FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"ZINC SALT OF ROSUVASTATIN 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
1

FIELD OF THE INVENTION
The present invention generally relates to a novel zinc salt of the Rosuvastatin (also known as [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, a process for its preparation, pharmaceutical compositions containing same and a method of treatment for hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type Ha and IIb)comprising administration of the salt are provided.
BACKGROUND OF THE INVENTION
The present invention is directed to zinc salt of the Rosuvastatin (also known as [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid. Rosuvastatin has the following structural Formula I:

Generally, rosuvastatin is a synthetic lipid-lowering agent that acts as an inhibitor of 3 -hydroxy-3 -methylglutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoA Reductase inhibitor). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. HMG-CoA reductase inhibitors are commonly referred to as "statins." Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Rosuvastatin is used in the treatment of hypercholesterolemia (heterozygous familial and nonfamilial) and mixed
2

dyslipidemia (Fredrickson Type Ha and lib). Rosuvastatin calcium is sold under the brand name CRESTOR®.
U.S. Patent No. 5,260,440 ("the '440 patent") discloses pyrimidine derivatives such as rosuvastatin, its calcium salt (2:1) and its lactone form. The '440 patent further discloses a process for the preparation of pyrimidine derivatives in a four step reaction scheme.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention provides zinc salt of Rosuvastatin, that is, Rosuvastatin zinc.
In accordance with a second embodiment of the present invention, a process for the preparation Rosuvastatin Zinc is provided, which comprises contacting Rosuvastatin ester, rosuvastatin acid or salt thereof with zinc salt of an acid in a suitable solvent to form Rosuvastatin zinc.
In accordance with a third embodiment of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of a zinc salt of rosuvastatin.
In accordance with a fourth embodiment of the present invention, a method for treating hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (fredrickson type iia and iib) is provided, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a zinc salt of rosuvastatin.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRD pattern of Rosuvastatin Zinc salt.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with one embodiment of the present invention provides zinc salt of Rosuvastatin, that is, Rosuvastatin zinc.
In accordance with a second embodiment of the present invention, a process for the preparation Rosuvastatin Zinc is provided, which comprises contacting Rosuvastatin
3

ester, rosuvastatin acid or salt thereof with zinc salt of an acid in a suitable solvent to form Rosuvastatin zinc.
The zinc salt of an acid to be used in the process can be the salt of any inorganic or Organic acid. Examples of such salts include zinc chloride, zinc bromide, zinc nitrate, zinc sulphate, zinc phosphate, zinc carbonate, zinc oxalate, zinc acetate, zinc lactate, zinc succinate, zinc citrate and zinc tartrate.
Examples of suitable solvents for carrying out the process include water, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, chlorinated hydrocarbons such as methylene chloride and ethylene dichloride, cyclic ethers such as dioxan and tetrahydrofuran, alcohols such as methanol, ethanol and isopropanol, nitrites such as acetonitrile, dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide, and mixtures thereof.
In accordance with a third embodiment of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of a zinc salt of rosuvastatin.
In accordance with a fourth embodiment of the present invention, a method for treating hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (fredrickson type iia and iib) is provided, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a zinc salt of rosuvastatin.
In another aspect of the present invention provides a zinc salt of the rosuvastatin, having a chemical purity of 96% or more as measure by HPLC, preferably 99% or more, more preferably 99.5% or more.
In another aspect of the present invention provides a pharmaceutical composition containing at least a zinc salt of the rosuvastatin wherein the D50 and D90 particle size of the unformulated zinc salt of the rosuvastatin used as starting material is less than about 300 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 10 microns. Any milling, grinding micronizing or other particle size reduction
4

method known in the art can be used to bring the solid state a zinc salt of the rosuvastatin into any desired particle size range 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 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
5

and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as; well as human pharmaceutical use. "A pharmaceutical^ 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".
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.
In another embodiment, the invention provides pharmaceutical compositions containing the rosuvastatin zinc salt, 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,
6

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 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% 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 rosuvastatin zinc salt 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
7

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 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, carboxymethylethylcellulose, 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.
8

EXAMPLE
Process for the preparation of bis [7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino]-5-pyrimidinyl]-3, 5-dihydroxy-6-heptenoic acid zinc salt (Rosuvastatin Zinc)

Rosuvastatin tert-butyl ester (30.0 g) was dissolved in ethanol (300 ml) followed by addition of aqueous sodium hydroxide (2.25 g) dissolved in water (225.0 ml)), stirring the reaction mass for 1 hour at 25 - 30°C. Ethanol was removed by distillation from reaction mass under vacuum at 35 to 40°C. The resulted residue was dissolved in purified water (500.0 ml) and filtered through hyflo bed. 10% prefiltered aqueous zinc bromide solution (80.0 ml) was added dropwise to clear filtrate at 20 - 25°C followed by stirring for 2 hr at 20 - 25°C. The resulted solid was filtered and washed with purified water. The wet product was dried at 40 to 45°C under reduced pressure to afford 22.0 grams of 7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methylamino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid zinc salt (Rosuvastatin zinc).
Dated this Fourth (04th) day of August, 2006
(Signed) Y^^2 VISHAL AMRUTLAL SODHA SENIOR MANAGER-IPM GLENMARK PHARMACEUTICALS LIMITED
9