FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10, rule 13)
"POLYMORPHIC FORM OF OLMESARTAN AND PROCESS FOR ITS
PREPARATION"
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
461/MUM/2005, filed on April 12, 2005, and entitled "POLYMORPHIC FORM OF
OLMESARTAN AND PROCESS FOR ITS PREPARATION", the contents of each of which
are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
[0001] The present invention generally relates to a novel polymorphic form of
olmesartan medoxomil and a process for its preparation.
2. Description of the Related Art
{0002} The chemical name for olmesartan medoxomil is 2,3-dihydroxy-2-butenyl 4-
(1-hydroxy-1-methylethyl)-2-propyl-l-[p-(o-lH-tetrazol-5-ylphenyl)benzyl]imidzole-5-
carboxylate, cyclic 2,3-carbonate. Olmesartan medoxomil is represented by the structure of
formula I.
p

[0003] Olmesartan medoxomil is a prodrug that is hydrolyzed to olmesartan during
absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin
II receptor antagonist. Angiotensin II is formed from angiotensin I in a reaction catalyzed by
angiotensin converting enzyme (ACE, kinase II). Angiotensin II is the principal pressor agent
of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of
synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium.
Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the
2

binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Olmesartan
medoxomil is indicated for hypertension and is commercially sold under the trade name
Benicar®. See, e.g., The Merck Index, Thirteenth Edition, 2001, pp. 1223-24, monograph
6909; and Physician's Desk Reference, "Benicar," 58th Edition, pp. 3000-3001 (2004).
[0004J U.S. Patent No. 5,616,599 ("the '599 patent"), herein incorporated by
reference, discloses olmesartan medoxomil and a process for its preparation.
[0005] Polymorphism is the occurrence of different crystalline forms of a single
compound and it is a property of some compounds and complexes. Thus, polymorphs are
distinct solids sharing the same molecular formula, yet each polymorph may have distinct
physical properties. Therefore, a single compound may give rise to a variety of polymorphic
forms where each form has different and distinct physical properties, such as different
solubility profiles, different melting point temperatures and/or different x-ray diffraction
peaks. Since the solubility of each polymorph may vary, identifying the existence of
pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable
solubility profiles. It is desirable to investigate all solid state forms of a drug, including all
polymorphic forms, and to determine the stability, dissolution and flow properties of each
polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by
X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
Additionally, polymorphic forms of the same drug substance or active pharmaceutical
ingredient, can be administered by itself or formulated as a drug product (also known as the
final or finished dosage form), and are well known in the pharmaceutical art to affect, for
example, the solubility, stability, flowability, tractability and compressibility of drug
substances and the safety and efficacy of drug products.
[0006] Accordingly, there remains a need for improved forms of olmesartan
medoxomil and processes for their preparation.
SUMMARY OF THE INVENTION
[0007] In accordance with one embodiment of the present invention, a process for the
preparation of olmesartan medoxomil substantially in polymorph Form G is provided
comprising the steps of:
3

(a) providing a solution comprising olmesartan medoxomil and one or more solvents
selected from the group consisting of a nitrile, alcohol and mixtures thereof at a suitable
temperature; and
(b) recovering olmesartan medoxomil substantially in polymorph Form G from the
solution,
[0008] In accordance with a second embodiment of the present invention, olmesartan
medoxomil substantially in the polymorph Form G is provided.
[0009] In accordance with a third embodiment of the present invention, olmesartan
medoxomil substantially in the polymorph Form G and exhibiting a characteristic peak
(expressed in degrees 20 ± 0.2°6) at about 13.4 is provided.
[0010] In accordance with a fourth embodiment of the present invention, olmesartan
medoxomil substantially in the polymorph Form G and exhibiting characteristic peaks
(expressed in degrees 29 ± 0.2°9) at approximately one or more of the positions: about 13.4,
16.8 and/or 17.7 is provided.
[0011] In accordance with a fifth embodiment of the present invention, olmesartan
medoxomil substantially in polymorph Form G and characterized by having at least one of the
following properties is provided: (a) a differential scanning calorimetric (DSC) mermogram
substantially in accordance with Figure 1, (b) a X-ray diffraction (XRD) pattern substantially
in accordance with Figure 2, (c) a XRD pattern listing shown in Table 1 and/or (d) a
Thermogavimetric Analysis (TGA) substantially in accordance with Figure 3.
[0012] In accordance with a sixth embodiment of the present invention, olmesartan
medoxomil substantially in the polymorph Form G prepared by the process comprising (a)
providing a solution comprising olmesartan medoxomil and one or more solvents selected
from the group consisting of a nitrile, alcohol and mixtures thereof at a suitable temperature;
and (b) recovering olmesartan medoxomil in polymorph Form G from the solution is
provided.
[0013] In accordance with a seventh embodiment of the present invention, a
pharmaceutical composition is provided comprising a therapeutically effective amount of
olmesartan medoxomil substantially in the polymorph Form G and at least one
pharmaceutically acceptable excipient.
4

