FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10, rule 13)
"AMORPHOUS RIZATRIPTAN BENZOATE AND PROCESS FOR THE
PREPARATION THEREOF"
Glenmark Pharmaceuticals 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 AND THE MANNER IN WHICH IT IS TO BE 'PERFORMED

PRIORITY
[0001] This application claims the benefit under Indian Provisional Application No.
1323/MUM/2005, filed on October 20, 2005, and entitled "AMORPHOUS RIZATRIPTAN BENZOATE AND PROCESS FOR THE PREARATION THEREOF" the contents of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
[0002] The present invention generally relates to an amorphous form of rizatriptan
benzoate and a process for its preparation.
2. Description of the Related Art
1*3003] Rizatriptan benzoate, also known as N,N-dimethyl-5-(lH-l,2,4-triazol-l-
ylmethyl)-lH-indole-3-ethanamine monobenzoate, can be represented by the structure of Formula I.

Rizatriptan binds with high affinity to human cloned 5-HTiB and 5-HTiD receptors. Rizatriptan has weak affinity for other 5-HTi receptor subtypes (5-HTiA, 5-HT)E, 5-HT)F) and the 5-HT7 receptor, but has no significant activity at 5-HT2, 5-HT3, alpha- and beta-adrenergic, dopaminergic, histaminergic, muscarinic or benzodiazepine receptors. Rizatriptan benzoate is marketed under the brand name of MAXALT® and indicated for the acute treatment of migraine attacks with or without aura in adults. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 1480, monograph 8324; and Physician's Desk Reference, "Maxalt," 58th Edition, p. 2013-2017 (2003).
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[0004] Processes for the preparation of rizatriptan benzoate are known. See, e.g., GB-
A-2315673; WO-A-95/32197; EP-A-497512; Cheng-yi Chen et al., Tetrahedron Letters, Vol. 35, pp. 6981-6984 (1994)and L.J.Stre et all- Journal of Medicinal Chemistry, Vol. 38, pp. 1799-1810 (1995). Each of the references disclose rizatriptan benzoate being isolated from ethanol as a white solid with a melting point of 178-180°C.
[0005] WO 2005/068453 ("the '453 application") discloses polymorphic Forms A and
B of rizatriptan benzoate. The '453 application further discloses that crystallization from a
C)-Cg alcohol produces Form A. i
[0006] The amorphous forms in a number of drugs exhibit different dissolution
characteristics and in some cases different bioavailability patterns compared to crystalline forms. See, e.g., Konne T., Chem Pharm Bull, 38, 2003 (1990). For some therapeutic indications, one bioavailability pattern may be favored over another. An amorphous form of cefuroxime axietil is an example of one amorphous drug exhibiting much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for cefdroxirn^ axie'til pharmaceutical dosage form development. Additionally, the aqueous solubility? .©'f ];cTy$talline atorvastatin calcium is lower than its amorphous form, which may result in the difference in their in vivo bioavailability. An amorphous form of rizatriptan benzoate has now been discovered.
SUMMARY OF THE INVENTION
[0007] In accordance with one embodiment of the present invention, an amorphous
form of rizatriptan benzoate is provided.
|008] In accordance with a second embodiment of the present invention, a process
for preparing an amorphous form of rizatriptan benzoate is provided, the process comprising
the steps of:
(a) preparing a solvent solution comprising non-amorphous rizatriptan benzoate and one or more solvents capable of dissolving the non-amorphous rizatriptan benzoate; and
(b) recovering the amorph^&lbrM'Ofrizairiptan benzoate from the solution.
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[0009] In accordance with a third embodiment of the present invention, a
pharmaceutical composition is provided comprising a therapeutically effective amount of an amorphous form of rizatriptan benzoate.
DEFINITIONS
[0010] The term "treating" or "treatTiunt" of a state, disorder or condition as used
herein means: (1) preventing or delaying the appearance of clinical symptoms of the state,
disorder or condition developing in a mammal that may be afflicted with or predisposed to the
state, disorder or condition but does not yet experience or display clinical or subclinical
symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition,
i.e., arresting or reducing the development of the disease or at least one clinical or subclinical
symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or
condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be
treated is either statistically significant or at least perceptible to the patient or to the physician.
[0011] The term "therapeutically effective amount" as used herein means the amount
of a compound that, when administered to a .mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
[0012] The term "delivering" as used herein means providing a therapeutically
effective amount of an active ingredient to a particular location within a host means causing a
therapeutically effective blood concentration of the active ingredient at the particular location.
This can be accomplished, e.g., by topical^ locator by systemic administration of the active
ingredient to the host.
[0013] The term "subject" or "a patient" or "a host" as used herein refers to
mammalian animals, preferably human.
[0014] The term "buffering agent" as used herein is intended to mean a compound
used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and-without limitation, potassium metaphosphate, potassium
4

