F0RM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention -"PROCESS FOR PREPARING TADALAFIL FORMULATION"
2. Applicant(s)
(a) NAME: ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR PREPARING TADALAFIL FORMULATION
FIELD OF THE INVENTION
Present invention relates to process for preparing tadalafil formulation.
BACKGROUND OF THE INVENTION
Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) and chemically known as pyrazino[1 ',2': 1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12ahexahydro-2-methyl-, (6R,12aR)-. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol. In USA it is approved as CIALIS® for treating erectile dysfunction and ADCIRCA® for the treatment of pulmonary arterial hypertension. CIALIS® is available as almond-shaped tablets for oral administration as 2.5, 5, 10 and 20 mg strengths and contains inactive ingredients: croscarmedose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
US5859006 discloses a class of (3-carboline compound including tadalafil and also describes pharmaceutical compositions thereof which are useful in the treatment of conditions which required the inhibition of PDE5.
As tadalafil is used for the treatment of erectile dysfunction, it should provide immediate effect and for that tadalafil should be rapidly disintegrate and dissolved from the dosage form for available at site of absorption. As tadalafil is practically insoluble in water, it is very difficult to formulate a solid pharmaceutical formulation with desired physico chemical properties like disintegration and dissolution.

US5985326 discloses solid dispersion in the form of co-precipitates of poorly water soluble drugs like selective inhibitors of cGMP specific PDE5, process for preparing the same and their use in the pharmaceutical composition.
US6821975 discloses tadalafil in the form of free drug wherein at least 90% of the particles have a particle size of less than about 40 microns and pharmaceutical composition of the same with pharmaceutical^ acceptable carriers, diluents or excipients.
US7417044 describes particulate tadalafil having particle size distribution such that at least 90% of the particles, by volume, have a particle size of about 200 to about 600 microns.
US20080009502 discloses pharmaceutical composites for making pharmaceutical formulation for oral administration that provides rapid dissolution of the PDE5 inhibitor tadalafil wherein the tadalafil is in the form of solid solution.
US2009098211 discloses compressed solid dosage form of tadalafil with starch wherein weight ratio of starch to tadalafil is about 4:5:1 or more and tadalafil has a particle size distribution such that d(0.9) is greater than or equal to 40 microns.
US2011263606 describes buccal and/or sublingual oral film dosage form and process for preparing the same using solubility enhancer for better absorption and improved bioavailability.
Many techniques like size reduction of API, modified process for manufacturing pharmaceutical formulation, preparing solid dispersions, addition of solubilising agents have been employed to improve the

solubility and thereby dissolution of the active ingredients like tadalafil having poor aqueous solubility. However the stated techniques may or may not be found suitable for each and every active ingredients because of the varying nature of active ingredients based on their chemical and physical properties. Still there is need for the improved pharmaceutical formulation of tadalafil which provides desired dissolution characteristics to give patient an immediate therapeutic effect and robust yet simple process for preparing such formulation.
The inventors of the present invention have surprisingly found that the formulation of tadalafil can be prepared with simple process as per the present invention which exhibits desired dissolution characteristics.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to a process for preparing tadalafil formulation comprising the steps of;
a) granulating at least one water soluble pharmaceutically acceptable excipient with solution comprising tadalafil and at least one pharmaceutically acceptable excipients in solvent,
b) granulating step a) with binder solution,

c) drying the granules of step b),
d) mixing the dried granules with at least one pharmaceuticaly acceptable excipient and optionally with tadalafil and
e) compressing the resulting blend of step d) into tablets and
f) coating the tablets of step e);
wherein water soluble excipient is present in 50 to 90 % w/w of the total composition and has a surface area in the range of 0.4648 m2/g to 0.8632 m2/g.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to process for preparing tadalafil formulation. The process comprise the steps of granulating at least one water soluble pharmaceutically acceptable excipient with solution comprising tadalafil and at least one pharmaceutically acceptable excipient in solvent which is further granulated by binder solution. The granulated material is dried and mixed with at least one pharmaceutically acceptable excipient which is compressed into tablets and optionally coated wherein water soluble excipient is present in 50 to 90 % w/w of the total composition and has a surface area in the range of 0.4648 m2/g to 0.8632 m2/g.
As used herein, "tadalafil" unless otherwise indicated, includes pharmaceutically acceptable salts or free base or enantiomeric forms of tadalafil. In a preferred embodiment, tadalafil is in the form of free base.
Surface area of any excipient can be calculated by any know method in the art.
Formulation as used herein is in the form of solid oral pharmaceutical formulation selected from the group consisting of powders, granules, tablet and capsules. Preferably the formulation is in the form of tablets which is either uncoated tablets or film coated.
In another embodiment the dried tadalafil comprising granules can be mixed further with tadalafil and at least one pharmaceutically acceptable excipient and the resulting blend can be then compressed into tablets and optionally coated.

