DESC:FIELD OF THE INVENTION
The invention relates to pharmaceutical composition comprising crystalline Erlotinib hydrochloride, colloidal anhydrous silica, surfactant and disintegrant selected from sodium starch glycolate or croscarmellose sodium or crospovidone, wherein said composition exhibiting cumulative in vitro release profile.
The invention also relates to the process for preparation of an oral pharmaceutical composition comprising Erlotinib hydrochloride.
BACKGROUND OF THE INVENTION
Erlotinib hydrochloride (I) is chemically named as N-(3-ethynylphenyl)-6, 7-bis (2-methoxy ethoxy)-4-quinazolinamine hydrochloride and its structural formula is:

Erlotinib is a compound that inhibits the human epidermal growth factor receptor tyrosine kinase, also known as EGFR-TK that is critical for growth of malignant cells. EGFR over expression is associated with disease progression, and reduced survival. Erlotinib acts by blocking tyrosine kinase activity of EGFR-TK, resulting in inhibition of the signaling pathway, and decreased growth of malignant tumors. Erlotinib is thus useful for the treatment of proliferative disorders such as cancers in humans. Erlotinib is marketed as its hydrochloride salt under such brand names as Tarceva® (OSI Pharmaceuticals, Inc.) for the treatment of certain lung cancers and pancreatic cancer.
TARCEVA tablets for oral administration are available in three dosage strengths containing Erlotinib hydrochloride (27.3 mg, 109.3 mg and 163.9 mg) equivalent to 25 mg, 100 mg and 150 mg Erlotinib. The U.S. Food and Drug administration (FDA) have approved Erlotinib as indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen and in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.
Erlotinib hydrochloride is very slightly soluble in water and slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.
US5747498B1 first disclosed 4-(substituted phenylamino)quinazoline derivatives which are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals.
US7625911B2 discloses solid dispersion composition of amorphous Erlotinib hydrochloride with polyvinylpyrolidone or polyethylene glycol and the excipients were lactose anhydrous, pregelatinized starch, sodium starch glycolate and microcrystalline cellulose. The pharmaceutical composition was prepared by dry granulation process.
WO2010/086441 relates to a pharmaceutical composition comprising Erlotinib hydrochloride and discloses pharmaceutical compositions comprising polymorph A of Erlotinib hydrochloride and a hydrophilic excipient i.e., microcrystalline cellulose is preferred in the range of about 10 wt % to about 90 wt %, most preferably in the range of about 50 wt % to about 70 wt %, apart from microcrystalline cellulose also a surfactant, i.e. sodium lauryl sulphate, was included in the formulation of Form A, the present invention relates to an alternative pharmaceutical composition comprising Erlotinib hydrochloride Form A in a thermodynamically stable form and with suitable release rate, which does not require the use of a surfactant, particularly sodium lauryl sulphate (SLS).
WO2014118112 relates to pharmaceutical compositions suitable for administration of polymorphic form A of Erlotinib hydrochloride, which do not require the use of a surfactant. The composition comprises, besides Erlotinib hydrochloride form A, microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, an effective amount of a carbomer. This amount of carbomer decreases the dissolution rate of the pharmaceutical composition and thereby compensates for the faster dissolving polymorph A resulting in a composition bioequivalent to commercial Tarceva®. The drawback of these compositions is that they are not robust, i.e. minor changes in the amount of carbopol used have a significant effect on the release rate.
WO2016/082879 relates to a pharmaceutical composition comprising granulation of Erlotinib hydrochloride polymorph A and a water soluble binder selected from sodium carboxymethylcellulose and xanthan gum, exhibiting an in vitro release profile by using USP apparatus II at 75 RPM and a dissolution medium of 0.1 N HCl, pH 1.0 at 37ºC.
However, the described prior art processes result in composition with Erlotinib shows slow release profile and take longer time for the drug release which for pharmaceutical preparations administrating active ingredients to the human body is highly undesirable. The present invention provides a simple, stable and easy to manufacture, and the composition is scalable on industrial scale with enhanced release profile.
As Erlotinib hydrochloride is an important anticancer therapeutic agent. There is still exists a need to develop such process for composition/formulation, which is scalable on industrial scale and results in stable pharmaceutical composition. Therefore, inventers of the present invention have developed a commercially viable pharmaceutical composition of Erlotinib hydrochloride that is found to be comparable with marketed Tarceva® tablet.