DEFINITIONS
[0014] The term "treating" or "treatment" 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.
[0015] 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.
[0016] 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, local or by systemic administration of the active
ingredient to the host.
[0017] As used herein, the term "buffering agent" 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
phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other
such material known to those of ordinary skill in the art.
[0018] As used herein, the term "sweetening agent" 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.
5

[0019] As used herein, the term "binders" 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, methyl cellulose, povidone and pregelatinized starch, combinations thereof and
other material known to those of ordinary skill in the art.
[0020] 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, poly(propylene 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.
[0021] As used herein, the term "diluent" or "filler" 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.
[0022] As used herein, the term "glidant" 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.
[0023] As used herein, the term "lubricant" is intended to mean substances used in
tablet formulations to reduce friction during tablet compression. Such compounds include, by
way of example and without limitation, calcium stearate, magnesium stearate, mineral oil,
6

stearic acid, zinc stearate, combinations thereof and other such materials known to those of
ordinary skill in the art.
[0024] As used herein, the term "disintegrant" 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 as corn starch, potato starch, pre-gelatinized and
modified starched thereof, sweeteners, clays, such as beritonite, micro crystalline cellulose
(e.g. Avicel™), carsium (e.g. Amberlite™), alginates, sodium starch glycolate, gums such as
agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such
materials known to those of ordinary skill in the art.
[0025] As used herein, the term "wetting agent" 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 and without limitation, gelatin, casein, lecithin
(phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glycerol monostearate, cetostearyl alcoho|5 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 dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose
sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose,
hydroxypropylmethylcellulose phthalate, noncrystalline Cellulose, magnesium aluminum
silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a
nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or
triton) is another useful wetting agent, combinations thereof and other such materials known
to those of ordinary skill in the art.
[0026] Most of these excipients are described in detail in, e.g., Howard C. Ansel et al.,
Pharmaceutical Dosage Forms and Drug Delivery 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 Excipients, (3rd Ed. 5.000), which are incorporated by
reference herein.
7

BRIEF DESCRIPTION OF THE DRAWINGS
[0027J Figure 1 is a characteristic DSC thermogram of polynaorph Form G of
olmesartan medoxomil.
[0028] Figure 2 is a characteristic XRD pattern of polymorph Form G of olmesartan
medoxomil.
[0029] Figure 3 illustrates the graphical results of a Thermogavimetric Analysis of
polymorph Form G of olmesartan medoxomil,
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0030] The present invention is directed to a novel polymorphic form of olmesartan
medoxomil, designated Form G. Olmesartan medoxomil substantially in the polymorph G
form may be used in a pharmaceutical composition as, for example, an antihypertensive. In
general, a process for preparing olmesartan medoxomil substantially in polymorph Form G
includes at least (a) preparing a solution containing at least olmesartan medoxomil with a
solvent selected from the group consisting of one or more nitriles, one or more alcohols and
mixtures thereof at a suitable temperature; and (b) recovering olmesartan medoxomil
substantially in polymorph Form G from the solution.
[0031] Olmesartan medoxomil is well known and can be obtained by any method
known in the art. See, e.g., U.S. Patent No. 5,616,599 and U.S. Patent Application
Publication No. 2006/0069141, the contents of each of which are incorporated by reference
herein. In step (a) of the process of the present invention, a solution containing at least
olmesartan medoxomil and one or more solvents selected from the group consisting of a
nitrile, alcohol and mixtures thereof is prepared at a suitable temperature by, for example,
dissolving olmesartan medoxomil in one or more of the solvents. Suitable nitriles include,
but are not limited to, acetonitrile, propionitrile and the like and mixtures thereof. Suitable
alcohols include those having from 1 to about 12 carbon atoms such as, for example,
methanol, ethanol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, and the like and
mixtures thereof. Preferred solvents for use herein include acetonitrile, methanol, ethanol and
8

