FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"AMORPHOUS BUPROPION HYDROBROMIDE AND PREPARATION
THEREOF"


Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
The following specification describes the nature of the invention:


FIELD OF THE INVENTION
The present invention relates to amorphous Bupropion hydrobromide, processes for preparation thereof, and stable pharmaceutical compositions therewith.
BACKGROUND OF THE INVENTION

Bupropion is the free base form of Bupropion hydrobromide, which has a CAS number of 905818-69-1 and the following structure:

Bupropion is an antidepressant agent that is chemically distinct from tricyclic, tetracyclic and other commercially available antidepressants, e.g., selective serotonin-reuptake inhibitors, or "SSRIs." m-chloro-a-(t-butylamino) propiophenone (herein "Bupropion") has a CAS No. of 34911-55-2, described in U.S. Pat. Nos. 3,819,706 and 3,885,046, and is represented by the structure of Formula I:
Bupropion hydrobromide was approved by the USFDA under the name APLENZIN, and is indicated for the treatment of major depressive disorder.
US Publication No. 2008/051606 discloses three different crystalline polymorphic forms of bupropion hydrobromide named as form-I, II, and III out of these form-I and II are reported as stable.
The discovery of new amorphous forms of active pharmaceutical ingredients ("APIs") provides opportunities to improve the performance characteristics, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products of a pharmaceutical product. Such discoveries
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enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Generally, amorphous solids offer opportunities for solubility and bioavailability enhancement since these materials are more soluble than the crystalline form of the same compound. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
None of the prior art references discussed above disclose amorphous form of Bupropion hydrobromide.
SUMMARY OF THE INVENTION
In one aspect, the invention encompasses amorphous bupropion hydrobromide. Preferably, the amorphous bupropion hydrobromide contains less than about 20% crystalline bupropion hydrobromide by weight, more preferably less than about 10% by weight, and even more preferably less than about 5% by weight.
In another aspect, the invention encompasses purely amorphous bupropion hydrobromide.
In another aspect, the present invention provides a process of preparing amorphous bupropion hydrobromide comprising: providing a solution of bupropion hydrobromide in at least one organic solvent and/or mixture with water; optionally, filtering the solvent solution to remove any extraneous matter and removing the solvent from the resulting solution to obtain amorphous bupropion hydrobromide.
In another aspect, the present invention provides a pharmaceutical composition comprising: a therapeutically effective amount of an amorphous bupropion hydrobromide of the present invention and at least one pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method of treating a patient suffering from major depressive disorders. The method comprises orally administering to
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the patient the pharmaceutical composition of the present invention, within the context of
»
a dosing regimen effective to treat the particular condition.
DETAILED DESCRIPTION OF THE INVENTION
The degree of crystalinity of the portion of the crystalline material is established using powder X-ray diffraction. The integrated peak intensity of the crystalline peaks divided by the overall integrated area of the pattern is used to deduce the percent of the crystalline portion. Crystalline peaks produced by an X-ray diffraction measurement, are characterized by having a half- value width below 2 degrees.
Amorphous solids, in contrast to crystalline forms, do not possess a distinguishable crystal lattice and do not have an orderly arrangement of structural units so that amorphous solids are not giving a definitive X-ray diffraction pattern (XRPD). They also do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point. Amorphous forms are generally more soluble, and thus they are desirable for pharmaceutical purposes because the bioavailability of amorphous compounds may be greater than their crystalline counterparts.
In one aspect, the invention encompasses amorphous bupropion hydrobromide. Preferably, the amorphous bupropion hydrobromide contains less than about 20% crystalline bupropion hydrobromide by weight, more preferably less than about 10% by weight, and even more preferably less than about 5% by weight.
Preferably, the amorphous form is free of detectable bupropion hydrobromide Form-I, II, and III crystalline peaks.
When the amorphous bupropion hydrobromide has less than about 1% crystalline bupropion hydrobromide by weight, the bupropion hydrobromide is purely amorphous.
