FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(Section 10 and Rule 13)
"PHARMACEUTICAL COMPOSITION COMPRISING DRONEDARONE
HYDROCHLORIDE"
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
and having its registered office at
B/2, Mahalaxmi Chambers, 22 Bhulabhai Desai Road,
Mumbai - 400 026
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF INVENTION:
The present invention relates to a surfactant free pharmaceutical composition comprising Dronedarone hydrochloride and atleast a pharmaceutically acceptable excipient and a process for preparation thereof.
BACKGROUND OF THE INVENTION:
Dronedarone hydrochloride is a benzofuran derivative chemically known as N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} methanesulfonamide, hydrochloride.
US5223510 of Sanofi Aventis first disclosed the benzofuran derivative e.g. Dronedarone and its pharmaceutically acceptable salt for the treatment of arrhythmia.
In United States, Dronedarone is marketed by Sanofi Aventis as 400 mg tablet for oral
© administration under the brand name MULTAQ . Dronedarone is an antiarrhythmic drug and is
effective in reducing the risk of cardiovascular hospitalization in patients with paroxysmal or
persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and
associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular
accident, left atrial diameter >50 mm or left ventricular ejection fraction [LVEF] <40%), who are in
sinus rhythm or who will be cardioverted.
According to the disclosure of US7323493, Dronedarone hydrochloride has very low solubility in aqueous medium and it is practically insoluble in water. The reference patent also discloses that Dronedarone hydrochloride displays a maximum solubility at acidic pH of around 3 to 5, which is about 1 to 2 mg/ml, however as the pH increases to about 6 - 7, the solubility reduces, e.g. the solubility is only about 10μg/ml at pH 7. Because of pre-systemic first pass metabolism, the absolute bioavailability of dronedarone without food is low, about 4%. However, it increases to approximately 15% when administered with a high fat meal.
US patent 7323493 tried to solve the low solubility problem of Dronedarone hydrochloride by formulating a tablet dosage form with a pharmaceutically acceptable nonionic hydrophilic

surfactant. The nonionic hydrophilic surfactant can be ethyleneoxide / propyleneoxide copolymers, polyethoxylated castor oils, ethoxylated polysorbates etc wherein poloxamer 407 is most preferred. The non-ionic surfactant maintains the solubilization of the benzofuran derivative (e.g. Dronedarone hydrochloride) in neutral medium and reduces the variability of drug absorption in the blood. According to the reference patent, the non-ionic surfactant also contributes in reducing by a factor of 2 to 5 the variation in maximum plasma concentration of active ingredient obtained in non fasted individual compared with fasted individual.
The commercially marketed product Multaq® of Sanofi Aventis contains the non-ionic surfactant i.e. poloxamer 407. According to US7323493 and US20080139645, a non-ionic surfactant is essential in the composition comprising Dronedarone hydrochloride, to maintain the solubility and bioavailability of the composition to an acceptable limit and reduce any variation in the extent of drug absorption from the dosage form into the blood. Hence the non-ionic surfactant e.g. Poloxamer 407 is used as a "functional excipients" which exhibit a significant role in enhancing the bioavailability of the composition.
Prior to the present invention, it has not been found practical to formulate a surfactant free solid oral pharmaceutical composition comprising Dronedarone hydrochloride, which exhibits good formulation properties and provide an acceptable bioavailability independent of the presence of food.
The inventors of the present invention have now surprisingly found that a surfactant free pharmaceutical composition comprising Dronedarone hydrochloride, has good formulation properties as well as an improved dissolution and bioavailability.
SUMMARY OF THE INVENTION:
The present invention provides a surfactant free pharmaceutical composition of Dronedarone hydrochloride which releases more than 70% of Dronedarone within 30 minutes, in a phosphate buffer system at pH 4.5.

