Patent,ibubrofen sodium tablets,sticking,immediate release tablet

1. (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property
Organization
International Bureau
(10) International Publication Number
(43) International Publication Date WO 2017/060920 Al13 April 2017 (13.04.2017) P O P C T
(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
A61K 31/00 (2006.01) D01G 13/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM,
A61Q 13/00 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
(21) International Application Number: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME,
PCT/IN2016/050337 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ,
(22) International Filing Date: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA,
5 October 2016 (05. 10.2016) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM,
TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
(25) Filing Language: English ZW.
(26) Publication Language: English 4 Designated States (unless otherwise indicated, for every
(30) Priority Data: kind of regional protection available): ARIPO (BW, GH,
5304/CHE/2015 5 October 201 5 (05. 10.2015) IN GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
(71) Applicant: STRIDES SHASUN LIMITED [IN/IN]; TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
165/2 Bilekahalli Village, Begur Hobli, Bangalore South DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
Taluk, JP Nagar 7th Phase, Bannerghatta Road, Opposite LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
to Kalyani Magnum, Bengaluru 560076 (IN). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
GW, KM, ML, MR, NE, SN, TD, TG).
(72) Inventors: SUNDARARAJAN, Gurubalaji; Door No.
34, Periyanna Street, Kaikkolan Thottam, Erode, Tamil Declarations under Rule 4.17 :
Nadu, Erode 638001 (IN). SARKER, Shubhrangshu
— as to applicant's entitlement to apply for and be granted a
Shekher; S/o Subhas Chandra Sarker, Chandibhawan,
patent (Rule 4.1 7(H))
Newtown Post, Jalpaiguri District, West Bengal 735 101
(IN). RAMALINGAM, Selvakumar; No. 354, South — as to the applicant's entitlement to claim the priority of the
Street, Kodali Post, Udayarpalayam Taluk, Perambalur earlier application (Rule 4.1 7(in))
District, Tamil Nadu 612902 (IN). DEVARAJAN, Sam- — of inventorship (Rule 4.17(iv))
pathkumar; Plot No.l, Flat Fl, MBM Flats, Balamurugan
Nagar, 3rd Street, Velacherry, Chennai, Tamil Nadu Published:
600042 (IN). — with international search report (Art. 21(3))
(74) Agent: P., Aruna Sree; Gopakumar Nair Associates, 3rd — before the expiration of the time limit for amending the
Floor, 'Shivmangal', Near Big Bazaar, Akurli Road, Kan- claims and to be republished in the event of receipt of
divali (East), Maharashtra, Mumbai, 400101 (IN). amendments (Rule 48.2(h))
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
©
©
o
(54) Title: PHARMACEUTICAL COMPOSITIONS
o (57) Abstract: Disclosed herein is a pharmaceutical composition of Ibuprofen or its pharmaceutically acceptable salt, enantiomers
thereof and methods of preparing them. The present invention further discloses a cost effective method of producing stable pharma
o ceutical compositions of Ibuprofen or its pharmaceutically acceptable salts, enantiomers thereof. The process of the present inven
tion involves the use of glidant in three stages of formulation to obtain free flowing granules that impart better mold release proper
ties and minimize the tablet weight variation.

2. ' PHAR MAC EUTICA L COM POSITIONS O F IBUPROF EN AND
PROC ESS T H EREO F.
FIE L D O F T HE INV ENTION:
The present invention relates to pharmaceutical compositions of Ibuprofen or its
pharmaceutically acceptable salt, enantiomers thereof and methods of preparing
them. Particularly, the present invention relates to a cost effective method of
producing stable pharmaceutical compositions of Ibuprofen or its
pharmaceutically acceptable salts, enantiomers thereof. The process of the present
invention particularly involves the use of glidant in three stages of formulation to
obtain free flowing granules that impart better release properties and minimize the
tablet weight variation.
BAC K GROUND O F T H E INV ENTION:
Ibuprofen, chemically known as 2-(4~isobutyl phenyl) propionic acid, is a well-
known medicament or NSAID with anti- inflammatory, antipyretic, and analgesic
activities. Ibuprofen is primarily used for the treatment of pain and inflammation
in musculoskeletal disorders such as rheumatoid arthritis, ankylosing spondylitis,
osteoarthritis, postoperative pain, post partum pain, headache, backache,
neuralgia, dysmenorrhoea, dental pain, colds and flu and soft tissue injuries,
generally at doses up to 3200 mg per day. Ibuprofen and its compositions are
disclosed in US3228831 and US3385886.
Active ingredients with a low melting range, such as ibuprofen or its
pharmaceutically acceptable salts, especially the sodium salt, that is described
as fluffy, soft, sticky, especially poorly compressible and also as having a poor
ability to be granulated, can lead to serious difficulties in the processing of
formulation, as a consequence of sintering processes and through sticking to the
punch and die plates of the tablet press and low tableting speeds. Even during the
mixing process to produce dry ibuprofen or its salt containing mixtures there may
be sticking of the mixing tools especially with a high energy input and heating of