SUMMARY OF INVENTION
In one aspect, the present invention provides a process for preparing tablet containing crystalline Erlotinib hydrochloride with enhance dissolution profile of Erlotinib hydrochloride within the composition.
In one aspects of the present invention, it relates a stable pharmaceutical composition derived from wet granulation process, comprising crystalline Erlotinib hydrochloride (30-40 wt%), colloidal anhydrous silica (1 - 2 wt%), surfactant (1-2 wt%) and disintegrant (4-8 wt%) selected from sodium starch glycolate or croscarmellose sodium or crospovidone.
In another aspect of the present invention, it relates a stable pharmaceutical composition derived from wet granulation process, comprising crystalline Erlotinib hydrochloride wherein said composition exhibiting cumulative in vitro release profile:
a) >60% of Erlotinib hydrochloride is released within 10 minutes,
b) >70% of Erlotinib hydrochloride is released within 15 minutes and
c) >85% of Erlotinib hydrochloride is released within 45 minutes employing dissolution performed in USP apparatus II paddle at 75 RPM for 45 minutes and dissolution medium 900ml of 1%w/v of SLS in 0.1M HCl at 37oC.
In yet another aspects of the present invention, it relates to a process for preparing stable pharmaceutical composition comprising crystalline Erlotinib hydrochloride, wherein said process is a wet granulation process comprising the steps of:
a) preparing the intragranular composition by sifting Erlotinib hydrochloride, sodium lauryl sulfate, lactose monohydrate, Microcrystalline cellulose, colloidal anhydrous silica and sodium starch glycolate;
b) dry mixing of intragranular composition;
c) wet granulation performed using purified water and organic solvent (ratio 3:1-4:1v/v) ;
d) drying of wet granules upto moisture content less than 2%w/w;
e) milling of dried granules;
f) preparing the extra granular composition derived from lubricant and mixing with dried granules of step e.
Various other specific aspects of the invention are further detailed in the description part of the specification, wherever appropriate.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an illustration of in vitro dissolution data for pharmaceutical composition of Erlotinib hydrochloride with marketed Tarceva® tablet (Type-A) in USP apparatus II paddle at 75 RPM for 45 minutes and dissolution medium 900ml of 1%w/v of SLS in 0.1M HCl at 37oC.
DETAILED DESCRIPTION
The present invention relates to a stable pharmaceutical composition derived from wet granulation process, comprising crystalline Erlotinib hydrochloride, wherein said composition exhibiting cumulative in vitro release profile and which are robust, cost effective, simple to prepare and suitable for use on a commercial scale.
In one embodiment according to present invention, it provides a stable pharmaceutical composition derived from wet granulation process, comprising crystalline Erlotinib hydrochloride (30-40 wt%), colloidal anhydrous silica (1-2 wt%), surfactant (1-2 wt%) and disintegrant (4-8 wt%) selected from sodium starch glycolate or croscarmellose sodium or crospovidone, wherein said composition exhibiting cumulative in vitro release profile:
a) >60% of Erlotinib hydrochloride is released within 10 minutes,
b) >70% of Erlotinib hydrochloride is released within 15 minutes and
c) >85% of Erlotinib hydrochloride is released within 45 minutes employing dissolution performed in USP apparatus II paddle at 75 RPM for 45 minutes and dissolution medium 900ml of 1%w/v of SLS in 0.1M HCl at 37oC.
The present invention relates to a stable pharmaceutical composition derived from wet granulation process, comprising crystalline Erlotinib hydrochloride, wherein said composition comprising wet granulation method was selected among the various conventional granulation method (i.e. direct compression, dry granulation and wet granulation) water insoluble silica colloidal anhydrous was selected as binder and purified water and isopropyl alcohol as solvent.
The present invention relates to a stable pharmaceutical composition derived from wet granulation process, comprising crystalline Erlotinib hydrochloride, wherein said composition comprising of one or more pharmaceutically acceptable excipients selected from the group consisting of diluent, wetting agent or surfactant, disintegrant, binder and solvent for binder and lubricant. Preferably, the pharmaceutical composition of drug product contains at least one extragranular excipients as pre lubricant & lubricant.