In a further embodiment, the present invention provides a surfactant free tablet of Dronedarone hydrochloride which exhibits excellent tablet properties e.g. tablet hardness, friability and disintegration time.
In another embodiment, the present invention provides a surfactant free tablet of Dronedarone hydrochloride which releases more than 70% of Dronedarone within 30 minutes, in a phosphate buffer system at pH 4.5.
In one more embodiment, the present invention provides a process of preparing surfactant free pharmaceutical composition comprising Dronedarone hydrochloride and atleast a pharmaceutically acceptable excipient.
DETAILED DESCRIPTION OF INVENTION:
The present invention relates to a surfactant free pharmaceutical composition comprising Dronedarone hydrochloride and atleast a pharmaceutically acceptable excipient. The inventors of the present invention have surprisingly found that a surfactant free pharmaceutical composition , comprising Dronedarone hydrochloride and atleast a pharmaceutically acceptable excipient, exhibits excellent tablet properties e.g. tablet hardness, friability & disintegration time and an acceptable dissolution profile such that more than 70% of Dronedarone is released within 30 minutes, in a phosphate buffer system at pH 4.5.
The pharmaceutically acceptable excipient of the present invention, comprises one or more diluent, one or more disintegrant, one or more binder, and one or more lubricant, optionally with other excipients like flowing aids, anti-adherents or glidants.
The surfactant free pharmaceutical composition comprising Dronedarone hydrochloride of present invention can be a tablet, capsule, granules, powder, or pellets; however tablet form is more preferred.

The surfactant free pharmaceutical composition comprising Dronedarone hydrochloride and a pharmaceutically acceptable excipient, is prepared by dry mixing Dronedarone hydrochloride with diluent(s) and disintegrant(s); granulating the dry mix blend with binder solution prepared by dissolving a binder in a purified water; drying the granulated mass, sizing the granules and optionally mixing with extra-granular material and finally lubricating and compressing the blend. The compressed core is then coated with a film coating solution.
In an aspect, the surfactant free pharmaceutical composition of present invention is a tablet comprising Dronedarone hydrochloride, a diluent in an amount of about 5 to 50 wt. % of the composition, binder in an amount of about 0.5 to 15 wt. % of the composition, disintegrant in an amount of about 0.5 to 15 wt. % of the composition, and lubricant in an amount of about 0.1 to 10 wt. % of the composition, optionally with a film coat enclosing core of the tablet. The film coat of present invention varies in range of 0.5- 5 wt% of the total weight of core tablet.
In another aspect, the surfactant free pharmaceutical composition is a tablet comprising Dronedarone hydrochloride and a diluent in an amount of about 5 to 50 wt. % of the composition, binder in an amount of about 0.5 to 15 wt. % of the composition, disintegrant in an amount of about 0.5 to 15 wt. % of the composition, and lubricant in an amount of about 0.1 to 10 wt. %-of the composition, optionally with a film coat enclosing core of the tablet; wherein the said tablet is prepared by a wet granulation process, dry granulation process or direct compression method.
The surfactant free Dronedarone tablet as per the above description can be prepared by conventional formulation process e.g. wet granulation process comprising the steps of dry mixing Dronedarone hydrochloride with diluent(s) and disintegrant(s); granulating the dry mix blend with binder solution prepared by dissolving binder(s) in purified water to obtain the granules. The granulated mass is then dried, lubricated and finally compressed into core tablet, which may optionally be coated with a film coating solution.
In an additional aspect of the present invention, the surfactant free pharmaceutical composition comprising Dronedarone hydrochloride comprises:

i) Diluent(s) selected from the group comprising of, but not limited to lactose monohydrate, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts like dicalcium phosphate, cellulose derivatives (e.g. microcrystalline cellulose), calcium sulfate, xylitol, lactitol and the likes.
ii) Disintegrant(s) selected from the group comprising of, but not Limited to, crospovidone, crosscarmallose sodium, polyvinylpyrrolidone, modified starch, sodium starch glycolate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and the likes.
iii) Binder(s) selected from the group comprising of, but not limited to, polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, crospovidone, polyethylene glycol, polyvinyl alcohol, gelatin, sodium alginate and the likes.
iv) Lubricant(s) selected from the group comprising of, but not limited to, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols, sodium stearyl fumarate and the likes.
In a preferred aspect of the present invention, the granules are prepared by dry mixing Dronedarone hydrochloride with one or more diluent(s) selected from Lactose monohydrate & maize starch along with one or more disintegrant(s) selected from crospovidone.
The resulting dry mix is granulated in a rapid mixer granulator with a binder solution prepared by dissolving a binder selected from polyvinylpyrrolidone (PVP) in purified water.
The granulated mass is then dried, milled and optionally mixed with flowing aids selected from colloidal anhydrous silica and the final blend is then lubricated with a lubricant selected from magnesium stearate.