3. the agitators. The sticking can admittedly be rectified by the addition of a large
quantity of anti-sticking agents. However, using said mixing process the end
mixtures become hydrophobic and the release of the active ingredient is slowed
thereby. Problems further arise in the processing of ibuprofen or its
pharmaceutically acceptable salt containing mixtures especially with relatively
low compressive forces too in order to save the high-cost compression tools from
wear. The unwanted phenomenon of adhesion to the compression tools is
observed to persist as the duration of production cycle increases.
Compositions produced by wet granulation method require relatively large
percentages of excipients to produce a compressible formulation, leading to
increase in tablet size which is undesirable both from manufacturing and
handling standpoint and a patient acceptability standpoint.
US4609675 discloses a method of preparing a pharmaceutical ibuprof en-
containing granulate composition suitable for preparing tablets of relatively high
dosage. This is accomplished by dry mixing ibuprofen with 1 to 15 percent by
weight of croscarmellose sodium as disintegrant and small amounts of colloidal
silica with short mixing times in the region of a few minutes, and is subsequently
roll -compacted. Croscarmellose sodium is a relatively expensive additive and it
contributes significantly to the cost of the formulation. A n insufficient
improvement in tablet ability is achieved with these formulations.
US4806358 discloses tablet composition manufactured through aqueous/non-
aqueous granulation comprising ibuprofen or a pharmaceutically acceptable salt
thereof, a pharmaceutically acceptable effervescent couple that produces carbon
dioxide in the presence of water, a pharmaceutically acceptable surfactant, a
pharmaceutically acceptable water-insoluble hydrophilic polymer consisting of
microcrystalline cellulose and croscarmellose sodium and a saccharide, for
example sucrose, lactose, dextrose or sorbitol, to enhance the stability of the
composition dispersed therein. The physico chemical stability of effervescent

4. formulations is relatively less comparable to conventional formulations and need
special precautions and packaging materials.
US4839176 discloses a stable composition comprising ibuprofen or a
pharmaceutically acceptable salt thereof, codeine or a pharmaceutically acceptable
salt thereof together with a sufficient amount of pharmaceutically acceptable
insoluble salt of carboxymethyl cellulose to prevent discoloration of the
composition.. The composition based on ibuprofen and codeine is ineffective and
is not patient compliant.
US4859704 discloses water soluble alkali metal salt (potassium and sodium) of
ibuprofen prepared by reacting ibuprofen and alkali metal bicarbonate in an
aqueous medium. This process of wet granulation involves the evolution of C0 2
gas, which may lead to pressurization inside the reactor which makes the process
less attractive.
US4904477 discloses a spray dried ibuprofen composition suitable for direct
compression into tablets and include a spray dried dispersion in water of
ibuprofen, pregelatinized starch, a disintegrate and a wetting agent. Spray drying
is a complex granulation method, which involves use of high temperatures.
US491 1921 provides a granular pharmaceutical composition containing t
ibuprofen, binder, and polyvinyl pyrrol idone, wherein the polyvinyl pyrrol idone
forms a film with a portion of said binder to form agglomerates. The process for
preparing the tablets includes fluidizing Ibuprofen with a portion of the binder in a
fluid bed apparatus and spraying the aqueous dispersion of polyvinylpyrrolidone
and the remainder of the binder. The granulation may be subsequently blended
with additional excipients and, optionally, additional active pharmaceutical
ingredients for direct compression into tablets. The process requires extra
processing steps involving sophisticated equipment and a relatively high operating
cost.

5. US5191 114 discloses a process for producing ibuprofen powders for direct
tableti ng, in which powders with improved flowability are said to be obtained by
dry mixing of ibuprofen with amorphous silica gel. Direct compressible ibuprofen
particles are also formed by treating commercially available, dry ibuprofen with a
hydrophilic solvent or a mixture of a hydrophilic solvent and one or more
hydrophobic organic solvents so as to change at least the external crystalline
shape of the ibuprofen from a flow- retarding shape to a free-flowing, easily
compressible configuration. A typical hydrophilic solvent is water and among the
hydrophobic solvents which may be used are acetone, methyl alcohol, ethyl
alcohol, isopropyl and N-propyl alcohol. A s is known to the skilled worker, the
flowability can be improved in this way after only a short mixing time. However,
the tablet ability is not improved in practice in this way.
US5445827 relates to an effervescent ibuprofen preparation comprising a) basic
granules consisting of 1 part by weight of water-soluble ibuprofen salt preferably
sodium salt, 2 to 10 parts by weight of excipient, 0.3 to 0.8 part by weight of
stabilizer and 0.1 to 1 part by weight of sodium carbonate or potassium carbonate
and b) 1 to 4 parts by weight of an acid component. The patent did not have the
object to describe (the preparation of) a very water soluble ibuprofen granulates in
an efficient and cheap manner from insoluble ibuprofen. The physico chemical
stability of effervescent formulations is relatively less comparable to conventional
formulations and thus need special precautions and packaging materials.
US5320855 discloses a chewable medicament tablets made from coated
rotogranules of a medicament wherein the rotogranules are formed from a wet
granulation mixture of medicament, e.g. ibuprofen, polyvinylpyrrolidone, sodium
starch glycolate and sodium lauryl sulfate and the rotogranules are coated with
hydroxyl ethyl cellulose or a mixture of hydroxyl ethyl cellulose and hydroxyl
propyl methyl cellulose and a process for making such tablets and a method of
providing taste masking of medicaments utilizing such coated rotogranules in a
tablet. While resulting in a significant taste improvement, this method has been