The present invention particularly provides a pharmaceutical composition of crystalline Erlotinib hydrochloride wherein Erlotinib hydrochloride dose is equivalent to Erlotinib base.
The invention provides that the pharmaceutical composition of crystalline Erlotinib hydrochloride comprising diluent wherein diluent is selected from lactose monohydrate, lactose anhydrous, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, pregelatinized starch, fructose, maltose, dextrose, mannitol, maltitol, starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, sodium carbonate, cellulose acetate, ethyl cellulose, cellulose powdered, kaolin and the like or combinations thereof.
In a specific embodiment according to present invention the diluent used in the pharmaceutical composition was lactose monohydrate, microcrystalline cellulose or combinations thereof to get the bulk volume of mixture and thus the size of the dosage form.
The invention provides that the pharmaceutical composition of crystalline Erlotinib hydrochloride comprising surfactant wherein surfactant is selected from carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis (2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate.
In a specific embodiment according to present invention the surfactant used in the pharmaceutical composition was sodium lauryl sulfate (1-2%wt) to improve the drug release rate.
The present invention also provides the pharmaceutical composition of crystalline Erlotinib hydrochloride comprising disintegrant wherein disintegrant is selected from mannitol, alginic acid, carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone, magnesium aluminum silicate, methylcellulose, sodium alginate, starches or modified starches such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch.
Present invention also provides the pharmaceutical composition of crystalline Erlotinib Hydrochloride comprising disintegrant as sodium starch glycolate (4-8 wt%) and used in the intragranular components to promote the break-up of the tablet into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the drug substance.
The invention provides that the pharmaceutical composition of crystalline Erlotinib hydrochloride comprising binder wherein binder is selected from cellulose derivatives e.g. ethyl cellulose, methyl cellulose, guar gum, blende guar gum and other cellulose e.g. cellulose gums (carboxymethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose), polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pregelatinized starch, acacia, alginic acid, carbomer, dextrin, maltodextrin.
In a specific embodiment according to present invention the binder used in the pharmaceutical composition was silica colloidal silica anhydrous (1-2%wt) to facilitate bonding of powder particles during granulation.
In one embodiment according to present invention, it provides it provides a stable pharmaceutical composition derived from wet granulation process, comprising crystalline Erlotinib hydrochloride (30-40 wt%), colloidal silica (1-2 wt%), surfactant (1-2 wt%) and disintegrant (4-8 wt%) selected from sodium starch glycolate or croscarmellose sodium or crospovidone, wherein the composition is prepared using binder in isopropyl alcohol and water (ratio 3:1-4:1%v/v).
The pharmaceutical composition of Erlotinib hydrochloride according to present invention involves necessarily use of lubricant, wherein lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, vegetable oil, mineral oil.
Present invention also provides the pharmaceutical composition of crystalline Erlotinib hydrochloride comprising lubricant selected as magnesium stearate (1-2 wt %) and used as the extra granular excipient to improve the flow of powders during the manufacturing of tablets.
Surprisingly, it was found that employing the wet granulation technique for the preparation of the granules of the present invention, comprising stable pharmaceutical composition derived from wet granulation process, comprising crystalline Erlotinib hydrochloride, colloidal silica, surfactant and disintegrant selected from sodium starch glycolate or croscarmellose sodium or crospovidone, wherein the composition is prepared using binder in isopropyl alcohol and water. No conversion of dissolution profile was observed in time, even after long term storage. In general, the production costs of a wet granulation process are lower when compared to a dry granulation process. Another advantage of the wet granulation technique is that it is not relying on the intrinsic properties of the drug and excipients and that, in general, it is easier to obtain maximal tablet stability by using this method. Furthermore, from a safety perspective wet granulation is preferred over dry techniques in order to eliminate dust.
In wet granulation more uniform mixing than dry granulation, more binding in less quantity of binder, better content uniformity, Suitable for very low to very high drug content and reduces sticking of blend to compression tooling.
The invention, provides a process for preparing pharmaceutical composition comprising crystalline Erlotinib hydrochloride, the process particularly comprises wetting intragranular part with a granulation fluid, which is isopropyl alcohol and purified water containing binding agent, and granulating the mixture in a suitable granulator, high shear (Rapid mixer granulator/RMG) or fluid bed granulator (FBG or FBP), followed by drying, and optionally, sieving and/or milling.