Pharmaceutically acceptable excipients as used herein can be selected from the group consisting of diluent, binder, disintegrant, lubricant, anti-adherent and/or wetting agent.
Suitable diluents in a composition of the present invention may be one or more compounds which are capable of providing bulk to obtain a desired tablet mass. The suitable diluents may be water soluble or water insoluble. Suitable diluents include inorganic phosphates such as dibasic calcium phosphate; sugars such as lactose monohydrate, lactose anhydrous, mannitol, sorbitol, sucrose, dextrose; and cellulose or cellulose derivatives such as microcrystalline cellulose and the like. The diluent can be added intragranularly and optionally extragranularly. Preferably, a water soluble diluent is to be used. More preferably the diluent is lactose monohydrate form. Most preferably the lactose monohydrate having surface area in the range of 0.4648 m2/g to 0.8632 m2/g is to be used. The diluent can be present in a suitable amount from about 10-95 % w/w, preferably 50-90 % w/w of the total composition.
Suitable solvents used for dissolving tadalafil can be selected from acetone isopropanol, methanol, ethanol, ethyl acetate and dichloromethane and the like or mixtures thereof.
Suitable binder in a composition of the present invention may be one or more compounds which are capable of facilitating granulation of tadalafil into aggregates and/or more free-flowing particles and include cellulose, carboxymethylcellulose sodium, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch, alginic acid, sodium alginate, gelatin and the like. The binder can be present in a suitable amount from 0.5-10 % w/w or 0.5-5 % w/w or 0.5-3 % w/w of the total

composition. Binder may be present either in the dry form or in the solution.
Suitable disintegrant in a composition of the present invention may be one or more compounds which are capable of facilitating the break up of a tablet prepared from the composition when placed in contact with an aqueous medium and include cellulose, carboxymethylcellulose sodium, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, pregelatinized starch, sodium starch glycolate, starch and the like. The disintegrant can be present in a suitable amount from 0-10 % w/w or 2-8 % w/w of the total composition.
Suitable antiadherent in a composition of the present invention may be one or more compounds capable of prevent sticking to punch faces such as silicon dioxide, magnesium trisilicate, talc and the like. The antiadherent can be present in a suitable amount from 0-7 % w/w or 0-5 % w/w or 0-2 % w/w of the total composition.
Suitable lubricant in a composition of the present invention may be one or more compounds capable to decrease friction at the interface between the tablet surface and the die wall during ejection and include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, talc and the like. The lubricant can be present in a suitable amount from 0-7 % w/w or 0-5 % w/w or 0-2 % w/w of the total composition.
Suitable wetting agent in a composition of the present invention can be selected from the group consisting of anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride and benzethonium chloride. The

wetting agent can be present in a suitable amount from 0.01-2 % w/w or 0.05-1 % w/w of the total composition.
Suitable coloring agent in a suitable amount in a composition of the present invention may be one or more compounds which impart a desired color to a tablet prepared from the composition and include FDA approved colors for oral use such as ferric oxides.
A coating can be applied using the materials and methods known to a person skilled in the art. Examples of film coating material includes Opadry® which is Colorcon's customized, one-step film coating system which combines polymer, plasticizer and pigment, as required, in a dry concentrate. The film coating can be applied in an amount up to about 5% w/w of the formulation.
Suitable solvents for coating can be selected from solvents such as water, isopropanol, ethanol, dichloromethane and the like.
The coating solutions may be applied using techniques, such as spray coating in a conventional coating pan or fluidized bed processor or dip coating as known to person skilled in the art.
Dissolution of Tadalafil tablets were carried out as per the below
parameters:
Media: 0.1N HCI + 0.15% SLS
Volume: 1000 ml
Apparatus: USP II
RPM: 50

For the comparison purpose for in-vitro dissolution study as well as for bio study as a reference the immediate release tablets of tadalafil marketed by Eli Lilly & company under the brand name Cialis® were used.
The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
EXAMPLES
Example 1: Tadalafil Tablets 20mg