In another aspect, the invention encompasses purely amorphous bupropion hydrobromide.
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Preferably, the purely amorphous form is free of detectable bupropion hydrobromide Form-I, II, and III crystalline peaks.
The invention encompasses processes for preparing amorphous bupropion hydrobromide by removing the solvent from the solution containing bupropion hydrobromide and an organic solvent and/or mixture with water.
The process of the present invention comprises: providing a solution of bupropion hydrobromide in at least one organic solvent and/or mixture with water; optionally, filtering the solvent solution to remove any extraneous matter and removing the solvent from the resulting solution to obtain amorphous bupropion hydrobromide.
The bupropion hydrobromide in the solution may be any crystalline or other form of bupropion hydrobromide, including various solvates and hydrates, as long as amorphous bupropion hydrobromide is produced during the process of the invention or bupropion hydrobromide obtaining an existing solution from a previous processing step.
Suitable organic solvents include, but are not limited to, alcoholic solvents having from 1 to 6 carbon atoms; aromatic solvents such as alkyl, aryl, halo substituted or unsubstituted aromatic solvents and the like; non-aromatic solvents such as chlorinated solvents, ketones, esters, and the like; and mixture thereof.
Bupropion hydrobromide can be present in any amount that will produce the amorphous form upon the process of the present invention. Preferably, the bupropion hydrobromide is present in an amount of about 1% to about 30% by weight of the solvent, more preferably about 1% to about 20% by weight, more preferably about 1% to about 10% by weight, and most preferably about 2% to about 7% by weight. One skilled in the art would understand that depending on the choice of solvent, the amount of bupropion hydrobromide used may be varied.
The solution may be heated to dissolve the bupropion hydrobromide. The , temperature suitable for dissolving bupropion hydrobromide depends on the solvent used and the amount of bupropion hydrobromide in the solution. Typically, the solution is
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heated at a temperature of at least about 30°C to about reflux. Preferably, the solution is heated at about 40°C to about 85°C, and more preferably at about 40°C to about 60°C. The solution may be prepared at other suitable temperatures as long as the bupropion hydrobromide is sufficiently dissolved. Increasing the amount of bupropion hydrobromide would generally require the use of higher temperatures. Routine experimentation will provide the approximate range of suitable temperatures for a given solvent and amount of bupropion hydrobromide. The resulting clear solution optionally filtered to remove any extraneous matter present in the solution using any standard filtration techniques known in the art.
Removal of the solvent from the resulting solution is accomplished by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain amorphous form and filtering the solid under inert atmosphere. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique. The solution may also be completely evaporated in, for example, a Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg or by flash evaporation techniques by using an agitated thin film dryer ("ATFD"), or evaporated by spray drying to obtain a dry amorphous powder.
One of the preferred methodologies to remove the solvent involves spray-drying, in which a solution of bupropion hydrobromide is sprayed into the spray drier at the flow rate ranging from 10 to 300 ml/hr, preferably flow rate is 40 to 200ml/hr. The air inlet temperature to the spray drier used may range from 25 to 200°C and preferably from 25° C to 150° C. An "inlet temperature" is the temperature at which the solution enters the spray dryer.
The outlet air temperature used may range from 5°C to 100°C, preferably outlet temperature is from about 5°C to about 60°C, and most preferably outlet temperature is from about 5°C to about 45°C . An "outlet temperature" is the temperature at which the gas exits the spray dryer.
Another preferred method is vertical agitated thin-film drying (or evaporation). Agitated thin film evaporation technology involves separating the volatile component
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using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled condition. In vertical agitated thin-film drying (or evaporation) (ATFD-V), the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor rotation agitates the downside-flowing solution while the heating jacket heats it.
The method using cooling the solution to preparing the amorphous bupropion hydrobromide comprises cooling the resultant solution after dissolution of starting bupropion hydrobromide in at least one organic solvent and/or mixture with water to temperature ranges from -20 to 20°C, preferably from 0 to 10°C. The resulting solid can then be filtered and washed with an organic solvent, to provide amorphous bupropion hydrobromide. Amorphous bupropion hydrobromide obtained by the present process can be dried using conventional drying process, as appropriate.