Present invention also provides a process for preparing pharmaceutical composition comprising crystalline Erlotinib hydrochloride whereas the granules further followed by drying, and optionally, sieving and/or milling.
Further steps of present invention involve addition of extragranular part of excipients and blending to make final blend for tablet compression.
In yet another embodiment of the present invention, it provides to a process for preparing stable pharmaceutical composition, wherein said process is a wet granulation process comprising the steps of:
a) preparing the intragranular composition by sifting Erlotinib hydrochloride, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silica and sodium starch glycolate;
b) dry mixing of intragranular composition;
c) wet granulation performed using purified water and organic solvent (ratio 3:1-4:1v/v) ;
d) drying of wet granules upto moisture content less than 2%w/w;
e) milling of dried granules;
f) preparing the extra granular composition derived from lubricant and mixing with dried granules of step e.
According to the present invention of step a) of preparing the intragranular composition by sifting Erlotinib hydrochloride, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, colloidal silica and sodium starch glycolate, carried out in a Vibrosifter by conventional method however it was found that sifting carried out using mesh size of ranging between 20#-60# at temperature ranging between 15-30° C and relative humidity not more than 55%.
According to the present invention of step b) transfer the sifted materials into Rapid mixer granulator (RMG) for 15 min for dry mixing.
According to the present invention of step c) Add required amount of granulating fluid (Isopropyl alcohol & Purified water) to dried granules for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules so formed from Rapid mixer granulator (RMG) followed by wet milling through 8 mm screen.
According to the present invention of step d) transfer the wet granules of. into Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire LOD reaches not more than 2.0% (or product temperature reach 26°C to 29°C).
According to the present invention of step e) milled the dried granules of through Co- mill with 1.5 mm screen and collect separately.
According to the present invention of step f) transfer the milled granules and/or Lot(s) and allow it to blend for 10 minutes and add pre-sifted Magnesium Stearate and lubricate for 5 minutes.
In yet another embodiment of the present invention, it provides the preparation of pharmaceutical compositions for oral administration comprising a step of admixing the Erlotinib hydrochloride granulate with pharmaceutically acceptable excipients, comprising a step of compressing the composition into tablets and followed by a film-coating.
Present invention, provides a process for making the pharmaceutical composition for oral administration comprising a step of admixing the Erlotinib hydrochloride granulate with pharmaceutically acceptable excipients, comprising a step of compressing the composition into tablets, followed by a aqueous film-coating with solid contents ranging from 5-20%, which was found capable to provide adequate coating with gloss surface appearance of solid oral composition.
The coating of the tablet according to the present invention is carried out by using Opadry white and commercially available Purified Water. The coating of core tablets can be carried out in conventional pan coating apparatus.
The preparation of coating material according to the present invention comprising required quantity of purified water in a solution preparation tank. Add dispensed quantity of Opadry white (20B580002) slowly to purified water in a solution preparation tank with continuous stirring. Continue the stirring until a homogenous dispersion (or no lump) forms. Filter the coating dispersion form through #200 mesh nylon cloth. Load the uncoated tablets to perforated coating pan and allow it to warm for 4–8 minutes until the product temperature reaches 40-45°C. Spray the coating dispersion until reaches the desire weight gain of 3.0% w/w. As desire Weight gain achieved, turn off the spray and dry the tablets by operating the pan at low speed of 3 RPM.
Inventors of the present application additionally found the advantage of addition of lubricant as magnesium stearate which upon addition as extragranular component gives the improved flow of granules in hopper while performing the compression.
It has been surprisingly observed by present inventors that various composition discussed in prior art suffer a disadvantage during film coating on tablet like non-uniform which leads to blistering, chipping, picking, blushing, cracking (splitting) the tablet and further dissolution parameters also effected.
In yet another embodiment of the present invention, conventionally availalabe marketed drug product manufactured by dry granulation method in which the drug and excipients in various proportion were blended and followed by preparation of dry granules with compaction process followed by lubrication and compression of tablet. This conventionally market available method involves various numbers of process and tedious instrument and also there is a chance of hazardous exposure to operators and containment breach chances.