phosphate, monobasic sodium acetate; and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.
[0015] The term "sweetening agent" as used herein is intended to mean a compound
used to impart sweetness to a preparation. Such compounds include, by way of example and
without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol,
sucrose, fructose and other such materials known to those of ordinary skill in the art.
[0016] The term "binders" as used* herein is intended to mean substances used to cause
adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.
[0017] When needed, other binders': may also be included in the present invention.
Exemplary binders include starch poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC™ F68, PLURONIC™ F127), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, polypropylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.
[0018] A "pharmaceutically acceptable carrier" refers to media generally accepted in
the; art for the delivery of biologically: active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the merapeu^;&d|eatii5H;--\|)feing targeted. Pharmaceutically acceptable carriers include both aqueous ahdrprt-^iie^^s' liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and
5

additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, 'e.g stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutical^ acceptable carriers, and factors involved, in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, which is incorporated herein by reference in its entirety.
[0019] The term "diluent or filler|" as used herein is intended to mean inert
substances used as fillers to create the desired, bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
[0020] The term "glidant as used herein is intended to mean agents used in tablet and
capsule formulations to improve flow-properties during tablet compression and to produce an
anti-caking effect. Such compounds include, by way of example and without limitation,
colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc,
combinations thereof and other such materials known to those of ordinary skill in the art.
[0021] The term "lubricant" as used herein is intended to mean substances used in
tablet formulations to reduce frictibtfdufihg^ablejtcompression. Such compounds include, by
way of example and without limitation,-calcium stearate, magnesium stearate, mineral oil,
stearic acid, zinc stearate, combinations1 thereof and other such materials known to those of
ordinary skill in the art.
[0022] The term "disintegrant" as used herein is intended to mean a compound used in
solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved; Exemplary disintegrants include, by way of example and without limitation, starches such^a|#6^; stareh^potato starch, pre-gelatinized and modified starched thereof, sweeteners, d^^]B^ht|asfi!behtonite, microcrystalline cellulose (e.g. Avicel™), carsium (e.g. AmberliteTM), alginates, sodium starch glycolate, gums such as agar,
6

guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
[0023] The term "wetting agent" as used herein is intended to mean a compound used
to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting
agents include, by way of , example;jiar^^wtithout; limitation, gelatin, casein, lecithin
(phosphatides), gum acacia, chole^tergl^tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax,
sorbitan esters, polyoxyethylene. alkyl ethers (e.g., macrogol ethers such as cetomacrogol
1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g.,
TWEEN™s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide,
phosphates, sodium dodecylsulfateiiearboxymethylcellulose calcium, carboxymethylcellulose
sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose,
Iiydroxypropylmethylcellulose phthalatej noncrystalline cellulose, magnesium aluminum
silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone (PVP), tyloxapol (a
nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or
triton), combinations thereof and other such materials known to those of ordinary skill in the art
[0024] Most of these excirie^sfarej ^escribed in detail in, e.g., Howard C. Ansel et al.,
Pharmaceutical Dosage Forms' !ahi;:(Diug«([|e%ery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipi^nts, (3rd Ed. 2000), which are incorporated by reference herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0025] The present invention- provides rizatriptan benzoate in an amorphous form. In
one. embodiment, the present invention provides rizatriptan benzoate substantially in an amorphous form. Substantially amorphous rizatriptan benzoate contains a very low content of crystalline rizatriptan benzoate, e.g., less than about 5% crystallinity, preferably less than about 2%, and more preferably less than about 1% crystallinity. Crystallinity may be
7