mixtures thereof, and most preferably methanol. The solvent(s) will ordinarily be present in
an amount ranging from about 2 volumes to about 30 volumes.
[0032] In preparing the solution, olmesartan medoxomil may be stirred in the solvent
at a temperature ranging from about 25°C to about 75°C, preferably at about 30°C to about
60°C, and most preferably at about 40°C to about 50°C. The solution may then be cooled to
induce crystallization. Preferably, the solution is cooled to a temperature ranging from about
-10°C to about 30°C, preferably to about -5°C to about 20°C, and most preferably to about
0°C to about 10°C by techniques known in the art. A crystalline solid will then precipitate out
of the solution. The resulting crystals may then be recovered by techniques well known in the
art, e.g., filtration, centrifugation, decanting, etc. The filtered solid may then be washed and
dried to produce crystals of Form G of olmesartan medoxornil.
[0033] The present invention also provides olmesartan medoxomil substantially in
polymorph Form G. Crystallinity of the novel polymorph may be measured using methods
familiar to those skilled in the art. The novel polymorph of the present invention as described
hereinbelow was characterized by a DSC thermogram, X-ray powder diffraction (XRD), and
Thermogavimetric Analysis. As shown in Figure ], polymorph Form G of olmesartan
medoxomil exhibits a predominant endothermic peak at about 105.23°C as measured by a
Differential Scanning Calorimeter (DSC 822, Mettler Toledo) at a scan rate of 10°C per
minute with an Indium standard. In this regard, it should be understood that the endotherm
measured by a particular differential scanning calorimeter is dependent upon a number of
factors, including the rate of heating (i.e., scan rate), the calibration standard utilized,
instrument calibration, relative humidity, and upon the chemical purity of the sample being
tested. Thus, an endotherm as measured by DSC on the instrument identified above may vary
by as much as ± 1 °C or even ±1I/2oC. Accordingly, the tenn "about 105.23°C" is intended to
encompass such instrument variations.
[0034] The X-Ray powder diffraction spectrum for the polymorph was measured as
known in the art, e.g., by an X-ray powder Diffractometer. Olmesartan medoxomil
substantially in polymorph Form G can be characterized by an XRD pattern which exhibits
characteristic peaks (expressed in degrees 28 ± 0.2°9) at about 13.4, 16.8 and/or 17.7.
Additional peaks are listed in Table I below.
9

[0035] In one embodiment, olmesartan medoxomil substantially in polymorph Form
G of the present invention has at least one, and preferably all, of the following properties:
(a) a DSC thermogram with an endothermic peak at about 105.23°C;
(b) a DSC pattern pattern substantially in accordance with Figure 1;
(c) a X-ray powder diffraction pattern substantially in accordance with Figure 2;
(d) a TGA pattern substantially in accordance with Figure 3; and/or
(e) a XRD pattern comprising characteristic peaks summarized in Table 1 below:
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TABLE 1

Relative
Intensity (%) Angle (26)
28.14 4.59006
24.98 8.75645
21.91 9.09096
48.50 10.38614
28.81 10.51912
58.67 13.31240
88.10 13.42330
15.73 14.00358
18.14 15.65376
27.37 16.13896
24.74 16.23844
62.76 16.75931
60.02 17.72515
40.96 18.43222
22.90 19.27729
20.67 19.35142
30.81 20.48076
26.41 21.07227
25.26 21.29568
21.60 21.73946
100.00 23.12553
18.89 23.87661
21.09 24.81594
25.97 28.57259
42.00 28.96676
11

