DESC:FIELD OF THE INVENTION
The invention relates to pharmaceutical composition comprising crystalline Form B of Palbociclib having particle size less than 30µm (D90) comprising a process of wet granulation, wherein the composition optionally consisting organic acid and exhibiting in vitro drug release profile.
The invention also relates to the wet granulation process for preparation of an oral pharmaceutical composition comprising crystalline Form B of Palbociclib.
BACKGROUND OF THE INVENTION
Palbociclib is a potent and selective inhibitor of CDK4 and CDK6. It is chemically known as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl) pyridin-2-yl] amino} pyrido [2, 3-d] pyrimidin-7(8H)-one.

Palbociclib in the form of free base is approved in the form of capsules and tablets and marketed by Pfizer under the brand name IBRANCE®. The capsules and tablets are approved in the strengths of 75 mg, 100 mg and 125 mg.
Palbociclib is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; or fulvestrant in patients with disease progression following endocrine therapy. Palbociclib is a yellow to orange powder with pKa of 7.4 (the secondary piperazine nitrogen) and 3.9 (the pyridine nitrogen). At or below pH 4, palbociclib behaves as a high-solubility compound. Above pH 4, the solubility of the drug substance reduces significantly.
WO2003/062236A1 first discloses Palbociclib or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. The reference discloses that this invention relates to substituted 2-amino pyridines that are potent inhibitors of cyclin-dependent kinase 4. The compounds of the invention are useful for the treatment of inflammation, and cell proliferative diseases such as cancer and restenosis.
WO2016/193860A1 discloses a solid dosage form comprising palbociclib, a water-soluble acid, and a pharmaceutically acceptable carrier. This reference further discloses a solid dosage form comprises from about 10 wt% to about 35 wt% of palbociclib, from about 5 wt% to about 25 wt% of a water-soluble acid selected from the group consisting of succinic acid, malic acid and tartaric acid, and a pharmaceutically acceptable carrier.
WO2016/070833A1 discloses a composition comprising a solid dispersion prepared by Palbociclib, a disintegrant, a diluent, a binder, a lubricant, a glidant, wherein the composition is granulated by dry method.
WO2016/070834A1 discloses a composition comprising Palbociclib or a salt thereof, and a pharmaceutically acceptable excipient as a carrier, wherein the salt is selected from the group consisting of hydrochloride and isethionate. This publication discloses composition comprising different percentages of Palbociclib, diluent, disintegrant, lubricant, binder and surfactant.
WO2017/130219A1 discloses composition comprising a stable amorphous solid dispersion of Palbociclib with one or more pharmaceutically acceptable carrier, optionally with one or more pharmaceutically acceptable excipients and process for the preparation of the composition.
WO2017/166451A1 discloses a pharmaceutical formulation of palbociclib, comprising a palbociclib free base or a pharmaceutically acceptable salt thereof and an acidic auxiliary material, wherein the acidic auxiliary material is one or more selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid and malic acid.
WO2018/191950A1 discloses a Palbociclib composition comprising Palbociclib co-milled with at least one hydrophilic excipient.
As Palbociclib 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 Palbociclib that is found to be comparable with marketed IBRANCE® table.
SUMMARY OF INVENTION
In one aspect of the present invention, it relates a pharmaceutical composition of crystalline Form B of Palbociclib having particle size less than 30µm (D90) comprising a process of wet granulation, wherein the composition optionally consisting organic acid and exhibiting in vitro drug release of more than 90% of active released within 30 minutes employing dissolution performed in USP apparatus II paddle at 50 RPM and dissolution medium 900mL in 0.1M HCl at 37oC.
In another specific aspect, the present invention provides a process for preparing capsule or tablet containing crystalline Form B Palbociclib with enhance dissolution profile within the composition.
In another aspects of the present invention, it relates a pharmaceutical composition is a capsule or tablet comprising one or more pharmaceutically acceptable excipients selected from the group consisting of:
i. as intragranular components comprising, 25-31 %w/w of palbociclib, 50-70 %w/w of diluents, 0.25-0.5 %w/w of water insoluble binder, and 5-7 %w/w of disintegrant;
ii. as extragranular component comprising, 0.5 -1.5 %w/w of disintegrant, optionally 6-12 %w/w an organic acid; and
iii. 0.5-1.5 %w/w of lubricant.