The term "oral solid composition" or "oral pharmaceutical composition" comprises capsule, tablet (film coated tablet, controlled release tablet, modified release tablet, delayed release etc.), micro tablet, powder, granule and pellets. Capsules used as oral dosage form can be soft or hard capsules, though oral dosage form of the present invention is tablet.
Based on context of discussion, the term "% w/w" refers to the relative value to total weight of granules or to total weight of pharmaceutical composition and “% v/v” refers to volume by total volume percentage.
In one of embodiments, the invention relates to pharmaceutical formulations having a disintegration time of less than about 15 minutes. In embodiments, the invention relates to pharmaceutical formulations having friability not more than about 1 % w/w.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES
Examples 1: Tablet composition of Erlotinib Hydrochloride
INGREDIENTS Quantity mg/ Unit %w/w of coated tablet
100 mg 150 mg
Intragranular
Erlotinib Hydrochloride$
(Eq. to Erlotinib) 109.267 163.90 35.36
Microcrystalline Cellulose
(PH 102)* 81.920 122.88 26.51
Lactose monohydrate 78.213 117.32 25.31
Sodium Laurylsulfate 6.000 9.000 1.94
croscarmellose sodium / crospovidone 15.000 22.500
4.85
Silica, Colloidal Anhydrous 3.600 5.400 1.16
Granulating Fluid
Isopropyl Alcohol# 0.049 mL 0.073 mL
Purified water# 0.193 mL 0.290 mL
Extragranular
Magnesium Stearate 6.000 9.000 1.94
Core Tablet 300.000 450.000
Coating
Opadry White (20B580002) 9.000 13.500 2.91
Purified water# 59.940 89.910
Coated Tablet Weight 309.000 463.500 99.97
# Evaporate during processing, except present in traces.
Manufacturing process of film coated tablet composition using wet granulation:
1. Mixing the intragranular composition by sifting Erlotinib hydrochloride, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silica and croscarmellose sodium or crospovidone manually followed by co-sifting.
2. Sift Magnesium stearate through sieving and collect separately for lubrication.
3. Transfer the sifted materials of step 1 into Rapid mixer granulator (RMG) for 15 min for dry mixing and add required amount of granulating fluid (Isopropyl alcohol &Purified water) to step 4 for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules from RMG followed by wet milling through 8 mm screen.
4. Transfer the wet granules of step 3 in Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire LOD reaches not more than 2.0%.
5. Milled the dried granules of step 4 through Co- mill with 1.5 mm screen and collect separately.
6. Transfer the milled granules and/or Lot(s) (if any) to conta/bin blender of step 5 and allow it to blend for 10 minutes.
7. Add pre-sifted Magnesium Stearate of step 6 to blend of step 8 and lubricate for 5 minutes.
8. The final blend of step 7 is compressed with appropriate round shape, biconcave, plain on both sides for 100mg & 150mg tablets respectively.
9. The core tablet of step 8 is coated with organic or aqueous dispersion of coating material.
Examples 2: Tablet composition of Erlotinib Hydrochloride
INGREDIENTS Quantity mg/ Unit %w/w of coated tablet
100 mg 150 mg
Intragranular
Erlotinib Hydrochloride$
(Eq. to Erlotinib) 109.267 163.90 35.36
Microcrystalline Cellulose
(PH 102)* 81.920 122.88 26.51
Lactose monohydrate 69.213 103.82 22.39
Sodium Laurylsulfate 6.000 9.000 1.94
Sodium Starch Glycolate (Type-A) 24.000 36.000 7.76
Silica, Colloidal Anhydrous 3.600 5.400 1.16
Granulating Fluid
Isopropyl Alcohol# 0.049 mL 0.073 mL
Purified water# 0.193 mL 0.290 mL
Extragranular
Magnesium Stearate 6.000 9.000 1.94
Core Tablet 300.000 450.000
Coating
Opadry White (20B580002) 9.000 13.500 2.91
Purified water# 59.940 89.910
Coated Tablet Weight 309.000 463.500 99.97
# Evaporate during processing, except present in traces.
Manufacturing process of film coated tablet composition using wet granulation:
1. Mix Erlotinib hydrochloride and intra-granular excipient Sodium Lauryl sulfate manually followed by co-sifting with Lactose monohydrate through sieving.