[0036] Figure 3 shows the results of a Thermogavimetric Analysis of polymorph
Form G of olmesartan medoxomil. The Thermogavimetric Analysis was performed using a
Mettler Toludo TA4000 Series (TG50) thermoanalyzer system. Approximately 8 to 8.5 mg of
the sample was accurately weighed in an aluminum crucible. The samp/e was heated from
35-350°C @5°C/min under nitrogen pressure.
[0037] Yet another aspect of the present invention is directed to pharmaceutical
compositions containing at least olmesartan medoxomii substantially in polymorph Form G
disclosed herein. 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. Oral dosage forms include, but are not limited to, tablets, pills,
capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The
olmesartan medoxomil substantially in polymorph Form G disclosed herein also may be
administered as suppositories, ophthalmic ointments and suspensions, and parenteral
suspensions, which are administered by other routes. The dosage^forms may contain the
olmesartan medoxomil substantially in polymorph Form G disclosed herein as is or,
alternatively, may contain the olmesartan medoxomil substantially in polymorph Form G
disclosed herein 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 and
disintegrants described hereinabove.
[0038J Capsule dosages will contain olmesartan medoxomil substantially in
polymorph Form G 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, carboxy methyl ethyl cellulose, 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
12

capsule may have a coating on the surface of the capsule or may be a capsule comprising a
powder or granules with an enteric-coating.
[0039] A composition for tableting or capsule filing can be prepared by wet
granulation. In wet granulation, some or all of the active ingredients and excipients in powder
form are blended and then further mixed in the presence of a liquid, typically water, which
causes the powders to clump up into granules. The granulate is screened and/or milled, dried
and then screened and/or milled to the desired particle size. The granulate can then be
tableted or other excipients can be added prior to tableting, such as a glidant and/or a
lubricant.
[0040] A tableting composition can be prepared conventionally by dry blending. For
example, the blended composition of the actives and excipients can be compacted into a slug
or a sheet and then comminuted into compacted granules. The compacted granules can be
compressed subsequently into a tablet. As an alternative to dry granulation, a blended
composition can be compressed directly into a compacted dosage form using direct
compression techniques. Direct compression produces a more uniform tablet without
granules.
[0041] 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 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.
[0042] 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
13

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.
[0043] In one embodiment, the olmesartan medoxomil substantially in poiymorph
Form G disclosed herein 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. The particle sizes can be
obtained by, for example, any milling, grinding, micronizing or other particle size reduction
method known in the art to bring the solid state olmesartan medoxomil substantially in
polymorph Form G into any of the foregoing desired particle size range.
[0044] Actual dosage levels of olmesartan medoxomil substantially in polymorph
Form G may be varied to obtain an amount of olmesartan medoxomil substantially in
polymorph Form G that is effective to obtain a desired therapeutic response for a particular
composition and method of administration for treatment of a mammal. 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 novel polymorph 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, time and route of administration, rates of absorption and excretion,
combination with other drugs, the severity of the particular condition being treated, etc.
[0045] The following example is provided to enable one skilled in the art to practice
the invention and is merely illustrative of the present invention. The example should not be
read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLE 1
[0046] Preparation of Polymorph Form G of Olmesartan Medoxomil
[0047] A four-neck 500 ml flask equipped with a mechanical stirring condenser and
thermometer was charged with methanol (100 ml) and olmesartan medoxomil (10 g; 18
mmol) was slowly added. The suspension was slowly heated to a temperature ranging from
14

about 45°C to about 50°C and maintained for about 60 minutes. Next, about 60-70ml of
methanol was distilled. The mixture was then slowly cooled to room temperature and then
further cooled to a temperature ranging from about 0°C to about 5°C such that crystalline
olmesartan medoxomil precipitated out of solution. The precipitate product was filtered on a
Buchner funnel and washed with methanol (10 ml). The filtered product was then dried to
provide polymorph Form G of olmesartan medoxomil (5 g). Yield - 50%.
[0048] The average values of diffraction angles and the relative intensities in the
powder X-ray diffraction spectrum of olmesartan medoxomil substantially in polymorph
Form G are given above in Table 1. The DSC, XRD and TGA of the final product are set
forth in Figures 1-3, respectively, and were recorded and identified as polymorph Form G of
olmesartan medoxomil.
[0049] While the above description contains many specifics, these specifics should not
be construed as limitations of the invention, but merely as exemplifications of preferred
embodiments thereof. Those skilled in the art will envision many other embodiments within
the scope and spirit of the invention as defined by the features and advantages appended
hereto.
15

WE CLAIM:
1. A process for the preparation of olmesartan medoxomil substantially in polymorph
Form G, the process comprising:
(a) providing a solution comprising olmesartan medoxomil and one or more solvents
selected from the group consisting of a nitrile, alcohol and mixtures thereof at a suitable
temperature; and
(b) recovering olmesartan medoxomil substantially in polymorph Form G from the
solution.