6. found not to completely eliminate the throat burn_ associated with ibuprofen in
chewabl e dosage forms.
US5696165 discloses the use of the sodium salt of S(+)-ibuprofen dihydrate with
a pharmaceutical composition comprising 10-99% wA/v of S(+)-ibuprofen sodium;
1-90% w/w of a diluent; 0.1-10% w/w of a lubricating agent; 0.1-15% w/w of a
disintegrating agent; optionally 0.1-15% w w of a binder and optionally 0.1-10%
of a flow aid. It permits the preparation of a tablet using wet granulation technique
comprising dissolving polyvinyl pyrrolidone in a mixture of isopropanol and
water (1:1 parts by vol ume).
US61 97336 discloses a tablet composition comprising ibuprofen, arginine, linear
poly vinyl pyrrolidone, and alkaline bicarbonate having good workability and fast
dissolution so as to assure a prompt analgesic effect. The patent states that it is
possible that during preparation of the composition and/or tablets, some
interaction or reaction may occur between two or more components, but it is silent
about the extent and type of such interaction. The tablets containing 200 mg
ibuprofen weigh 600 mg which is rather large for such dosage; tablets containing
400 mg ibuprofen weigh 980 mg which can hardly be swallowed. Moreover, the
large quantity of expensive arginine required significantly increases the costs.
US8846085 discloses a directly tabletable ibuprofen formulation comprising
crystalline ibuprofen; finely divided silica with a surface area of at least 100 rr /g
together with pharmaceutically acceptable excipients wherein at least 50% of the
surface of the ibuprofen crystals is covered with finely divided excipient.
US20020034540 discloses a solid non-effervescent compressed dosage form
comprising ibuprofen combined with a disintegrating component. The
composition comprises a carrier material such as alkali metal carbonate or
bicarbonate in an amount such that the dosage form has a crushing strength in the
range 6.5-15Kp and a disintegration time of less than 10 minutes. The dosage

7. form is supposedly particularly advantageous to the formulation with the poorly
compressible alkali metal salts and especially the sodium salt, that is described as
fluffy, soft sticky, especially poorly compressible and also as having a poor
ability to be granulated. Further US20020034540 discloses the wet granulation
process comprising pre-granulating ibuprofen with a binder, such as polyvinyl
pyrrol idone in water or hydrocarbon solvent.
US20040102522 provides directly compressible dosage form of sodium
ibuprofen and discloses a non -effervescent tablet of ibuprofen, comprising a
tablet core and, if desired, a sugar or film coat, wherein the tablet core, based on
the weight of the tablet core, consists of 50 to 100% by weight sodium ibuprofen
hydrate and 50 to 0% by weight auxiliary material component and contains no
lubricant and no disintegrant, and wherein the sodium ibuprofen hydrate has a
water content of 8 to 6% by weight preferably to 6% by weight, possesses a
sufficient hardness, is comparably small and leads to a particularly rapid increase
in blood level and thereby to an accelerated onset of analgesic effect. However,
the tablets only possess sufficient not optimal hardness and contain large total
sodium content which is not advantageous to patients, especially frequent and
daily users of such over the counter medicaments. Further, crumbling and
breakage of such tablets prior to ingestion may lead to uncertainty as to the dosage
of active ingredient per tablet and core defects, including picking and sticking.
Furthermore, high friability also causes tablet breakage leading to waste during
factory handling.
US20100323005 discloses sodium ibuprofen compositions and methods of
manufacturing tablets and caplets using roller compaction. Tablets made by roll
compaction often show inferior tensile strength compared to tablets prepared by
wet granulation or direct compaction. Because this phenomenon is more profound
in plastic substances, adjusting the plastic/brittle balances of starting materials by
selecting appropriate excipients is much more. Also, minimum compaction force
should be used, as well as a smaller particle size of starting powder is required. A

8. second disadvantage of roll compaction is the production of noniiompacted
powder. Because no liquid binder is used, high amounts of fines remain and less
product yield is obtained.
The problems associated with the prior art compositions of ibuprofen and
processes for preparation include; (a) inadequate bulk density of ibuprofen or its
pharmaceutically acceptable salt granules to obtain a reasonably sized tablet; (b)
punch filming, picking or sticking during compression; (c) obtaining poor
flowing granulation formulation which are difficult to handle in typical
pharmaceutical plant scale equipment; (e) excessive disintegration time,
Lamination and friability problems; (f) using alcohol especially ethanol during
wet granulation requires special equipment which is highly undesirable.
Moreover, because of the high dosage strengths involved, only minimal amounts
of pharmaceutical excipients could be added to overcome the above problems
(i.e., punch filming, poor flow, excessive disintegration times, lamination, etc.) In
addition, besides the above problems facing by an industrial pharmacist or
pharmaceutical engineer, there is the concern that in some cases, the source of
supply of certain types of the bulk ibuprofen or its pharmaceutically acceptable
salt drug per se may not be reliable or dependable.
Therefore a need remains among the industrial pharmacist or pharmaceutical
engineer to provide process conditions, proportions of ingredients in the
manufacturing process of ibuprofen or its pharmaceutically acceptable salt to
obtain a final formulations (i.e., tablets and capsules or caplets) which will
overcome the above problems, acceptable to the pharmaceutical industry,
physicians and the pharmacists and patient populations alike.
The present invention addresses these and other problems associated with the
prior art by providing technically feasible process for manufacturing ibuprofen or
it ' s pharmaceutically acceptable salts, enantiomers thereof, being blended with