measured using methods familiar to those skilled in the art. Exemplary methods include, but are not limited to, powder X-ray difrractroriV^iMf eritial scanning calorimetry, dynamic vapor sorption, isothermal microcalorirrietry, inyefse gas chromatography, near infra-red spectroscopy, solid-state NMR arid the like:
[0026] Generally, rizatriptan benzoate in amorphous form can be prepared by at least
(a) preparing a solvent solution containing non-amorphous rizatriptan benzoate and one or
more solvents capable of dissolving the non-amorphous rizatriptan benzoate; and (b)
recovering the amorphous form of rizatriptan benzoate from the solution.
[0027] In step (a) of the process' of the present invention, non-amorphous rizatriptan
benzoate is dissolved in a solvent solution containing one or more solvents capable of dissolving rizatriptan benzoate to provide a clear solution. The non-amorphous rizatriptan benzoate used as a starting material in the process can be any known non-amorphous rizatriptan benzoate.
[0028] Suitable solvents for use herein include, but are not limited to, water, organic
e" like,:'a^imixtures thereof. Suitable alcohol-containing solvents include aromatic and aliphatic Ci-C 12 alcohols and the like and mixtures thereof. Suitable aliphatic alcohols include Gi-Cg alcohols such as, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol^ isdbutanol, tert-butanol and the like and mixtures thereof. Suitable aromatic alcohols include C3-C12 alcohols such as, for example, benzyl alcohol, benzyloxyethanol, phenoxyethanol and the like and mixtures thereof. Preferably the solvent is water or mixtures of water arid tan alcohol. Generally, the solvent can be present in an amount sufficient to dissolve the Parting1 material^ e.g., an amount ranging from about 2 to about 30% w/v and preferably frorn'ab6ut?5.t6 about 10% w/v. The dissolution can be carried out at a temperature ranging from about 20°G to about 80°C and preferably at room temperature.
[0029] If desired, the clear solution of step (a) can be filtered to remove any
extraneous matter present in the solution! using any standard filtration techniques known in the art. A filtering aid such as celite can be added'fb the -solution to assist in the filtration of the extraneous matter.
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[0030] In step (b) of the process of the present invention, rizatriptan benzoate in an
amorphous form is recovered from the solution. For example, amorphous rizatriptan benzoate
is recovered from the solution by substantially removing the solvent from the solution to
provide amorphous rizatriptan benzoate as, for example, a free-flowing powder. The solvent
may be removed by techniques well-known iniithe;art, for example, substantially complete
evaporation of the solvent, conce^ating-i&-iismution,-;cooling to a temperature sufficient to
precipitate an amorphous form and filtering the solid under nitrogen atmosphere. In one
embodiment, amorphous rizatriptan benzoate can be recovered by spray drying the solution.
[0031] When removing the solvent by evaporation, evaporation can be achieved at
sub-zero temperatures by the lyophilisation or freeze-drying technique. The solution may also be completely evaporated in a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques at a temperature of about 90°C, using ah-agitated thin film dryer ("ATFD"), or evaporated by spray drying at a temperature ranging from1 about room temperature to about 90°C to obtain a dry amorphous powder. When the solvent is* water, the solvent may be removed by distillation under vacuum in a pilot plant Rota vapor.
[0032] In another embodiment^ the solution may be concentrated under vacuum, for
example, about 720 mm Hg. For example; the initial mass is concentrated to about 1 to about 3 volumes. The concentration ma^M^takei plaice in, for example, a reactor with stirring, a rota vapor or vacuum paddle dryer with stirring1. ■ After concentrating the solution, the solution can then be cooled to a temperature of about 0PC to obtain a slurry. The slurry can then be filtered under controlled conditions using standard filtration techniques such as over a Nutsche filter, Agitated Nutsche filter, centrifugation, through a filter press or in a sparkler filter. Filtration can typically be carried out under controlled conditions such as, for example, a nitrogen atmosphere, a temperature 'bf about 25°C and a relative humidity ranging from about 45% to about 50%. The wet'^r0du'<#feayJttie:n be dried. Drying may be accomplished by evaporation, spray drying, dryin|'/'iifiaer"Wcuum, or freeze-drying. In one embodiment, the wet product can be dried at a temperature of about 60°C.
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[0033] The substantially pure amorphous rizatriptan benzoate 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.
[0034] Another embodiment of the present invention is directed to a process for
producing pure amorphous rizatriptan benzoate. Generally, the process includes (a) preparing
an organic solvent solution containing at least rizatriptan base, amorphous or crystalline, in an
alcoholic solvent capable of dissolving the starting material; (b) adding an aqueous or organic
solvent solution containing at least benzoic acid to the above solution of the base to provide a
clear solution in which the homogeneity of the clear solution is maintained or a slurry
containing the non-amorphous rizatriptan benzoate salt; (c) optionally filtering the cleai
solution to remove any extraneous matter in the case of aqueous or aqueous alcoholic
solution; and (d) recovering substantially pure amorphous rizatriptan benzoate from the
solution, e.g., by concentrating or evaporating the solution with or without heating solution at
atmospheric pressure or under vaCulim pr»fijtrati.6fi of the non-amorphous form of rizatriptan
benzoate followed by dissolution''0if--the;!h6ft-amorphous form in water or lower alcoholic
solvents such as methanol or ethanol of the mixtures thereof and evaporating the solvent by
methods such as, for example, freeze drying 01 spray drying as described hereinabove. The
concentration or evaporation may be carried out by any of the above described techniques.
[0035] Yet another embodiment of the present invention is directed to pharmaceutical
compositions containing at least/faf: therapeu^ally effective amount of the amorphous rizatriptan benzoate of the present invention. Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The amorphous rizatriptan benzoate:9|^PT"''tHi^ '.'pytfesefet' ■ invention may also be administered as suppositories, ophthalmic ointmeh#aii$ suspensions, and parenteral suspensions, which are administered by other routes. The dosage formr. may contain the amorphous rizatriptan
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b'enzoate of the present invention as is or, alternatively, as part of a composition. The
pharmaceutical compositions may further contain one or more pharmaceutically acceptable