The bupropion hydrobromide in an amorphous form obtained by the above processes may be further dried in, for example, Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor, to further lower residual solvents.
Amorphous bupropion hydrobromide may be analyzed to determine the amorphous nature of the product. The X-ray powder diffraction pattern of amorphous bupropion hydrobromide would show no peaks characteristic of crystal forms of bupropion hydrobromide, thus demonstrating the amorphous nature of the product. The presence of peaks would indicate presence of crystalline bupropion hydrobromide. When there are peaks in an XRD pattern, the area under the peaks pattern may be combined to determine the total amount of crystalline material.
Amorphous or purely amorphous bupropion hydrobromide prepared according to the invention may be formulated into pharmaceutical compositions and dosage forms according to methods known in the art and used for the treatment of major depressive disorders.
In another aspect of the present invention provides amorphous bupropion hydrobromide, having a chemical purity of 98% or more as measure by HPLC, preferably
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99% or more, more preferably 99.8% or more. Moreover, the amorphous bupropion hydrobromide may be obtained substantially free of any unknown impurity, e.g., a content of less than about 0.1% of impurities.
Another aspect of the present invention is directed to a pharmaceutical composition containing at least the amorphous bupropion hydrobromide disclosed herein and at least one pharmaceutically acceptable carrier. Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectabe solution, etc.
In yet another aspect of the present invention, when a pharmaceutical composition comprising amorphous bupropion hydrobromide prepared according to the present invention is formulated for oral administration. Accordingly, D50 and D90 particle size of the unformulated amorphous bupropion hydrobromide of the present invention used as starting material in preparing a pharmaceutical composition generally is less than 300 microns preferably less than about 200 microns, more preferably less than 150 microns, still more preferably less than about 50 microns and still more preferably less than about 10 microns.
Any milling, grinding micronizing or other particle size reduction method known in the art can be used to bring the solid state amorphous bupropion hydrobromide of the present invention into any desired particle size range as set forth above.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or
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similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.
For purposes of the present invention, the following terms are defined below.
The term "composition" includes, but is not limited to, a powder, a suspension, an emulsion and/or mixtures thereof. The term composition is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. A "composition" may contain a single compound or a mixture of compounds.
The term 'pharmaceutical composition" is intended to encompass a product comprising the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, cornplexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing the active ingredient, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term "excipient" means a component of a pharmaceutical product that is not the active ingredient, such as filler, diluent, carrier, and so on. The excipients that are useful in preparing a pharmaceutical composition are preferably generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as; well as human pharmaceutical use. "A pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.
The term "isolating" is used to indicate separation of the compound being isolated regardless of the purity of the isolated compound from any unwanted substance which presents with the compound as a mixture. Thus, degree of the purity of the isolated or separated compound does not affect the status of isolating".
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It is known that different solid forms of the same drug may have substantial differences in certain pharmaceutically important properties such as dissolution characteristics and bioavailability, as well as stability of the drug. Furthermore, different physical forms may have different particle size, hardness and glass transition temperatures.
The invention also relates to a composition of solid amorphous bupropion hydrobromide wherein at least 80% of the total weight of bupropion hydrobromide is in the amorphous form. A preferred form of this composition, the solid amorphous bupropion hydrobromide is suitable for use as a bulk active ingredient in formulating pharmaceutical products. The remainder of the solid bupropion hydrobromide in the composition, i.e., 20% or less of the total weight of bupropion hydrobromide, may be other forms of bupropion hydrobromide, e.g., crystalline forms. In an aspect of the invention, the composition may include at least 95% of the amorphous form of bupropion hydrobromide with respect to total weight of the solid bupropion hydrobromide in the composition. In another aspect of the invention, the composition may include at least 99% of the amorphous form of bupropion hydrobromide with respect to total weight of the solid bupropion hydrobromide in the composition.