9. external excipients to produce a formulation capable of being directly formed into
a tablet or caplet having suitable hardness, short disintegration time and fast
dissolution time. The method provides suitable blending of ibuprofen or i s
pharmaceutically acceptable salts, enantiomers thereof with suitable
pharmaceutically acceptable excipients for tabletization so as to achieve a long
production cycle running for as many hours as possible without compromising on
standards.
OBJ ECT O F T H E INV ENTION:
It is therefore the primary object of the present invention to provide a cost
effective, industrially feasible method of producing stable, formulations of
Ibuprofen or its pharmaceutically acceptable salts or its enantiomers adaptable to
final formulation with varying dosage size having suitable hardness, short
disintegration time and fast dissol ution time.
SUM MA RY O F T H E INV ENTION:
To meet the above objectives, the present invention provides a method/process for
preparing a stable pharmaceutical composition of Ibuprofen or its
pharmaceutically acceptable salts, enantiomers thereof which are adaptable to
final formulations having a variety of dosage forms such as compressed tablets,
caplets and filled capsules with varying dosage size.
In an aspect, the present invention provides a method of preparing stable
pharmaceutical composition of Ibuprofen or its pharmaceutically acceptable salts,
enantiomers thereof, characterized in that the glidant used is added in pre-
blending, blending and lubricating stage of said process; comprising;
(i) Granulating ibuprofen with one or more pharmaceutically acceptable
excipients;
(ii) Milling the granules of step (i) and mixing with glidant to form a pre-
blend mixture;

10. (iii) Blending mixture of step (ii) with one or more pharmaceutically
acceptable excipients and a glidant;
(iv) Lubricating the blend of step (iii) with one or more pharmaceutically
acceptable excipients and glidant,
(v) Formulating the blend obtained in step (iv) into a suitable dosage form;
and
(vi) Optionally coating the dosage form obtained in step (v).
The method of producing said pharmaceutical composition comprises dry
granulation or wet granulation, preferably wet granulation.
The pharmaceutically acceptable excipients for the process are selected from
diluents, binders, disintegrants, glidants, lubricants, surfactants, flavorants, colors,
and such like alone or in combination thereof. The granules obtained by the
process of the present invention are further compressed in to tablets or caplets or
as filled capsules in a suitable dosage size. Optionally, the pharmaceutical
composition of ibuprofen or its pharmaceutically acceptable salts, enantiomers
thereof may contain other suitable active ingredients.
In another aspect, the present invention provides stable pharmaceutical
composition with short disintegration time and increased dissolution rate without
being unacceptably friable comprising;
i. Ibuprofen or its pharmaceutically acceptable salts, enantiomers
thereof, in an amount of about 40 percent or more on a dry weight
basis;
ii. one or more pharmaceutically acceptable fillers/diluents in an
amount of about 20 percent or more on a dry weight basis;
iii. one or more pharmaceutically acceptable wetting agents/surfactants
in an amount of about 0.1 percent or more on a dry weight basis;
iv. one or more pharmaceutically acceptable disintegrants in an amount
of about 3 percent or more on a dry weight basis;

11. v . one or more pharmaceutically acceptable binders in a binding
amount of about 2 percent or more on a dry weight basis;
vi. one or more pharmaceutically acceptable lubricants in an amount of
about 1 percent or more on a dry weight basis; and
vii. one or more pharmaceutically acceptable glidants in an amount of
about 1 percent or more on a dry weight basis.
D ETAIL ED D ESC RIPTION O F T H E INV ENTION:
The present invention relates to novel pharmaceutical granulation, comprising
ibuprofen or its pharmaceutically acceptable salts, enantiomers thereof, having
specific advantageous properties including (a) excellent physical stability,
especially regarding compressed tablets dissolution properties, (b) high bulk
density, (c) excellent bioavailability and (d) excellent processing properties in
pharmaceutical plant equipment including good flowability, no sticking or picking
during compression process or filling into capsules.
The ingredients and processes set forth herein allow for the manufacture of tablets
and caplets or capsules with advantageous characteristics including rapid
dissolution and excellent tablet strength. A s used herein, the word tablets is
intended to comprise tablets, caplets, capsule shaped tablets, pills or any other
synonym thereof. Further, tablet refers to a pharmacological composition in the
form of a small, essentially solid pellet of any shape. Tablet shapes maybe
cylindrical, spherical, rectangular, capsular, or irregular.
A s used herein, the term ' about (or ' approximately ) means a particular value
can have a range acceptable to those of ski 11in the art given the nature of the val ue
and method by which it is determined.
In an embodiment, the present invention discloses a method of preparing stable
granular pharmaceutical composition of Ibuprofen or its pharmaceutically
acceptable salts, enantiomers thereof, characterized in that the glidant used is

12. added in pre-blending, blending and lubricating stage of said process;
comprising;
i. Granulating ibuprofen with one or more pharmaceutically acceptable
excipients;
ii. Milling the granules of step (i) and mixing with glidant to form a pre-
blend mixture;
iii. Blending mixture of step (ii) with one or more pharmaceutically
acceptable excipients and a glidant;
iv. Lubricating the blend of step (iii) with one or more pharmaceutically
acceptable excipients and glidant,
v . Formulating the blend obtained in step (iv) into a suitable dosage form;
and
v i. Opti onal ly coati ng the dosage form obtai ned in step (v)
The method or process of producing said pharmaceutical composition comprises
dry granulation or wet granulation, preferably wet granulation. The solvents for
wet granulation are selected from water, isopropyl alcohol, ethanol and/or
mixtures thereof.
The pharmaceutically acceptable excipients for the process are selected from
diluents/fillers, binders, disintegrants, glidants, lubricants, surfactants, flavoring
agnets, colors, lubricants, souring agents, sweeteners, and wetting
agents/surfactants and such like alone or in combination thereof.
The glidants are used in the present invention to improve the flow of the powder
blend, to impart better mold release properties and minimize tablet weight
variation. The Glidant is selected from the group comprising of talc, silicon
dioxide, silicic acid, cornstarch, maize starch or starch derivatives, calcium
silicate, magnesium carbonate, magnesium oxide, magnesium silicate, colloidal
silicon dioxide, starch, castor wax and combination thereof. Those of ordinary
skill will further appreciate that other glidant could be added or substituted to