excipients. Suitable excipients and the amounts to use may be readily determined by the
formulation scientist based upon experience and consideration of standard procedures and
reference works in the field, e;g., the buffering agents, sweetening agents, binders, diluents,
fillers, lubricants, wetting agents ^fdiSmiegrarit^ described hereinabove.
[0036] Capsule dosages willfcdritain'tf e aniorphous rizatriptan benzoate of the present
invention 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 containing at least phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid 'and'tnethyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the' surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.
[0037] Tableting compositions may have few or many components depending upon
the tableting method used, the release rate desired and other factors. For example, the
compositions of the present invehtion-may contain diluents such as cellulose-derived
materials like powdered cellulo^fef;:mi|fec^piiilihe cellulose, microfine cellulose, methyl
cellulose, ethyl cellulose, i'liydrbkyelhylV cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, cairboxymethyl 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 the
art. Yet other suitable diluents include) waxes, sugars (e.g. lactose) and sugar alcohols like
mannitol and sorbitol, acrylate''p'bl^^Va^d'Pc'(!jp6lymers, as well as pectin, dextrin and
gelatin. ; , ■ ;: /i;
[0038] 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
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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.
[0039] In one embodiment, the amorphous rizatriptan benzoate of the present
invention for use in the pharmaceutical compositions of the present invention can have a D50 and D90 particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 15 microns. It is noted the notation Dx means that X% of the particles have a diameter less .than a specified diameter D. Thus, a D50 of about 400 microns means that 50% of the mieronized particles in a composition have a diameter less than about 400 microns. The term "micronization" used herein means any process or methods by which the size of the particles is reduced For example, the particle sizes of the amorphous rizatriptan benzoate of the present invention can be obtained by any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state forms into any of the foregoing desired gartieleisiizeraaige.
[0040] Actual dosage levels of the amorphous rizatriptan benzoate of the present
Sjwerition may be varied to obtain an amount that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon such factors as, for example, the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors. The total daily dose of the compounds of this invention administered to a host in single or divided dose and can vary widely depending upon>a variety of 'factors including, for example, the body weight, general health, sex, diet, timeandjftfutei of-'administration, rates of absorption and excretion, combination with other drugs, the severity of the particular condition being treated, etc. The pharmaceutical compositions herein can formulated in any release form, e.g., immediate release, sustained release, controlled release, etc.
[0041] The following examples are provided to enable one skilled in the art to practice
the invention and are merely illustrMv^^ofthfe invention. The examples should not be read as limiting the scope of the invention as defined in 1 the claims.
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[0042] Preparation of non-amorphous rizatriptan benzoate
[0043] Rizatriptan base (1.0'kg) arnorphous was dissolved in isopropyl alcohol' (8;5 L)
at room temperature, a temperature,, ranging from about 25°C to about 30°C. Benzoic acid (0.49 kg) was dissolved in isopropyl acetate (3.5 L). The benzoic acid solution was added slowly to the solution of the rizatriptan base under nitrogen atmosphere with stirring. The reaction mixture was stirred for about 1 hour and filtered under nitrogen atmosphere. The filtrate was washed with isopropyl acetate (1.0 L) and dried at a temperature of about 60°C to obtain a non-amorphous rizatriptan benzoate. 'Weight: 1.0 kg.
EXAMPLE 2
[0044] Preparation of non-amorphous rizatriptan benzoate
[0045] Non-amorphous rizatriptan benzoate of Example 1 (1.0 kg) was dissolved in
isopropyl alcohol (8.5 L) at room terr^eria^ar^i Benzoic acid (0.49 kg) was dissolved in isopropyl acetate (3.5 L). The benzoic acid solution was added slowly to the solution of the rizatriptan base under nitrogen atmosphere with stirring. The reaction mixture was stirred for about 1 hour and filtered under nitrogen: atmosphere. The filtrate was washed with isopropyl acetate (1.0 L), and dried at a temperature of about 60°C to obtain a non-amorphous rizatriptan benzoate. Weight: 1.0 kg.;
:'EXAMPLE 3
[0046] Preparation of amor^poM;rizatriptan benzoate
[0047] Non-amorphous rizatriptan benzoate of Example 1 (1.0 kg) was dissolved in
water at room temperature and filtered through a filtration medium (or filter aid) to remove extraneous matter. The clear solution was spray-dried in a 'Lab-plant' model spray drier at a temperature of about 90°C to obtain a dry free-flowing amorphous powder. Weight: 0.7 kg.
EXAMPLE 4
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[0048] Preparation of amorphous rizatriptan benzoate
[0049] Non-amorphous rizatriptan benzoate of Example 1 (1.0 kg) was dissolved in
water at room temperature and filtered through a filtration medium (or filter aid) to remove extraneous matter. The clear solution was -subjected to distillation in a pilot plant Rota vapor under high vacuum until a dry free-flowing 'amorphous powder was obtained. Weight: 1.0 kg.
EXAMPLE 5
[0050] Preparation of amorphous rizatriptan benzoate
[0051] Rizatriptan base (1.0 kg) was dissolved in methanol (8.5 L) at room
temperature. Benzoic acid (0.49 kg) was dissolved in methanol (5 L). The benzoic acid solution was added slowly to the solution, of the rizatriptan base under nitrogen atmosphere with stirring. The reaction mixtufe'^as; stirred for about 1 hour. Water (5.0 L) was added to the clear rizatriptan benzoate solution. Methanol was stripped off under vacuum completely and the resulting in the aqueous solution of Uie benzoate salt, which is then filtered to remove any extraneous matter. The clear solution was subjected to lyophilisation for 24 hours until a free flowing amorphous solid is obtained.
[0052] Alternatively the amorphous'rizatriptan benzoate can be isolated from the
filtered aqueous solution by spray drying or distillation of water under high vacuum to get a
free-flowing amorphous powder.
Weight: 1.0 kg. .',,.,-
[0053] It will be understood that various modifications may be made to the
embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifiieatiqnis vof Referred embodiments. For example, the functions described above and irn^lern^te#as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in me art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto. ,.
14