In addition to X-ray powder diffraction, amorphous bupropion hydrobromide, or the presence of some amorphous bupropion hydrobromide, can be distinguished from crystalline bupropion hydrobromide, using Raman spectroscopy, solution calorimetry, differential scanning calorimetry, solid state nuclear magnetic resonance specka (ssNMR) or infra-red spectroscopy. Each of these techniques is well established in the art. Amorphous bupropion hydrobromide can also be identified based on the morphology of the particles seen under an electron microscope.
Furthermore, pure amorphous bupropion hydrobromide is likely to be much more soluble than crystalline bupropion hydrobromide because the former is lack of lattice energy, providing another means of discriminating between the crystalline and
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amorphous bupropion hydrobromide forms, or detecting an amount of amorphous form within a bupropion hydrobromide preparation.
In another embodiment, the invention provides pharmaceutical compositions containing the bupropion hydrobromide in an amorphous form, which can be formulated with a one or more pharmaceutically acceptable carriers, also known as excipients, which ordinarily lack pharmaceutical activity, but have various useful properties which may, for example, enhance the stability, sterility, bioavailability, and ease of formulation of a pharmaceutical composition. These carriers are pharmaceutically acceptable, meaning that they are not harmful to humans or animals when taken appropriately and are compatible with the other ingredients in a given formulation. The carriers may be solid, semi-solid, or liquid, and may be formulated with the compound in bulk. The resulting mixture may be manufactured in the form of a unit-dose formulation (i.e., a physically discrete unit containing a specific amount of active ingredient) such as a tablet or capsule. Generally, the pharmaceutical compositions of the invention may be prepared by uniformly admixing the active ingredient with liquid or solid carriers and then shaping the product into the desired form. The pharmaceutical compositions may be in the form of suspensions, solutions, elixirs, aerosols, or solid dosage forms. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. A tablet may be prepared by direct compression, wet granulation, or molding, of the active ingredient(s) with a carrier and other excipients in a manner known to those skilled in the art. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets may be made on a suitable machine. A mixture of the powdered compound moistened with an inert liquid diluent is suitable in the case of oral solid dosage forms (e.g., powders, capsules, and tablets). If desired, tablets may be coated by standard techniques. The compounds of this invention may be formulated into typical disintegrating tablets, or into controlled or extended release dosage forms. The amount of active ingredient included in a unit dosage form depends on the type of formulation that is formulated. A pharmaceutical
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composition of the invention will generally include about 0.1% by weight to about 99% by weight of active ingredient, preferably about 1% by weight to 50%o by weight.
Suitable carriers include but are not limited to fillers, binders, lubricants, inert diluents, surface active/dispersing agents, flavorants, antioxidants, bulking and granulating agents, adsorbants, preservatives, emulsifiers, suspending and wetting agents, glidants, disintegrants, buffers and preadjusting agents, and colorants. Examples of carriers include celluloses, modified celluloses, cyclodextrins, starches, oils, polyols, , sugar alcohols and sugars, and others. For liquid formulations sugar, sugar alcohols, ethanol, water, glycerol, and polyalkylene glycols are particularly suitable, and may also be used in solid formulations. Cyclodextrins may be particularly useful for increasing bioavailability. Formulations for oral administration may optionally include enteric coatings known in the art to prevent degradation of the formulation in the stomach and provide release of the drug in the small intestine. One example of pharmaceutical tablet of the amorphous bupropion hydrobromide may include, as inactive ingredients, hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide, triacetin and 1 or more of synthetic red and yellow iron oxides and talc.
The active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of high energy dispersion or as coated particles. Suitable pharmaceutical composition of the invention may be in coated or uncoated form as desired.
Tabletting compositions may have few or many components depending upon the tabletting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in
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the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon" dioxide.
Capsule dosages will contain the solid composition within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carbdxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric coating.
Dated this Tuesday (10th) day of June, 2008

(Signed).
DR. Madhavi Karnik DY General Manager - IPM Glenmark Generics Limited
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