In yet another aspect of the present invention, it relates to a process for preparing pharmaceutical composition comprising crystalline Form B Palbociclib, wherein the process comprising the steps of:
a) preparing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal silica and sodium starch glycolate;
b) dry mixing of intragranular composition;
c) wet granulation performed using purified water and/or organic solvent;
d) drying of wet granules upto moisture content ranging between 1-2.5%w/w;
e) milling of dried granules;
f) preparing the extra granular composition comprising lubricant, disintegrant, optionally an organic acid and mixing with dried granules of step e);
g) lubricating the granules from step f).
In yet another aspects of the present invention, it relates to preparing pharmaceutical compositions for oral administration comprising a step of admixing the crystalline Form B Palbociclib granulate with pharmaceutically acceptable excipients, optionally, comprising a step of compressing the composition into tablets or directly encapsulating in desired capsule size.
The solid oral pharmaceutical composition of crystalline Form B Palbociclib according to present invention may be useful in for the treatment of advanced or metastatic breast cancer.
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 Palbociclib with and without organic acid (Fumaric acid).
DETAILED DESCRIPTION
The present invention relates to a pharmaceutical composition comprising crystalline Form B having powder X-ray diffraction pattern comprising peaks at diffraction angles (2?) of 6.1±0.2, 11.1±0.2, 12.2±0.2, 13.0±0.2, 16.5±0.2, 18.3±0.2, 19.9±0.2, 22.7±0.2, 26.8±0.2, 28.3 ±0.2. of Palbociclib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The present invention relates to a pharmaceutical composition of crystalline Form B of Palbociclib having particle size less than 30µm (D90) comprising a process of wet granulation, wherein pharmaceutical 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 crystalline Form B of Palbociclib having particle size less than 30µm (D90) comprising a process of wet granulation, wherein the composition optionally consisting organic acid and exhibiting in vitro drug release of more than 90% of active released within 30 minutes employing dissolution performed in USP apparatus II paddle at 50 RPM and dissolution medium 900mL in 0.1M HCl at 37oC.
In one embodiment according to present invention, it provides a pharmaceutical composition is a capsule or tablet comprising one or more pharmaceutically acceptable excipients selected from the group consisting of:
i. as intragranular components comprising, 25-31 %w/w of palbociclib, 50-70 %w/w of diluents, 0.25-0.5 %w/w of water insoluble binder, and 5-7 %w/w of disintegrant;
ii. as extragranular component comprising, 0.5 -1.5 %w/w of disintegrant, optionally 6-12 %w/w an organic acid; and
iii. 0.5-1.5 %w/w of lubricant.
The present invention relates to a pharmaceutical composition comprising crystalline Form B Palbociclib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by wet granulation.
The present invention also relates to a capsule or tablet composition comprising crystalline Form B Palbociclib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The present invention relates to a capsule or tablet composition comprising crystalline Form B Palbociclib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by wet granulation.
As used herein, the term “% w/w” refers to the weight of the component based on the total weight of a composition comprising the component.
“Pharmaceutically acceptable excipient/s” are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc.
In another embodiment, the composition according to the present invention comprises crystalline Form B Palbociclib or a pharmaceutically acceptable salt thereof in an amount of 25-31% w/w of the composition.
In another embodiment, the composition according to the present invention further comprises one or more pharmaceutically acceptable excipients which include but not limited to diluents, disintegrants, binders, and lubricants. These excipients may be present intragranularly or extragranularly.
The present invention relates to a stable pharmaceutical composition derived from wet granulation process, comprising crystalline Form B Palbociclib, 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 or isopropyl alcohol as solvent.
The invention provides that the pharmaceutical composition of crystalline Form B Palbociclib 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, 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, silicified microcrystalline cellulose or combinations thereof.
The present invention also provides the pharmaceutical composition of crystalline Form B Palbociclib 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 Form B Palbociclib comprising disintegrant as sodium starch glycolate (0.5-8 %w/w) used as intragranular and extragranular components.
The invention provides that the pharmaceutical composition of crystalline Palbociclib comprising binder wherein water insoluble binder is selected from colloidal silica, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, pregelatinized starch, acacia, alginic acid, carbomer, dextrin, and maltodextrin.
In a specific embodiment according to present invention the water insoluble binder used in the pharmaceutical composition was colloidal silica anhydrous (0.25-0.5%w/w).
In a specific embodiment according to present invention optionally an organic acid used in the pharmaceutical composition was maleic acid, fumaric acid, citric acid, glucuronic acid, gluconic acid. (6-12 % w/w) or combinations thereof.
The pharmaceutical composition of crystalline Form B Palbociclib 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 Form B Palbociclib comprising lubricant selected as magnesium stearate (0.5-1.5 %w/w).