Ingredients %w/w
Intra-granular
Tadalafil 4.87
Hydroxy Propyl Cellulose 2.44
Lactose Monohydrate (Granulac 200) 65.07
Cros carmellose Sodium 2.93
Sodium Lauryl Sulphate 0.29
Povidone K -25 2.93
Dichloro Methane* q-s
Methanol* q.s
Purified Water* q.s
Extra-granular
Lactose Monohydrate (Flowlac 100) 17.56
Colloidal Silicone Dioxide 0.49
Magnesium stearate 0.98
Opadry Yellow 03F520005 2.44
Purified Water* q-s
Total 100.00
Will be removed during manufacturing process
Procedure
1. Lactose monohydrate(Granulac 200) and croscarmellose sodium were sifted through 30# sieve.
2. Hydroxypropyl cellulose followed by tadalafil was dissolved in mixture of Dichloro methane and methanol.

3. Sodium lauryl Sulphate followed by povidone K-25 were dissolved in purified water to get clear solution.
4. Material of step 1) was granulated with solution of step 2) by top spray process.
5. Material of step 4) was further granulated with solution of step 3).
6. Granules of step 5) were dried and sifted through 30# sieve.
7. Lactose Monohydrate (Flowlac 100) and Colloidal silicone dioxide were sifted through 40 # and mixed with dried granules of step 6).
8. Magnesium stearate was sifted through 40# and blend of step 7) was lubricated with sifted magnesium stearate.
9. Lubricated blend of step 8) was compressed to tablets using appropriate punch tooling.
10. Compressed tablets of step 9) were coated using the Opadry
Yellow 03F520005 dispersion prepared in purified water.
Dissolution data

Time (Minutes) CIALIS® 20 mg Example 1
0 0 0
10 58 46
15 65 60
20 69 70
30 73 77
45 75 84
60 75 87
Example 2
Bio study of Example 1
Fasted study
Open label, balanced, randomized, three-treatment, six-sequence, three-period, single dose, three way crossover oral bioequivalence study in healthy, adult, human male subjects under fasting conditions.

Fed study
Open label, balanced, randomized, three-treatment, six-sequence, three-period, single dose, three way crossover oral bioequivalence study in healthy, adult, human male subjects under fed conditions.
Bio study results

Bio Study (Fasted) Bio Study (Fed)
Cmax AUC o-t AUC o-inf Cmax AUC o-t AUCo,nf
Test (T) 298.5296 8271.1918 10150.4736 360.3815 9023.4157 10829.8284
Reference (R) 349.0389 9338.5151 11424.9704 353.8349 9452.6916 11496.6345
T/R 85.53 88.57 88.84 101.85 95.46 94.2
90% CL
LCL 78.79 79.97 78.58 93.1 83.01 80.29
UCL 92.84 98.1 100.45 111.42 109.77 110.53
Intra CV% 12.6 15.72 18.95 12.79 20.01 22.97
Power 99.51 97.18 91.45 98.91 84.69 75.42
Example 3
Tadalafil Tablets 5 mg

Ingredients %w/w
Intra-granular
Tadalafil 4.87
Hydroxy Propyl Cellulose 2.44
Lactose Monohydrate (Granulac 200) 65.07
Cros carmellose Sodium 2.93
Sodium Lauryl Sulphate 0.29
Povidone K -25 2.93
Dichloro Methane* q.s
Methanol* q.s
Purified Water* q.s
Extra-granular
Lactose Monohydrate (Flowlac 100) 17.56

Colloidal Silicone Dioxide 0.49
Magnesium stearate 0.98
Opadry Yellow 03F520005 2.44
Purified Water* q.s
Total 100.00
* Will be removed during manufacturing process
Procedure: Same as example 1 Dissolution data

Time (Minutes) CIALIS 5 mg Example 3
0 0 0
10 56 49
15 62 58
20 68 - 69
30 71 76
45 76 80
60 79 85
Example 4
Tadalafil Tablets 20 mg

Ingredients %w/w
Intra-granular
Tadalafil 4.88
Hydroxy Propyl Cellulose 2.44
Lactose Monohydrate (Granulac 200) 79.71
Cros carmellose Sodium 2.93
Sodium Lauryl Sulphate 0.29
Povidone K -25 2.93
Dichloro Methane* q.s
Methanol* q.s
Purified Water* q.s
Extra-granular
Cros carmellose Sodium 2.93
Colloidal Silicone Dioxide 0.48
Magnesium stearate 0.97
Opadry Yellow 03F520005 2.44
Purified Water* crs