13. formulate the compositions contemplated herein. The glidants are used in an
amount ranging from 0.1 to 30%.
The binder used in the present granulation refers to one or more ingredients added
before or during granulation to form granules and/or promote cohesive compacts
during compression. Thus, the binder component of the present granulation serves
to impart good binding and disintegrant properties to the final dosage forms
prepared from the granulation, i.e., tablets. It is included in an amount effective
for imparting to the granulation and formulations made there from, the capability
of being formed into tablets having optimum hardness, disintegration time, and
short dissolution time when compared against marketed one. Binders of the
present invention is selected from starches and starch derivatives, celluloses,
sugars, polymers like pregelatinized starch, corn starch, microcrystalline cellulose,
lactose, sucrose, mannitol, silicon dioxide, vinyl pyrrolidone vinyl acetate
copolymers, polyvinyl alcohol based compositions, hydroxyl propyl
methyl cellulose, hydroxyl propyl cellulose, methyl cellulose, ethyl cellulose,
hydroxyl ethyl cellulose, carboxymethyl cellulose and natural gums (e.g., gum
acacia, gum tragacanth, etc.) and synthetic polymer binders like
polyvinylpyrrolidone, hydrocolloids, sugars, povidone, copovidone, methacrylic
acid copolymers and combination or compatible mixtures of two or more such
materials in the range of 0.1 to 20%w/w.
Diluent/filler used in the present invention generally are auxiliary materials that
improve the compressi biIity. Preferably the diIuents/fi11ers are sel ected that neutral
to weakly acidic and can improve the compressibility which include cellulose
and its derivatives like microcrystalline cellulose, silicified microcrystalline
cellulose, powdered cellulose, carbohydrates and polyalcohol such as lactose,
sucrose, dextrose, saccharose, glucose, fructose, xylitol, mannitol, sorbitol,
lactitol, maltitol, starch, modified starches, hydrolysed or enzymatically split
starch such as maltodextrin, cyclodextrins such as §- and .-.cyclodextrin, non-
cross linked (water soluble) polyvinylpyrrolidone, polyvinyl alcohols,

14. polyethylene glycols, polypropylene glycols, alkali metal salts, alkaline earth
metal salts and ammonium salts of organic or inorganic acids, in particular
sodium, potassium, magnesium and calcium salts such as sodium chloride,
potassium chloride, magnesium chloride, sodium sulphate, potassium sulphate,
magnesium sulphate, tri magnesium dicitrate, tricalcium dicitrate, calcium lactate,
calcium gluconate, calcium hydrogen phosphate, dicalcium phosphate, tri basic
calcium phosphate, magnesium carbonate, magnesium oxide, talc, or combination
thereof. T he diIuent (s) are present in the range from 0.1 to 80%.
Disintegrant, which provide superior bioavailability of the medicament in the
granulations include but is not limited to cross linked vinylic polymers such as
cross-linked polyvinylpyrrolidone (crospovidone), polyvinyl pyrrolidine or
sodium starch glycolate. Other useful disintegrants may comprise derivatives of
starch and of cellulose such as sodium carboxy methyl-starch and cross linked
sodium carboxy methyl cellulose (croscarmellose sodium), cross linked calcium
carboxy methyl cellulose, microcrystalline cellulose, carboxy methyl cellulose,
hydroxyl propyl cellulose, low-substituted hydroxyl propyl cellulose, alginic acid,
sodium alginate, potassium alginate, calcium alginate, an ion exchange resins,
calcium silicate, a metal carbonate, sodium bicarbonate, calcium citrate, or
calcium phosphate starch and modified starches including pregelatinized starch,
formal in-casein, alginates, gums and combination or and mixtures thereof. The
disintegrant is present in the range from 0.1 to 30%.
Sodium lauryl sulfate (SLS) is a surfactant which aids in the wetting of the
granules in the body thereby increasing the disintegration of the tablet and release
rate of ibuprofen or other water insoluble medicaments. SLS is a surfactant with a
very high HLB (hydrophi Iic-l ipophi Iic balance) number and its use obtains good
wetting and rapid dissolution of the medicament granulation of the invention.
Other useful surfactants may include cationic, anionic and nonionic surfactants,
sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or
another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate, lecithin,

15. stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil,
polyoxyethylene fatty acid glycerides, poloxamer, potassium and sodium oleates
and polysorbates. T he surfactants are used in the range of 0.1 to 10%
Additionally, and optionally, other substances commonly used in pharmaceutical
formulations can be included such as flavors (e.g., burnt sugar flavor, strawberry
aroma, raspberry aroma, cherry flavor, magnasweet 135, key lime flavor, grape
flavor, fruit extracts and prosweet), flavor enhancers and sweeteners (e.g.,
sucralose, aspartame, sodium saccharine, sorbitol, glucose, sucrose), souring
agents (e.g. citric acid), dyes or colorants.
In another embodiment the present invention relates to a method/process of
preparing a stable pharmaceutical composition of Ibuprofen or its
pharmaceutically acceptable salts, enantiomers thereof, wherein the glidant used is
added in pre-blending, blending and lubricating stage of said process;
comprising;
i. Granulating ibuprofen with one or more pharmaceutically acceptable
excipients;
ii. Milling the granules of step (i) and mixing with glidant in an amount of
about .5%w/w to form a pre-blend mixture;
iii. blending mixture of step (ii) with one or more pharmaceutically acceptable
excipients and a glidant in an amount of about .0%w/w;
iv. lubricating the blend of step (iii) with one or more pharmaceutically
acceptable excipients and glidant in an amount of about 0.5%w/w,
v . formulating the blend obtained in step (iv) into a suitable dosage form; and
v i. opti onal ly coati ng the dosage form obtai ned in step (v) .
The granulation thus produced could be directly compressed to form tablets.
However, better tablets are produced by blending the granulation by known
methods, such as using double cone blender, with additional excipients that aid in
the compression and provide improved properties such as hardness and excellent

16. disintegration time. These excipients may be selected from the whole range
known in the art and are chosen in the present invention based on the desired
properties of the tablet produced.
It is highly desirable to add a lubricant that aids in the production of the tablets to
facilitate ejection of the finished tablet from dies after compression and to prevent
tablets from sticking to punch faces and each other. Examples of such lubricants
are stearic acid, metal stearates like calcium/magnesium/sodium stearate, sodium
stearyl fumarate, leucine, glycerol behenate, sodium benzoate, talc, silicon
dioxide, silicic acid, colloidal silicon dioxide, mineral oil, fumaric acid, sodium
stearyl fumarate, stearic acid, talc, vegetable oil, castor wax and combination
thereof and polyethylene glycol, poloxamers, sodium lauryl sulfate, micro
crystalline cellulose and hydrogenated vegetable oils. Those of ordinary skill will
further appreciate that other lubricants could be added or substituted to formulate
the compositions contemplated herein. The lubricants are used in an amount
ranging from 0.1 to 10%.
The pharmaceutical granules of ibuprofen or its pharmaceutically acceptable salts
or enantiomer thereof obtained by the process of the present invention is further
compressed in to tablets or caplets or as filled capsules and can be formulated in
dosage size ranging from 100 to 1200mg per dosage unit.
In another embodiment, the present invention discloses stable pharmaceutical
composition with short disintegration time and increased dissolution rate without
being unacceptably friable comprising;
i. Ibuprofen or its pharmaceutically acceptable salts, enantiomers thereof, in
an amount of about 40 percent or more on a dry weight basis;
ii. one or more pharmaceutically acceptable fillers in an amount of about 20
percent or more on a dry weight basis;
iii. one or more pharmaceutically acceptable wetting agents/surfactants in an
amount of about 0.1 percent or more on a dry weight basis;

17. iv. one or more pharmaceutically acceptable disintegrants in an amount of
about 3 percent or more on a dry weight basis;
v . one or more pharmaceutically acceptable binders in a binding amount of
about 2 percent or more on a dry weight basis;
vi. one or more pharmaceutically acceptable lubricants in an amount of about
1 percent or more on a dry weight basis; and
vii. one or more pharmaceutically acceptable glidants in an amount of about
1 percent or more on a dry weight basis.
According to one embodiment the pharmaceutical composition comprises a coated
core having at least one coating, comprising a sugar or film coating with
pharmaceutically acceptable coating agents, in which all customary sugar and film
coating materials are in principle suitable as coating materials. The thickness of
the coat is not critical; however in general the proportion of the coat, based on the
weight of the tablet core, is only about 1 to 25% by weight, preferably about 2 to
6% by weight.
In a preferred embodiment, the stable pharmaceutical composition with short
disintegration time and increased dissolution rate without being unacceptably
friable comprises;
i. Ibuprofen or its pharmaceutically acceptable salts, enantiomers thereof, in
an amount of about 50 percent or more on a dry weight basis;
ii. about 20 percent or more a pharmaceutically acceptable filler preferably
lactose on a dry weight basis;
iii. about 0.1 percent or more a pharmaceutically acceptable surfactant
preferably sodium lauryl sulphate on a dry weight basis;
iv. about 3 percent or more a pharmaceutically acceptable disintegrant
preferably crospovidone or its derivatives on a dry weight basis;
v . about 2 percent or more a pharmaceutically acceptable binder preferably
poly vinyl pyrrolidone or its derivatives on a dry weight basis;