The invention, provides a process for preparing pharmaceutical composition comprising crystalline Form B Palbociclib, the process particularly comprises extragranular part with a granulation liquid, which is purified water and or isopropyl alcohol containing binder, and granulating the mixture in a suitable granulator, e.g. high shear (Rapid mixer granulator/RMG) or fluid bed granulator (FBG or FBP), followed by drying, and optionally, sieving and/or milling, slugging.
Further step of present invention involves addition of extragranular part of excipients and blending to make final blend for tablet compression, or filling into hard gelatin capsules.
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 co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal silica and sodium starch glycolate;
b) dry mixing of intragranular composition;
c) wet granulation performed using purified water and/or organic solvent;
d) drying of wet granules upto moisture content ranging between 1-2.5%w/w;
e) milling of dried granules;
f) preparing the extra granular composition comprising lubricant, disintegrant, optionally an organic acid and mixing with dried granules of step e);
g) lubricating the granules from step f).
According to the present invention of step a) of preparing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, 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) for dry mixing transfer the sifted material into Rapid mixer granulator (RMG) for 15 min.
According to the present invention of step c) to make a wet mass add required amount of granulating fluid (Purified water and or Isopropyl alcohol) to dried granules for 6-8 min and kneading the wet mass for 2 min and then unload the wet granules for further chopping the wet mass 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 the Fluid bed dryer and allow the granules to dry at temperature ranging between 45°C - 55°C until desire LOD reaches ranging between 1-2.5%w/w.
According to the present invention of step e) milled the dried granules through co - mill with 1.5 mm screen and collected separately.
According to the present invention of step f) transfer the milled granules into a container and allow it to blend for 10 minutes and add extra granular sodium starch glycolate and optionally an organic acid for pre-lubrication along with further 18 minutes blending.
According to the present invention of step g) in order to lubricate the pre-lubrication blended and add pre-sifted Magnesium Stearate and lubricate for 5 minutes.
In yet another embodiment of the present invention, it provides to preparing pharmaceutical compositions for oral administration (capsule or tablet) comprising a step of admixing the Palbociclib granulate with pharmaceutically acceptable excipients, comprising a step of compressing the composition into tablets and optionally followed by a film-coating or directly encapsulating in desired capsule size.
The term "pharmaceutical composition" or "oral pharmaceutical composition" or "oral dosage form" comprises capsule, tablet (film coated tablet, controlled release tablet, modified release tablet etc.), micro tablet, suspension, solution, dispersion, 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 preferably tablet or capsule.
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.
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
Example 1: Pharmaceutical composition of Palbociclib
Pharmaceutical composition of Palbociclib is derived from intragranular and extragranular composition wherein intragranular composition is derived using purified water as granulating fluid.
Below table summarizes the unit composition for 75mg, 100mg and 125mg, respectively.
INGREDIENTS Quantity mg/ Unit
%w/w
75 mg 100 mg 125 mg
Intragranular
Palbociclib 75.000 100.000 125.000 29.94
Silicified Microcrystalline Cellulose (HD 90) 56.718 75.624 94.530 22.64
Lactose monohydrate 80.000 106.667 133.333 31.93
Silicified Microcrystalline Cellulose (90) 17.495 23.327 29.158 6.98
Sodium starch glycolate(Type A) 15.030 20.040 25.050 6.00
Silica, Colloidal Anhydrous 0.752 1.003 1.253 0.30
Granulating Fluid
Purified water# 0.112 0.150 0.187 0.04
Extragranular
Sodium starch glycolate(Type A) 2.505 3.340 4.175 1.00
Magnesium Stearate 3.000 4.000 5.000 1.19
Fill Weight 250.50 334.00 417.50 100.00
EHG Cap “0” ----- ----- 96.000
EHG Cap “1” ----- 76.000 -----
EHG Cap “2” 63.000 ----- -----
Gross Capsule Weight 313.50 410.00 513.50
# Evaporate during processing, except present in traces.
Manufacturing process of pharmaceutical composition using wet granulation comprises the following steps:
1. Mixing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal silica and Sodium starch glycolate(Type A).
2. Sifting extragranular composition Sodium starch glycolate(Type A) through sieving and collected separately.
3. Sifting magnesium stearate through sieving and collect separately for lubrication.
4. Transferring the sifted materials of step 1 into Rapid mixer granulator (RMG) for 15 min for dry mixing and add required amount of granulating fluid (Purified water and or Isopropyl alcohol) for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules for further chopping the wet mass from RMG followed by wet milling through 8 mm screen.