Total 100.00
* Will be removed during manufacturing process
Procedure
1. Lactose monohydrate (Granulac 200) and croscarmellose sodium were sifted through 30# sieve.
2. Hydroxypropyl cellulose followed by tadalafil was dissolved in mixture of Dichloro methane and methanol.
3. Sodium lauryl Sulphate followed by povidone K-25 were dissolved in purified water to get clear solution.
4. Material of step 1) was granulated with solution of step 2) by top spray process.
5. Material of step 4) was further granulated with solution of step 3).
6. Granules of step 5) were dried and sifted through 30# sieve.
7. Cros carmellose Sodium and Colloidal silicone dioxide w6re sifted through 40 # and mixed with dried granules of step 6).
8. Magnesium stearate was sifted through 40# and blend of step 7) was lubricated with sifted magnesium stearate.
9. Lubricated blend of step 8) was compressed to tablets using appropriate punch tooling.
10. Compressed tablets of step 9) were coated using the Opadry
Yellow 03F520005 dispersion prepared in purified water.
Dissolution data

Time (Minutes) CIALIS^ 20 mg Example 4
0 0 0
10 58 40
15 65 59
20 69 72
30 73 83
45 75 103
60 75 98

Example 5
Bio study of Example 4
Fasted study
Open label, balanced, randomized, two-treatment, two-sequence, two-period, single-dose, crossover oral bioequivalence study in healthy, adult, human male subjects under fasting conditions
Fed study
Open label, balanced, randomized, two-treatment, two-sequence, two-period, single-dose, crossover oral bioequivalence study in healthy, adult, human male subjects under fed conditions
Result of bio study

Bio Study (Fasted) Bio Study (Fed)
Cmax AUC 0-t AUC o-inf Cmax AUC 0-t AUC o.inf
Test (T) 392.7446 10515.2393 13630.7943 402.271 11101.6186 14341.0255
Reference (R) 323.4804 9878.6231 12819.9074 375.0927 11020.664 13391.9959
T/R 121.41 106.44 106.33 107.25 100.73 107.09
90% CL
LCL 109.54 96.67 95.12 100.16 89.63 94.4
UCL 134.58 117.21 118.84 114.84 113.21 121.48
Intra CV% 14.65 13.7 15.85 9.13 15.66 16.92
Power 97 98.12 95.07 99.89 93.51 90.34
Example 6
Tadalafil Tablets 20 mg

Ingredients %w/w
Intra-granular
Tadalafil 4.51
Hydroxy Propyl Cellulose 2.44

Lactose Monohydrate (Granulac 200) 69.71
Cros carmellose Sodium 2.93
Sodium Lauryl Sulphate 0.29
Povidone K -25 2.93
Dichloro Methane* qs
Methanol* q.s
Purified Water* q.s
Extra-granular
Tadalafil 0.37
Lactose Monohydrate (Flowlac 100) 10.00
Cros carmellose Sodium 2.93
Colloidal Silicone Dioxide 0.48
Magnesium stearate 0.97
Opadry Yellow 03F520005 2.44
Purified Water* q.s
Total 100.00
* Will be removed during manufacturing process
Procedure
1. Lactose monohydrate (Granulac 200) and croscarmellose sodium were sifted through 30# sieve.
2. Hydroxypropyl cellulose followed by tadalafil was dissolved in mixture of Dichloro methane and methanol.
3. Sodium lauryl Sulphate followed by povidone K-25 were dissolved in purified water to get clear solution.
4. Material of step 1) was granulated with solution of step 2) by top spray process.
5. Material of step 4) was further granulated with solution of step 3).
6. Granules of step 5) were dried and sifted through 30# sieve.
7. Tadalafil, Lactose Monohydrate (Flowlac 100), Cros carmellose Sodium and Colloidal silicone dioxide were sifted through 40 # and mixed with dried granules of step 6).
8. Magnesium stearate was sifted through 40# and blend of step 7) was lubricated with sifted magnesium stearate.