18. vi. about 1 percent or more a pharmaceutically acceptable lubricant preferably
a metal stearate on a dry weight basis; and
vii. one or more pharmaceutically acceptable glidants in an amount of about 1
percent or more on a dry weight basis.
In another aspect, the method of preparing the granulation described by a wet
granulation method comprises, Sifting the composition components of the present
invention selected from diluent, surfactant, disintegrant including Ibuprofen or its
pharmaceutically acceptable salts and dry mixing for not less than 5 minutes.
Granulating the dry mix in RMG using binder solution prepared using water or
alcoholic or hydro-alcohol. Drying the resulting granules using FBD followed by
milling/sizing and mixing the granules with a part of glidant for not less than 10-
20minutes. Further blending with diluent, disintegrant and a part of the glidant of
not Iess than 3- 0 minutes. Lubri cati ng the f inal blend of not Iess than 2-6 minutes
using lubricant and a final part of the glidant. The manufacturing process of the
present invention involves the use of glidant in three stages of formulation i.e. pre-
blending, blending and lubrication and at 1.5, 1.0 and 0.5%w approximately
respectively.
The amounts of the added excipients are preferably the minimum amounts
necessary to accomplish their purposes. For example, the lubricant component is
present in a lubricating amount sufficient to impart mold release properties to
tablets formed from the formulation and preferably insufficient to increase
disintegration time and dissolution time of such tablets, and preferably insufficient
to decrease the hardness obtainable for tablets formed from a formulation having
no additional lubricant.
The final drug forms (resulting from the new granulation formulations) will have
specific advantageous properties including (a) excellent physical stability,
especially regarding compressed tablet s dissolution properties, (b) high bulk
density (c) excellent bioavailability and (d) excellent processing properties in

19. pharmaceutical plant equipment including good flowability, minimal tablet punch
or plunger sticking during compressing or capsule filling and good compression
characteristics.
The composition of the present invention obtained by the process exhibits a
significant improvement in dissolution profile and assay during stability in stress
and accelerated condition as compared to marketed formulation.
EXAM PL ES
Example 1:
Example 2:
Ingredients % Concentration
Ibuprofen Sodium 55.65
Lactose monohydrate 24.78
Sodium lauryl sulphate 0.25
Crospovidone 9.78
Polyvinyl pyrrol idone 2.93
Isopropyl alcohol Qs
Silicon dioxide 4.16
Talc 0.98
Magnesium stearate 1.47

20. Example 3:
Example 4:
Example 5: Wet granulation method of producing the Ibuprofen granules
Sifted Ibuprofen sodium dihydrate, Lactose monohydrate, Sodium lauryl sulphate,
Crospovidone through mesh. Prepared the binder solution with povidone and
Isopropyl alcohol. Loaded the sifted Ibuprofen sodium dihydrate, lactose
monohydrate, Sodium lauryl sulphate, crospovidone into Rapid Mixer Granulator
(RMG) and mixed for 10 minutes. Granulated the dry mix using povidone binder
solution. Dried the granules in Fluid Bed Drier (FBD) followed by Sizing &

21. milling. Pre-blended the silicon dioxide and dried granules into blender and mixed
for 15 minutes at10e1 RPM. Sifted lactose monohydrate, crospovidone, silicon
dioxide and talc and added to pre blended mixture, were mixed for 8 minutes at
10e1 RPM. Lubricated the blend mixture with magnesium stearate and silicon
dioxide for 3 minutes at 10e1 RPM. The granules obtained were then compressed
in to tablets by a process known in the art. Coating was carried with known
coating agents.
Similar procedure was conducted to obtain the pharmaceutical granules of
example 2, example 3 and example 4 respectively.
Any patents or publications mentioned in this specification are indicative of the
levels of those skilled in the art to which the invention pertains. Further, these
patents and publications are incorporated by reference herein to the same extent as
if each individual publication was specifically and individually incorporated by
reference. One skilled in the art will appreciate readily that the present invention
is well adapted to carry out the objects and obtain the ends and advantages
mentioned, as well as those objects, ends and advantages inherent herein. Changes
therein and other uses which are encompassed within the spirit of the invention as
defined by the scope of the claims will occur to those ski Iled in the art.

22. W e claim,
1. A method of preparing stable pharmaceutical composition of Ibuprofen or
its pharmaceutically acceptable salts, enantiomers thereof, characterized in
that the glidant used is added in pre-blending, blending and lubricating
stage of said process; comprising;
i. Granulating ibuprofen with one or more pharmaceutically
acceptable excipients;
ii. Milling the granules of step (i) and mixing with glidant to form a
pre-blend mixture;
iii. Blending mixture of step (ii) with one or more pharmaceutically
acceptable excipients and a glidant
iv. Lubricating the blend of step (iii) with one or more
pharmaceutically acceptable excipients and glidant;
v . Formulating the blend obtained in step (iv) into a suitable dosage
form; and
vi. Optionally coating the dosage form obtained in step (v).
2. The method according to claim 1, wherein pharmaceutically acceptable
excipients are selected from diluents, binders, disintegrants, glidants,
lubricants, surfactants, wetting agents, colorants, flavorants and the like in
combi nati on thereof.
3. The method according to claim 2, wherein the diluent is selected from the
group consisting of lactose, sucrose, fructose, dextrose, mannitol, sorbitol,
xylitol, lactitol, starch, modified starches, dibasic calcium phosphate,
tri basic calcium phosphate, magnesium carbonate, magnesium oxide, talc,
powdered cellulose, microcrystalline cellulose, silicified microcrystalline
cellulose and combination thereof in an amount ranging from 0.1 to
80%w/w.
4. The method according to claim 2, wherein the binder is selected from the
group consisting of ethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, methyl cellulose and hydroxyethyl