WE CLAIM:
1. Rizatriptan benzoate in an amorophous form.
2. The amorphous rizatriptan benzoate of Claim 1, containing less than about 5%
crystalline rizatriptan benzoate.
3. A pharmaceutical composition comprising a therapeutically effective amount of the
compound as claimed in claim !>;and one or more pharmaceutically acceptable carriers,
excipients, or diluents.
4. The pharmaceutical composition ;as claimed in claim 3, wherein the amorphous
rizatriptan benzoate is a micronized amorphous rizatriptan benzoate having a particle size of
less than about 100 microns. ;
5. A process for preparing rizatriptan benzoate in an amorphous form as claimed in
claim 1, the process comprising the steps of:
(a) preparing a solvent solution comprising non-amorphous rizatriptan benzoate and
one or more solvents capable of dissolving the non-amorphous rizatriptan benzoate; and
(b) recovering the amorphous form of rizatriptan benzoate from the solution.
6. The process as claimed in claim 5, wherein the solvent is selected from the group consisting of water, alcohol and mixtures thereof.
7. The process as claimed in claim 6, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof.

Dated this Twentieth (20th) day of October, 2006

(Signed)
VISHAL A. SODHA
SENIOR MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED
15

ABSTRACT
[0054] Rizatriptan benzoate in an amorphous form is disclosed. Also disclosed is a
process for preparing rizatriptan benzoate substantially in amorphous form comprising the steps of (a) preparing a solvent solution comprising non-amorphous rizatriptan benzoate and one or more solvents capable of dissolving the non-amorphous rizatriptan benzoate; and (b) recovering the amorphous form of rizatriptan benzoate from the solution.