The lubricated granules are finally compressed into tablet core which may optionally be coated with a film coating solution.
While the present invention is disclosed by reference to the preferred embodiments and example below, it is understood that these example are intended in an illustrative rather than in a limiting sense. It is contemplated that modifications and combinations will readily occur to those skilled in the art, which modifications and combinations will be within the spirit of the invention and the scope of the following claims.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
EXAMPLE-1: In a preferred embodiment, below examples illustrates a surfactant free tablet composition comprising Dronedarone hydrochloride:
Table-1:

Sr. No. Inactive Ingredients mg/tablet
A Core Composition
1' Dronedarone HC1 (Eq. to base) 426
2 Hypromellose 6 mPa 15-30
Maize Starch (Corn starch) 30-50
4 Crospovidone 50-70
5 PVP 30-50
6 Lactose Monohydrate 30-50
7 Colloidal Anhydrous Silica 1-5
8 Magnesium Stearate 1-5
9 Purified Water Q.S
Weigh of Core Tablet 600-700
B. Film Coating:
Hypromellose 6 mPa 5-10
Titanium Dioxide 0.5-2
Polyethylene glycol 6000 0.5-2
Purified Water Q.S
Weight of Film Coated Tablet 600-700

PROCESS:
i) Dronedarone hydrochloride, lactose monohydrate, maize starch (corn starch) and
crospovidone were sifted through suitable mesh. ii) PVP was dissolved in purified water under stirring. iii) Material of step-(i) was granulated using granulation fluid of step-(ii) in rapid mixer
granulator. iv) The granules obtained from step-(iii) were dried. v) Then sizing of the granules of step-(iv) was carried out using suitable mesh and the
obtained granules were transferred to bin blender. vi) Colloidal anhydrous silica was sifted through suitable mesh and mixed with the granules of
step-(v) for 10 mins in bin blender. vii) The granules of step-(vi) was lubricated using magnesium stearate, which was already
passed through # 60 mesh, for 5 mins in bin blender. viii) The blend of step-(vii) was compressed into tablet core at suitable compression parameters. ix) The tablets obtained in step-(viii) were film coated using a film coating solution.

We claim,
1. A pharmaceutical composition comprising Dronedarone or a pharmaceutic ally acceptable salt thereof and a pharmaceutically acceptable excipient wherein the pharmaceutical^ acceptable excipient is not a surfactant.
2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable salt of dronedarone is hydrochloride.
3. The pharmaceutical composition as claimed in claim 1, wherein the composition is a solid dosage form comprising of one or more tablet, capsule, granules, powder, or pellets.
4. The pharmaceutical composition as claimed in claim 1, wherein the composition is a tablet optionally coated with a film coat.
5. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient comprises one or more diluent, disintegrant, binder, lubricant, flowing aids and anti-adherents or glidants.
6. The pharmaceutical composition as claimed in claim 1, wherein the composition releases more than 70% of Dronedarone within 30 minutes, in a phosphate buffer system at pH 4.5.
7. The pharmaceutical composition as claimed in claim 1, wherein the composition provides an acceptable bioavailability which is independent of the presence of food.
8. The pharmaceutical composition as claimed in claim 1, wherein the composition is prepared by direct compression or dry granulation or wet granulation method.

9. The pharmaceutical composition as claimed in claim 7S wherein the composition is prepared by wet granulation method comprising the steps of dry mixing Dronedarone hydrochloride with diluent(s) and disintegrant(s); granulating the dry mix blend with a binder solution; drying the granulated mass, sizing the granules and mixing with extra-granular material; lubricating and compressing the blend and optionally coating the compressed core with a film coat solution.