally sieved through a 0.7 mm sieve aperture.

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The dried granulate was mixed for 3 minutes with the extragranular phase (6-7) in a Turbula mixer and finally mixed with the lubricant (8) for 30 seconds.
Materials % (1) Sibutramine (free base) 16.00; (2) Kollidon VA64 2.32; (3) Lactose 350 mesh 38.98; (4) Com starch 20.00; (5) Purified water 25; (6) Avicel PH 200 (Microcrystalline cellulose) 20.00; (7) AcDi-Sol ((Cross carmellose sodium) 2.00; (8) Magnesium stearate 0.7.
Tablets were produced on a single punch tabletticg machine and it was seen that the tablets produced had satisfactory technical properties.
EXAMPLES
This Example refers to melt granulation and preparation of tablets of sibutramine free base.
The batch size was 200g. Sibutramine free base was sieved through a sieve aperture of 0.3 mm.
The granulation was performed in a small-scale laboratory high shear mixer (Micromixer).
The ingredients of the intra-granular phase were mixed at 1200 rpm. The jacket temperature was 80°C. The granulation process was terminated after 3.5 minutes. The granulate was sieved through a sieve aperture of 1.0 mm and mixed with the extragranular phase (4, 5) for 3 minutes and with the lubricant (6) for 30 seconds.
Composition of the resulting tablets. Materials %: (1) Sibutramine (base) - 16.00; (2) Polyethyleneglycol 6000 - 9.14; (3) Lactose 350 mesh - 38.98; (4) Avicel PH 200 (Microcrystalline cellulose) - 30.00; (5) Kollidon CL (Cross-linked povidone) - 4.00; and (6) Magnesium stearate - 0.7.
The tablets produced were seen to have satisfactory technical properties.

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EXAMPLE 6
This Example refers to preparation of capsules of sibutramine free base.
Sibutramine free base capsules: 15mg.

Ingredients Quantity per capsules (mg)
Sibutramine free base 12.60
Fumaric acid 50.00
Purified water q.s.
Lactose 100.00
Microcrystallinc cellulose 85.15
Aerosil 1.25
Magnesium stearate 1.00
Total 250.00
Capsule size: 1. Manufacturing process:
1. Sibutramine free base, a portion of the fumaric acid, lactose and microcrystalline cellulose were mixed for 5 minutes.
2. The remaining ingredients and remaining fumaric acid were dissolved in purified water.
3. The dry mix was granulated with the fumaric acid solution until a mass of suitable
consistency was obtained.
4. The granules were dried to LOD of less than 2.0%w/w and sized.
5. The sized granules were filled into size 1 capsules.

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CLAIMS
1. Sibutramine free base, in crystalline form.
2. Sibutramine free base, m crystalline form having an X-ray diffraction pattern, or substantially the same X-ray diffraction pattern, as shown in Figure 1.
3. Sibutramine free base, in crystalline form, having an X-ray diffraction pattern with characteristic peaks (29): 14.1989,14.6800,14.9092,17.3331,20.3059 and 24.2082.
4. Sibutramine free base, in crystalline form, characterised as having a melting point in the range of about 52-57°C and DSC characteristics as shown in Figure 2.
5. Sibutramine free base according to any of claims 1 to 4, which is more than about 99.5% w/w pure.
6. Sibutramine free base according to claim 5, which is more than about 99.8% w/w pure.
7. A pharmaceutical^ acceptable composition for administering to a patient suffering from, or susceptible to, a disease state prevented, ameliorated or eliminated by the administration of a neuronal monoamine reuptake inhibitor, which composition comprises a therapeutically effective amount of sibutramine free base according to any of claims 1 to 6, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
8. Sibutramine free base according to any of claims 1 to 6, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a neuronal monoamine reuptake inhibitor.
9. A method of treating a disease state prevented, ameliorated or eliminated by the administration of a neuronal monoamine reuptake inhibitor in a patient in need of such

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treatment, which method comprises administering to the patient a therapeutically effective amount of sibutramine free base according to any of claims l to 6.
10. Use of sibutramine free base according to any of claims 1 to 6, as an intermediate for the preparation of pharmaceutically acceptable salts of sibutramine.
11. Use according to claim 10, wherein the pharmaceutically acceptable salt of sibutramine is the hydrochloride salt.
12. A process of preparing a pharmaceutically acceptable salt of sibutramine, wherein sibutramine free base according to any of claims 1 to 6 is converted to a pharmaceutically acceptable salt of sibutramine.
13. A process according to claims 12, wherein the pharmaceutically acceptable salt of sibutramine is the hydrochloride salt
14. A process according to claim 12 or 13, wherein sibutramine free base according to any of claims 1 to 6 is reacted with an acid in a water miscible solvent.
15. A process according to claim 14, wherein the water miscible solvent is acetone or ethanol.
16. A process according to claim 12 or 13, wherein sibutramine free base according to any of claims 1 to 6 is reacted with an excess of an acid in a water immiscible solvent.
17. A process according to claim 16, wherein the water immiscible solvent is ethylether, ethylacetate or dichloromethane.
18. A sibutramine salt prepared by a process according to any of claims 12 to 17.
19. A sibutramine salt according to any claim 18, which is sibutramine hydrochloride.

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20. Sibutramine hydrochloride according to claim 19, which has a purity of more than about 99.8% w/w.
21. Sibutramine hydrochloride according to claim 20, which has a purity of more than about 99.9% w/w.
22. A process of preparing sibutramine free base according to any of claims 1 to 6, which process comprises dissolving a sibutramine salt in a first organic solvent medium, adding thereto a base, separating therefrom sibutramine free base and crystallising sibutramine free base from a second organic solvent medium.
23. A process according to claim 22, wherein the first organic solvent medium comprises toluene and / or ethyl acetate.
24. A process according to claim 22 or 23, wherein the base is sodium hydroxide or ammonia.
25. A process according to any of claims 22 to 24, wherein the second solvent medium comprises n-heptane, hexane, isooctane, methanol, ethanol and / or isopropanol.
26. Sibutramine free base, in crystalline form, prepared by any of Examples 1 to 3.
27. Sibutramine free base in crystalline form, a pharmaceutically acceptable composition; a method of treating a disease state prevented, ameliorated or eliminated; use of sibutramine free base; a process of preparing a pharmaceutically acceptable salt of sibutramine; a sibutramine salt; and sibutramine hydrochloride such as herein described with reference to the foregoing examples and accompanying drawings.
Dated this 26th day of October 2005.

VIBHASHUKLA
OFK&S PARTNERS
ATTORNEY FOR THE APPLICANT(S)
A&ENT

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ABSTRACT
Sibutramine, N-{l-[l-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N, N-dimethyl-amine, free base in crystalline form, compositions containing the same and uses thereof.