5. Transferring the wet granules of step 4 in Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire moisture content ranging between 1-2.5%w/w;
6. Milling the dried granules of step 5 through Co- mill with 1.5 mm screen and collect separately.
7. Transferring the milled granules and/or Lot(s) (if any) to conta/bin blender of step 6 and allow it to blend for 10 minutes.
8. Adding pre-sifted Extragranular composition Sodium starch glycolate(Type A) of step 2 to blend of step 7 and lubricate for 18 minutes for pre-lubrication.
9. For lubrication add pre-sifted Magnesium Stearate of step 3 to blend of step 8 and lubricate for 6 minutes.
10. The final blend of step 9 is lubricated granules composition filled in the capsule or compressed to tablets for 75mg, 100mg & 125mg respectively.
Example 2: Pharmaceutical composition of Palbociclib along with organic acid-Maleic acid
Pharmaceutical composition of Palbociclib is derived from intragranular and extragranular composition wherein intragranular composition is derived using purified water as granulating fluid and Maleic acid is used as extragranular composition.
Below table summarizes the unit composition for 75mg, 100mg and 125mg, respectively.
INGREDIENTS Quantity mg/ Unit
%w/w
75 mg 100 mg 125 mg
Intragranular
Palbociclib 75.000 100.000 125.000 29.95
Silicified Microcrystalline Cellulose (HD 90) 60.480
80.640
100.80
24.14

Lactose monohydrate 68.490 91.320 114.150 27.34
Silicified Microcrystalline Cellulose (90) 22.840 30.453 38.067 9.12
Sodium starch glycolate (Type A) 15.030 20.040 25.050 6.00

Silica, Colloidal Anhydrous 0.752 1.003 1.253 0.30

Granulating Fluid
Purified water# 0.112 0.150 0.187 0.04
Extragranular
Sodium starch glycolate(Type A) 2.505 3.340 4.175 1.00
Maleic acid 2.400 3.200 4.000 0.96
Magnesium Stearate 3.000 4.000 5.000 1.20
Fill Weight 250.50 334.00 417.50 100.00
EHG Cap “0” ----- ----- 96.000
EHG Cap “1” ----- 76.000 -----
EHG Cap “2” 63.000 ----- -----
Gross Capsule Weight 313.50 410.00 513.50
# Evaporate during processing, except present in traces.
Manufacturing process of pharmaceutical composition using wet granulation comprises the following steps:
1. Mixing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica and Sodium starch glycolate(Type A).
2. Sifting Extragranular composition sodium starch glycolate, Maleic acid through sieving and collect separately.
3. Sifting Magnesium stearate through sieving and collect separately for lubrication.
4. Transferring the sifted materials of step 1 into Rapid mixer granulator (RMG) for 15 min for dry mixing and add required amount of granulating fluid (Purified water and or Isopropyl alcohol) for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules for further chopping the wet mass from RMG followed by wet milling through 8 mm screen.
5. Transferring the wet granules of step 4 in Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire moisture content ranging between 1-2.5%w/w;
6. Milling the dried granules of step 5 through Co- mill with 1.5 mm screen and collect separately.
7. Transferring the milled granules and/or Lot(s) (if any) to conta/bin blender of step 6 and allow it to blend for 10 minutes.
8. Adding pre-sifted Extragranular composition Sodium starch glycolate(Type A), maleic acid of step 2 to blend of step 7 and lubricate for 18 minutes for pre-lubrication.
9. For lubrication add pre-sifted Magnesium Stearate of step 3 to blend of step 8 and lubricate for 6 minutes.
10. The final blend of step 9 is lubricated granules composition filled in the capsule or compressed to tablets for 75mg, 100mg & 125mg respectively.
Example 3: Pharmaceutical composition of Palbociclib along with organic acid- Fumaric acid
Pharmaceutical composition of Palbociclib is derived from intragranular and extragranular composition wherein intragranular composition is derived using purified water as granulating fluid and Fumaric acid is used as extragranular composition.
Below table summarizes the unit composition for 75mg, 100mg and 125mg, respectively.