23. cellulose, carboxymethyl cellulose, starch and its derivatives, polyvinyl
alcohol, polyvinyl alcohol based compositions, hydrocolloids, sugars,
polyvinyl pyrrol idone, povidone, copovidone, methacrylic acid
copolymers and combination thereof in an amount ranging from 0.1 to
20%w/w.
5. T he method accordi ng to claim 2, wherei n the disintegrant is sel ected from
the group comprising of low-substituted hydroxy propyl cellulose,
hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, polyvinyl
pyrrolidine, cross-linked sodium carboxymethyl cellulose, cross-linked
calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium
carboxy methyl cellulose, microcrystalline cellulose, croscarmellose
sodium, sodium starch glycolate, ion-exchange resins, starch and modified
starches including pregelatinized starch, formalin-casein, alginates, gums
and combination thereof in an amount ranging from 0.1 to 20%.w/w.
6. The method according to claim 2, wherein the glidant is selected from the
group comprising of talc, silicon dioxide, silicic acid, cornstarch, maize
starch, calcium silicate, magnesium carbonate, magnesium oxide,
magnesium silicate, colloidal silicon dioxide, starch, castor wax and
combination thereof in an amount ranging from 0.1 to 30%.w/w.
7. The method according to claim 2, wherein the lubricant is selected from
the group comprising of calcium stearate, glycerol behenate, sodium
benzoate, magnesium stearate, silicon dioxide, silicic acid, colloidal
silicon dioxide, zinc stearate, mineral oil, polyethylene glycol, sodium
lauryl sulphate, fumaric acid, sodium stearyl fumarate, stearic acid, talc,
vegetable oil, castor wax and combination thereof in an amount ranging
from 0.1 to 10%.w/w.
8. The method according to claim 2, wherein the surfactant is selected from
the group comprising cationic, anionic and nonionic surfactants, sodium
lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or
another ester of polyoxy ethylene sorbitane, sodium dioctylsulfosuccinate,
lecithin, stearyl ic alcohol, cetostearylic alcohol, cholesterol,

24. polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides,
poloxamer, or a mixture of two or more thereof in an amount ranging
from 0.1 to 10%.w/w.
9. A method of preparing a stable pharmaceutical composition of Ibuprofen
or its pharmaceutically acceptable salts, enantiomers thereof, wherein the
glidant used is added in pre-blending, blending and lubricating stage of
said process; comprising;
i. Granulating ibuprofen with one or more pharmaceutically
acceptable excipients;
ii. Milling the granules of step (i) and mixing with glidant in an
amount of about .5%w/w to form a pre-blend mixture;
iii. Blending mixture of step (ii) with one or more pharmaceutically
acceptable excipients and a glidant in an amount of about
.0%w/w;
iv. Lubricating the blend of step (iii) with one or more
pharmaceutically acceptable excipients and glidant in an amount
of about 0.5%w/w;
v . Formulating the blend obtained in step (iv) into a suitable dosage
form; and
vi. Optionally coating the dosage form obtained in step (v).
10. The method according to claim 1 or 9, wherein the method comprises wet
granulation or dry granulation.
. The method according to claim 10, wherein the solvent for wet
granulation selected from water, isopropyl alcohol, ethanol and/or
mixtures thereof.
12. The pharmaceutical composition of ibuprofen or its pharmaceutically
acceptable salts, enantiomers thereof together with pharmaceutically
acceptable excipients prepared by the process according to claim .

25. nternat ona app cat on o.
PCT/IN2016/050337
A CLASSIFICATION OF SUBJECT MATTER
A61K3 1/00, A61Q1 3/00, D01G1 3/00 Ver sion=2 017 .01
According to International Patent Classification (IPC) or to both national classification and IPC
B FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
A61Q 13/00, D01G 13/00, A61K31/00
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
Patseer, IPO Internal Database
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No
US20020034540 A l (THE BOOTS COMPANY PLC) 28Aug, 1-12
1997 (28.08.1998)
Page 5 , para[0048]; page 4 para [0026]
CA2063141 A l (MCNEIL PPC INC) 180ct, 1992 1-12
(18 .10 .1992)
abstract
US5445827 A (FRITSCH, ET AL .) 29Aug, 1-12
(29.08.1995) claims
Further documents are listed in the continuation of Box C. See patent family annex
* Special categories of cited documents: later document published after the international filing date or priority
"A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand
to be of particular relevance the principle or theory underlying the invention
"E" earlier application or patent but published on or after the international document of particular relevance; the claimed invention cannot be
filing date considered novel or cannot be considered to involve an inventive
"L" document which may throw doubts on priority claim(s) or which is step when the document is taken alone
cited to establish the publication date of another citation or other
speciai reason (as specified) document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
"O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination
means being obvious to a person skilled in the art
"P" document published prior to t international filing date but later than document member of the same pate family
the priority date claimed
Date of the actual completion of the international Date of mailing of the international search report
27-02-2017 27-02-2017
Name and mailing address of the ISA/ Authorized officer
Indian Patent Office Ravi Kumar Battini
Plot No. 32, Sector 14,Dwarka, ew Delhi-110075
Facsimile No. Telephone No. +91-1125300200
Form PCT/ISA/210 (second sheet) (January 2015)

26. International application No.
Information on patent family members
PCT/IN2016/050337
Citation Pub. Date Family Pub. Date
US 20020034540 A l 28-08-19 WO 1997030699 A2 28-08-1997
EP 0881899 Bl 18-08-2004
CA 2063141 A l 08-10- 1992 US 5320855 A 14-06-1994
US 5445827 A 29-08- 1995 EP 0369228 Bl 18-12-1991
CA 2002732 A l 12-05-1990
Form PCT/ISA/210 (patent family annex) (January 2015)