9. Lubricated blend of step 8) was compressed to tablets using appropriate punch tooling.
10. Compressed tablets of step 9) were coated using the Opadry Yellow 03F520005 dispersion prepared in purified water.
Dissolution data

Time (Minutes) CIALIS® 20 mg Example 6
0 0 0
10 58 41
15 65 57
20 69 66
30 73 74
45 75 82
60 75 87
Example 7
Bio study of Example 6
Fasted study
Open label, balanced, randomized, three-treatment, six-sequence, three-period, single dose, three way crossover oral bioequivalence study in healthy, adult, human male subjects under fasting conditions.
Fed study
Open label, balanced, randomized, three-treatment, six-sequence, three-period, single dose, three way crossover oral bioequivalence study in healthy, adult, human male subjects under fed conditions.
Bio study results

Bio Study (Fasted) Bio Study (Fed)
Cmax AUCo-t AUC o-inf Cmax AUC 0-t AUC 0,nf
Test (T) 321.388 9433.0937 11311.9967 405.1367 9536.0885 11411.2277

Reference (R) 349.0316 9379.717 11496.2273 355.4754 9276.5372 11255.2999
T/R 92.08 100.57 98.4 113.97 102.8 101.39
90% CL
LCL 81.85 88.35 84.19 107.33 93.64 91.45
UCL 103.59 114.48 115 121.02 112.85 112.4
Intra CV% 17.91 19.74 23.86 8.77 13.67 15.12
Power 93.17 88.88 77.15 99.98 98.55 96.99
Example 8
Tadalafil Tablets 20 mg

Ingredients %w/w
Intra-granular
Tadalafil 4.39
Hydroxy Propyl Cellulose 2.44
Lactose Monohydrate (Granulac 200) 79.71
Cros carmellose Sodium 2.93
Sodium Lauryl Sulphate 0.29
Povidone K -25 2.93
Dichloro Methane* q-s
Methanol* q.s
Purified Water* q.s
Extra-granular
Tadalafil 0.49
Cros carmellose Sodium 2.93
Colloidal Silicone Dioxide 0AS
Magnesium stearate 0.97
Opadry Yellow 03F520005 2.44
Purified Water* q.s
Total 100.00
* Will be removed during manufacturing process Procedure
1. Lactose monohydrate (Granulac 200) and croscarmellose sodium were sifted through 30# sieve.
2. Hydroxypropyl cellulose followed by tadalafil was dissolved in mixture of Dichloro methane and methanol.

3. Sodium lauryl Sulphate followed by povidone K-25 were dissolved in purified water to get clear solution.
4. Material of step 1) was granulated with solution of step 2) by top spray process.
5. Material of step 4) was further granulated with solution of step 3).
6. Granules of step 5) were dried and sifted through 30# sieve.
7. Tadalafil Cros carmellose Sodium and Colloidal silicone dioxide were sifted through 40 # and mixed with dried granules of step 6).
8. Magnesium stearate was sifted through 40# and blend of step 7) was lubricated with sifted magnesium stearate.
9. Lubricated blend of step 8) was compressed to tablets using appropriate punch tooling.
10. Compressed tablets of step 9) were coated using the Opadry
Yellow 03F520005 dispersion prepared in purified water.
Dissolution data

Time (Minutes) CIALIS® 20 mg Example 8
0 0 0
10 58 59
15 65 79
20 69 89
30 73 90
45 75 91
60 75 91

CLAIMS
We Claim,
1. A process for preparing tadalafil formulation comprising the steps of:
a) granulating at least one water soluble pharmaceutically acceptable excipient with solution comprising tadalafil and at least one pharmaceutically acceptable excipient in solvent,
b) granulating step a) with binder solution,

c) drying the granules of step b),
d) mixing the dried granules with at least one pharmaceutically acceptable excipient and optionally with tadalafil and
e) compressing the resulting blend of step d) into tablets and
f) coating the tablets of step e);
wherein water soluble excipient is present in 50 to 90 % w/w of the total composition and is having surface area in the range of 0.4648 m2/g to 0.8632 m2/g.
2. The pharmaceutically acceptable excipients according to claim 1 is selected from the group consisting of diluent, binder, disintegrant, lubricant, anti adherent and wetting agent.
3. The water soluble excipients according to claim 1, is selected from the group consisting of lactose monohydrate, lactose anhydrous, mannitol, sorbitol, sucrose and dextrose.

4. The water soluble excipients according to claim 3 is lactose monohydrate.
5. The pharmaceutically acceptable excipients according to claim 2, where in the wetting agent is selected from the group consisting of anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium

(dioctyl sulfosuccinate sodium salt), benzalkonium chloride and benzethonium chloride.
6. The process according to claim 1, wherein the solvent is aqueous.
7. The process according to claim 1, wherein the solvent is non-aqueous selected from the group consisting of isopropanol, methanol, ethanol, ethyl acetate and dichloromethane.