INGREDIENTS Quantity mg/ Unit
%w/w
75 mg 100 mg 125 mg
Intragranular
Palbociclib 75.000 100.000 125.000 29.95
Silicified Microcrystalline Cellulose (HD 90) 54.880 73.173 91.467 21.91
Lactose monohydrate 60.445 80.593 100.742 24.13
Silicified Microcrystalline Cellulose (90) 18.850 25.133 31.417 7.52
Sodium starch glycolate(Type A) 15.030 20.040 25.050 6.00
Silica, Colloidal Anhydrous 0.752 1.003 1.253 0.30
Granulating Fluid
Purified water# 0.112 0.150 0.187 0.04
Extragranular
Sodium starch glycolate(Type A) 2.505 3.340 4.18 1.00
Fumaric acid 20.040 26.720 33.400 8.00
Magnesium Stearate 3.000 4.000 5.000 1.20
Fill Weight 250.50 334.00 417.50 100.00
EHG Cap “0” ----- ----- 96.000
EHG Cap “1” ----- 76.000 -----
EHG Cap “2” 63.000 ----- -----
Gross Capsule Weight 313.50 410.00 513.50
# Evaporate during processing, except present in traces.
Manufacturing process of pharmaceutical composition using wet granulation comprises the following steps:
1. Mixing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica and Sodium starch glycolate(Type A).
2. Sifting Extragranular composition sodium starch glycolate, Fumaric acid through sieving and collect separately.
3. Sifting Magnesium stearate through sieving and collect separately for lubrication.
4. Transferring the sifted materials of step 1 into Rapid mixer granulator (RMG) for 15 min for dry mixing and add required amount of granulating fluid (Purified water and or Isopropyl alcohol) for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules for further chopping the wet mass from RMG followed by wet milling through 8 mm screen.
5. Transferring the wet granules of step 4 in Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire moisture content ranging between 1-2.5%w/w;
6. Milling the dried granules of step 5 through Co- mill with 1.5 mm screen and collect separately.
7. Transferring the milled granules and/or Lot(s) (if any) to conta/bin blender of step 6 and allow it to blend for 10 minutes.
8. Adding pre-sifted Extragranular composition Sodium starch glycolate(Type A), Fumaric acid of step 2 to blend of step 7 and lubricate for 18 minutes for pre-lubrication.
9. For lubrication add pre-sifted Magnesium Stearate of step 3 to blend of step 8 and lubricate for 6 minutes.
10. The final blend of step 9 is lubricated granules composition filled in the capsule or compressed to tablets for 75mg, 100mg & 125mg respectively.
Example 4: Pharmaceutical composition of Palbociclib along with organic acid- Citric acid
Pharmaceutical composition of Palbociclib is derived from intragranular and extragranular composition wherein intragranular composition is derived using purified water as granulating fluid and Citric acid is used as extragranular composition.
Below table summarizes the unit composition for 75mg, 100mg and 125mg, respectively.
INGREDIENTS Quantity mg/ Unit
%w/w
75 mg 100 mg 125 mg
Intragranular
Palbociclib 75.000 100.000 125.000 29.95
Silicified Microcrystalline Cellulose (HD 90) 52.480 69.973 87.467 20.95
Lactose monohydrate 55.810 74.413 93.017 22.28
Silicified Microcrystalline Cellulose (90) 15.870 21.160 26.450 6.34
Sodium starch glycolate(Type A) 15.030 20.040 25.050 6.00
Silica, Colloidal Anhydrous 0.752 1.003 1.253 0.30
Granulating Fluid
Purified water# 0.112 0.150 0.187 0.04
Extragranular
Sodium starch glycolate(Type A) 2.500 3.333 4.167 1.00
Citric acid 30.060 40.080 50.10 12.00
Magnesium Stearate 3.000 4.000 5.000 1.20
Fill Weight 250.50 334.00 417.50 100.00
EHG Cap “0” ----- ----- 96.000
EHG Cap “1” ----- 76.000 -----
EHG Cap “2” 63.000 ----- -----
Gross Capsule Weight 313.50 410.00 513.50
# Evaporate during processing, except present in traces.
Manufacturing process of pharmaceutical composition using wet granulation comprises the following steps:
1. Mixing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica and Sodium starch glycolate(Type A).
2. Sifting extragranular composition sodium starch glycolate, Citric acid through sieving and collect separately.
3. Sifting magnesium stearate through sieving and collect separately for lubrication.
4. Transferring the sifted materials of step 1 into Rapid mixer granulator (RMG) for 15 min for dry mixing and add required amount of granulating fluid (Purified water and or Isopropyl alcohol) for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules for further chopping the wet mass from RMG followed by wet milling through 8 mm screen.