2. The process of Claim 1, wherein the solvent is a nitrile selected from the group
consisting of acetonitrile, propionitrile and mixtures thereof.
3. The process of Claim 1, wherein the solvent is an alcohol having from 1 to about
12 carbon atoms.
4. The process of Claim 1, wherein the solvent is an alcohol selected from the group
consisting of methanol, ethanol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol and
mixtures thereof.
5. The process of Claim 1, wherein the solvent is a nitrile selected from the group
consisting of acetonitrile, propionitrile and mixtures thereof and an alcohol selected from the
group consisting of methanol, ethanol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol and
mixtures thereof.
6. The process of Claim 1, wherein the solvent is present in an amount of about 2 to
about 30 volumes.
16

7. The process of Claim 1, wherein the solution is cooled to precipitate olmesartan
medoxomil substantially in polymorph Form G out of the solution and the precipitate is
filtered to recover olmesartan medoxomil substantially in polymorph Form G.
8. The process of Claim 1, wherein the olmesartan medoxomil substantially in
polymorph Form G is recovered by crystallization out of the solution.
9. Olmesartan medoxomil substantially in polymorph Form G prepared by the process
of Claim 1.
10. Olmesartan medoxomil substantially in polymorph Form G.
11. Olmesartan medoxomil substantially in polymorph Form G and exhibiting a
characteristic peak (expressed in degrees 20 ± 0.2°9) at about 13.4.
12. The olmesartan medoxomil substantially in polymorph Form G of Claim 11,
further characterized by exhibiting characteristic peaks (expressed in degrees 26 ± 0.2°8) at
approximately one or more of the positions: about 13.4, 16.8 and/or 17.7.
13. The olmesartan medoxomil substantially in polymorph Form G of Claim 11,
further characterized by having at least one of the following properties: (a) a differential
scanning calorimetric (DSC) thermogram substantially in accordance with Figure 1, (b) a X-
ray diffraction (XRD) pattern substantially in accordance with Figure 2, and/or (c) a
Thermogavimetric Analysis (TGA) substantially in accordance with Figure 3.
14. The olmesartan medoxomil substantially in polymorph Form G of Claim 11,
further characterized by having a XRD pattern substantially in accordance with Figure 2.
15. The olmesartan medoxomil substantially in polymorph Form G of Claim 11,
further characterized by a DSC thermogram with an endothermic peak at about 105.23°C.
17

16. A pharmaceutical composition comprising a therapeutically effective amount of
olmesartan medoxomil substantially in polymorph Form G and one or more pharmaceutically
acceptable excipients.
17. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G is a micronized olmesartan medoxomil substantially in
polymorph Form G having a particle size of less than about 400 microns.
18. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G is a micronized olmesartan medoxomil substantially in
polymorph Form G having a particle size of less than about 200 microns.
19. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G is a micronized olmesartan medoxomil substantially in
polymorph Form G having a particle size of less than about 150 microns.
20. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G is a micronized olmesartan medoxomil substantially in
polymorph Form G having a particle size of less than about 50 microns.
21. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G is a micronized olmesartan medoxomil substantially in
polymorph Form G having a particle size of less than about 15 microns.
22. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G exhibits a characteristic peak (expressed in degrees 20 ±
0.2°9) at about 13.4.
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23. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G is further characterized by exhibiting characteristic peaks
(expressed in degrees 20 ± 0.2°9) at approximately one or more of the positions: about 13,4,
16.8 and/or 17.7.
24. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G is further characterized by having at least one of the
following properties: (a) a DSC thermogram substantially in accordance with Figure 1, (b) a
XRD pattern substantially in accordance with Figure 2, and/or (c) a TGA substantially in
accordance with Figure 3.
25. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G is further characterized by having a XRD pattern
substantially in accordance with Figure 2.
26. The pharmaceutical composition of Claim 16, wherein the olmesartan medoxomil
substantially in polymorph Form G is further characterized by a DSC thermogram with an
endothermic peak at about 105.23°C.
27. A method for treating or preventing hypertension comprising administering to a
subject in need of such treatment or prevention a therapeutically effective amount of the
olmesartan medoxomil substantially in polymorph Form G of Claim 10.
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Dated this Twelfth (12th) day of April, 2006