2. Mix Microcrystalline cellulose PH 102 and Silica, colloidal anhydrous manually followed by co-sifting with sodium starch glycolate through sieving to the step 1.
3. Sift Magnesium stearate through sieving and collect separately for lubrication.
4. Transfer the sifted materials of step 2 into Rapid mixer granulator (RMG) for 15 min for dry mixing.
5. Add required amount of granulating fluid (Isopropyl alcohol &Purified water) to step 4 for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules from RMG followed by wet milling through 8 mm screen.
6. Transfer the wet granules of step 5 in Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire LOD reaches not more than 2.0% (or product temperature reach 26°C to 29°C).
7. Milled the dried granules of step 6 through Co- mill with 1.5 mm screen and collect separately.
8. Transfer the milled granules and/or Lot(s) (if any) to conta/bin blender of Step 7 and allow it to blend for 10 minutes.
9. Add pre-sifted Magnesium Stearate of step 3 to blend of step 8 and lubricate for 5 minutes.
10. The final blend of step 9 is compressed with appropriate round shape, biconcave, plain on both sides for 100mg & 150mg tablets respectively.
11. The core tablet of step 10 is coated with organic or aqueous dispersion of coating material.
The dissolution study in USP apparatus II paddle at 75 RPM for 45 minutes and dissolution medium 900ml of 1%w/v of SLS in 0.1M HCl at 37oC.
Table 01: Dissolution testing results of marketed tablet and Examples 02 are shown in Table 01:
Table 01
Time
(Minutes) Cumulative % of Drug Dissolved
(Example 2) Tarceva®
100 mg 150 mg 100 mg 150 mg
Avg. % RSD Avg. % RSD Avg. % RSD Avg. % RSD
10 76.23 3.98 80.16 2.53 77.97 1.70 84.54 9.04
15 82.64 2.11 85.29 3.07 85.41 1.09 89.92 3.77
20 86.04 2.71 90.18 3.60 88.63 1.67 94.11 2.67
30 90.62 2.57 93.68 2.25 93.73 1.62 96.71 2.10
45 98.42 2.23 99.19 2.90 97.02 1.85 101.67 082

The abovementioned examples, which are provided by the way of illustration, should not be constructed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities used in any manner

,CLAIMS:We Claim:
1. A stable pharmaceutical composition derived from wet granulation process, comprising crystalline Erlotinib hydrochloride (30-40 wt%), colloidal anhydrous silica (1-2 wt%), surfactant (1-2 wt%) and disintegrant (4-8 wt%) selected from sodium starch glycolate or croscarmellose sodium or crospovidone, wherein said composition exhibiting cumulative in vitro release profile:
a) >60% of Erlotinib hydrochloride is released within 10 minutes,
b) >70% of Erlotinib hydrochloride is released within 15 minutes and
c) >85% of Erlotinib hydrochloride is released within 45 minutes employing dissolution performed in USP apparatus II paddle at 75 RPM for 45 minutes and dissolution medium 900ml of 1%w/v of SLS in 0.1M HCl at 37oC.
2. The composition as claimed in claim 1, wherein the pharmaceutical composition is a tablet further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of diluent, disintegrant, surfactant and lubricant.
3. The composition as claimed in claim 1, wherein the surfactant is sodium lauryl sulfate present in an amount ranging between 1 to 2 wt%.
4. The composition as claimed in claim 1, wherein the disintegrant is selected from sodium starch glycolate and used as intragranular components.
5. The composition as claimed in claim 1, wherein the lubricant selected as magnesium stearate (1-2 wt %) and used as the extra granular excipient.
6. A process for preparing stable pharmaceutical composition as claimed in claims 1, wherein said process is a wet granulation process comprising the steps of:
a) preparing the intragranular composition by sifting Erlotinib hydrochloride, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silica and sodium starch glycolate;
b) dry mixing of intragranular composition;
c) wet granulation performed using purified water and organic solvent (ratio 3:1-4:1v/v);
d) drying of wet granules upto moisture content less than 2%w/w;
e) milling of dried granules, and
f) preparing the extra granular composition derived from lubricant and mixing with dried granules of step e.
7. A process as claimed in claim 6, wherein a granulation solvent used in step b) is selected from acetone, ethanol, isopropyl alcohol or a mixture thereof.