5. Transferring the wet granules of step 4 in Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire moisture content ranging between 1-2.5%w/w;
6. Milling the dried granules of step 5 through Co- mill with 1.5 mm screen and collect separately.
7. Transferring the milled granules and/or Lot(s) (if any) to conta/bin blender of step 6 and allow it to blend for 10 minutes.
8. Adding pre-sifted Extragranular composition Sodium starch glycolate(Type A), Citric acid of step 2 to blend of step 7 and lubricate for 18 minutes for pre-lubrication.
9. For lubrication add pre-sifted Magnesium Stearate of step 3 to blend of step 8 and lubricate for 6 minutes.
10. The final blend of step 9 is lubricated granules composition filled in the capsule or compressed to tablets for 75mg, 100mg & 125mg respectively.
Example 5: Pharmaceutical composition of Palbociclib along with organic acid- Glucuronic acid
Pharmaceutical composition of Palbociclib is derived from intragranular and extragranular composition wherein intragranular composition is derived using purified water as granulating fluid and Glucuronic acid is used as extragranular composition.
Below table summarizes the unit composition for 75mg, 100mg and 125mg, respectively.
INGREDIENTS Quantity mg/ Unit
%w/w
75 mg 100 mg 125 mg
Intragranular
Palbociclib 75.000 100.000 125.000 29.94
Silicified Microcrystalline Cellulose (HD 90) 50.456 67.274 84.0925 20.14
Lactose monohydrate 67.476 89.967 112.458 26.93
Silicified Microcrystalline Cellulose (90) 11.233 14.977 18.7205 4.48
Sodium starch glycolate(Type A) 15.030 20.040 25.050 6.00
Silica, Colloidal Anhydrous 0.752 1.003 1.253 0.30
Granulating Fluid
Purified water# 0.112 0.150 0.187 0.04
Extragranular
Sodium starch glycolate(Type A) 2.505 3.340 4.175 1.00
Glucuronic acid 25.05 33.4 41.75 10.00
Magnesium Stearate 3.000 4.000 5.000 1.19
Fill Weight 250.50 334.00 417.50 100.00
EHG Cap “0” ----- ----- 96.000
EHG Cap “1” ----- 76.000 -----
EHG Cap “2” 63.000 ----- -----
Gross Capsule Weight 313.50 410.00 513.50
# Evaporate during processing, except present in traces.
Manufacturing process of pharmaceutical composition using wet granulation comprises the following steps:
1. Mixing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica and Sodium starch glycolate(Type A).
2. Sifting extragranular composition sodium starch glycolate, Glucuronic acid acid through sieving and collect separately.
3. Sifting magnesium stearate through sieving and collect separately for lubrication.
4. Transferring the sifted materials of step 1 into Rapid mixer granulator (RMG) for 15 min for dry mixing and add required amount of granulating fluid (Purified water and or Isopropyl alcohol) for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules for further chopping the wet mass from RMG followed by wet milling through 8 mm screen.
5. Transferring the wet granules of step 4 in Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire moisture content ranging between 1-2.5%w/w;
6. Milling the dried granules of step 5 through Co- mill with 1.5 mm screen and collect separately.
7. Transferring the milled granules and/or Lot(s) (if any) to conta/bin blender of step 6 and allow it to blend for 10 minutes.
8. Adding pre-sifted extragranular composition Sodium starch glycolate(Type A), Glucuronic acid of step 2 to blend of step 7 and lubricate for 18 minutes for pre-lubrication.
9. For lubrication add pre-sifted Magnesium Stearate of step 3 to blend of step 8 and lubricate for 6 minutes.
10. The final blend of step 9 is lubricated granules composition filled in the capsule or compressed to tablets for 75mg, 100mg & 125mg respectively.
Example 6: Pharmaceutical composition of Palbociclib along with organic acid- Gluconic acid
Pharmaceutical composition of Palbociclib is derived from intragranular and extragranular composition wherein intragranular composition is derived using purified water as granulating fluid and Gluconic acid is used as extragranular composition.
Below table summarizes the unit composition for 75mg, 100mg and 125mg, respectively.
INGREDIENTS Quantity mg/ Unit
%w/w
75 mg 100 mg 125 mg
Intragranular
Palbociclib 75.000 100.000 125.000 29.95
Silicified Microcrystalline Cellulose (HD 90) 57.240
76.320
95.400
22.85

Lactose monohydrate 59.480 79.307 99.133 23.74
Silicified Microcrystalline Cellulose (90) 19.460
25.947
32.433
7.77

Sodium starch glycolate(Type A) 15.030
20.040
25.050
6.00

Silica, Colloidal Anhydrous 0.752
1.003
1.253
0.30

Granulating Fluid
Purified water# 0.112 0.150 0.187 0.04
Extragranular
Sodium starch glycolate(Type A) 2.500 3.333 4.167 1.00
Gluconic acid 18.036 24.048 30.060 7.20
Magnesium Stearate 3.000 4.000 5.000 1.20
Fill Weight 250.50 334.00 417.50 100
EHG Cap “0” ----- ----- 96.000
EHG Cap “1” ----- 76.000 -----
EHG Cap “2” 63.000 ----- -----
Gross Capsule Weight 313.50 410.00 513.50
# Evaporate during processing, except present in traces.
Manufacturing process of pharmaceutical composition using wet granulation comprises the following steps:
1. Mixing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica and Sodium starch glycolate(Type A).
2. Sifting extragranular composition sodium starch glycolate, Gluconic acid through sieving and collect separately.
3. Sift magnesium stearate through sieving and collect separately for lubrication.
4. Transferring the sifted materials of step 1 into Rapid mixer granulator (RMG) for 15 min for dry mixing and add required amount of granulating fluid (Purified water and or Isopropyl alcohol) for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules for further chopping the wet mass from RMG followed by wet milling through 8 mm screen.
5. Transferring the wet granules of step 4 in Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire moisture content ranging between 1-2.5%w/w;
6. Milling the dried granules of step 5 through Co- mill with 1.5 mm screen and collect separately.
7. Transferring the milled granules and/or Lot(s) (if any) to conta/bin blender of step 6 and allow it to blend for 10 minutes.
8. Adding pre-sifted extragranular composition Sodium starch glycolate(Type A), Gluconic acid of step 2 to blend of step 7 and lubricate for 18 minutes for pre-lubrication.
9. For lubrication add pre-sifted Magnesium Stearate of step 3 to blend of step 8 and lubricate for 6 minutes.
10. The final blend of step 9 is lubricated granules composition filled in the capsule or compressed to tablets for 75mg, 100mg & 125mg respectively.
Example 7: Pharmaceutical composition of Palbociclib along with organic acid- Fumaric acid
Pharmaceutical composition of Palbociclib is derived from intragranular and extragranular composition wherein intragranular composition is derived using purified water as granulating fluid and Fumaric acid is used as extragranular composition.
Below table summarizes the unit composition for 75mg, 100mg and 125mg, respectively.
INGREDIENTS Quantity mg/ Unit
%w/w
75 mg 100 mg 125 mg
Intragranular
Palbociclib 75.000 100.000 125.000 29.94
Silicified Microcrystalline Cellulose (HD 90) 50.456 67.274 84.0925 20.14
Lactose monohydrate 67.476 89.967 112.458 26.93
Silicified Microcrystalline Cellulose (90) 11.233 14.977 18.7205 4.48
Sodium starch glycolate(Type A) 15.030 20.040 25.050 6.00
Silica, Colloidal Anhydrous 0.752 1.003 1.253 0.30
Granulating Fluid
Purified water# 0.112 0.150 0.187 0.04
Extragranular
Sodium starch glycolate(Type A) 2.505 3.340 4.175 1.00
Fumaric acid 25.05 33.4 41.75 10.00
Magnesium Stearate 3.000 4.000 5.000 1.19
Core Weight 250.50 334.00 417.50 100.00
Film coating 7.500 10.000 12.500 3.00
Gross Weight 258.015 344.00 430.00 103.00
# Evaporate during processing, except present in traces.
Manufacturing process of pharmaceutical composition using wet granulation comprises the following steps:
1. Mixing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica and Sodium starch glycolate(Type A).
2. Sifting Extragranular composition sodium starch glycolate, Fumaric acid through sieving and collect separately.
3. Sifting Magnesium stearate through sieving and collect separately for lubrication.
4. Transferring the sifted materials of step 1 into Rapid mixer granulator (RMG) for 15 min for dry mixing and add required amount of granulating fluid (Purified water and or Isopropyl alcohol) for 6-8 min followed by chopping of wet mass and knead the wet mass for 2 min and then unload the wet granules for further chopping the wet mass from RMG followed by wet milling through 8 mm screen.
5. Transferring the wet granules of step 4 in Fluid bed dryer and allow the granules to dry at 45°C - 55°C until desire moisture content ranging between 1-2.5%w/w;
6. Milling the dried granules of step 5 through Co- mill with 1.5 mm screen and collect separately.
7. Transferring the milled granules and/or Lot(s) (if any) to conta/bin blender of step 6 and allow it to blend for 10 minutes.
8. Adding pre-sifted Extragranular composition Sodium starch glycolate(Type A), Fumaric acid of step 2 to blend of step 7 and lubricate for 18 minutes for pre-lubrication.
9. For lubrication add pre-sifted Magnesium Stearate of step 3 to blend of step 8 and lubricate for 6 minutes.
10. The final blend of step 9 is lubricated granules composition compressed to tablets or filled in the capsule for 75mg, 100mg & 125mg respectively.
The dissolution study in USP apparatus II paddle at 50 RPM and dissolution medium 900ml in 0.1M HCl at 37oC.
Table 01: In Vitro dissolution data for pharmaceutical composition of Palbociclib.
Time
(Minutes) Cumulative % of Drug Dissolved (Example 1)
75 mg 100 mg 125 mg
Avg. % RSD Avg. % RSD Avg. % RSD
10 92.25 5.50 93.61 2.62 88.02 4.50
15 98.99 1.79 95.72 2.08 90.95 4.31
20 100.38 1.18 97.03 2.25 92.23 3.94
30 100.85 1.32 97.08 1.35 91.88 4.07
45 100.62 0.67 96.67 0.97 93.22 3.82

Table 02: In Vitro dissolution data for pharmaceutical composition of Palbociclib along with organic acid (Gluconic acid).
Time
(Minutes) Cumulative % of Drug Dissolved (Example 3)
75 mg 100 mg 125 mg
Avg. % RSD Avg. % RSD Avg. % RSD
15 94.35 3.21 96.79 4.32 99.38 2.39
20 95.02 3.93 96.35 3.13 99.55 1.58
30 94.07 3.66 96.65 3.65 98.99 1.76
45 94.36 4.52 97.79 2.39 99.16 2.04
60 96.97 2.87 99.99 2.40 98.78 2.22
The above mentioned 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. Pharmaceutical composition of crystalline Form B of Palbociclib having particle size less than 30µm (D90) comprising a process of wet granulation, wherein the composition optionally consisting organic acid and exhibiting in vitro drug release of more than 90% of active released within 30 minutes employing dissolution performed in USP apparatus II paddle at 50 RPM and dissolution medium 900mL in 0.1M HCl at 37oC.
2. Pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is a capsule or tablet comprising pharmaceutically acceptable excipients selected from the group consisting of:
i. as intragranular components comprising, 25-31 %w/w of palbociclib, 50-70 %w/w of diluents, 0.25-0.5 %w/w of water insoluble binder, and 5-7 %w/w of disintegrant;
ii. as extragranular component comprising, 0.5 -1.5 %w/w of disintegrant, optionally 6-12 %w/w an organic acid; and
iii. 0.5-1.5 %w/w of lubricant.
3. Pharmaceutical composition as claimed in claim 2, wherein the diluent is selected from silicified microcrystalline cellulose, lactose monohydrate, mannitol or a mixture thereof.
4. Pharmaceutical composition as claimed in claim 2, wherein the water insoluble binder is colloidal silica.
5. Pharmaceutical composition as claimed in claim 2, wherein an organic acid is selected from the group consisting of maleic acid, fumaric acid, citric acid, glucuronic acid, gluconic acid.
6. Pharmaceutical composition as claimed in claim 2, wherein the disintegrant is selected from sodium starch glycolate, crospovidone, croscarmellose sodium.
7. Pharmaceutical composition as claimed in claim 2, wherein the lubricant is selected from magnesium stearate, sodium stearyl fumarate.
8. A process for preparing pharmaceutical composition as claimed in claim 2, wherein the process comprising the steps of:
a) preparing the intragranular composition by co-sifting palbociclib, silicified microcrystalline cellulose, lactose monohydrate, colloidal silica and sodium starch glycolate;
b) dry mixing of intragranular composition;
c) wet granulation performed using purified water and/or organic solvent;
d) drying of wet granules upto moisture content ranging between 1-2.5 %w/w;
e) milling of dried granules;
f) preparing the extra granular composition comprising lubricant, disintegrant, optionally an organic acid and mixing with dried granules of step e);
g) lubricating the granules from step f).
9. A process as claimed in claim 8, wherein a organic solvent used in step c) is selected from acetone, ethanol, isopropyl alcohol or a mixture thereof.
10. A process as claimed in claim 8, wherein lubricated granules composition filled in the capsule or compressed to tablets.