international journal of innovative pharmaceutical ... · t.bindu*, 2p.prem kumar , 3y ......

RESEARCH ARTICLE T.Bindu et.al / IJIPSR / 2 (7), 2014, 1386-1401

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com July Issue 1386

FORMULATION AND DEVELOPMENT OF SORAFENIB

TOSYLATE IMMEDIATE RELEASE TABLET

1T.Bindu*,

2P.Prem Kumar,

3Y.Raja Jaya Rao,

4P.Nagaswara Rao,

5M.Manasa

Department of Pharmaceutics, Sims college of pharmacy, Guntur, AP, INDIA

Corresponding Author:

T.Bindu

Department of Pharmaceutics,

SIMS Institute of Pharmacy,

GUNTUR, AP, INDIA

Email:[email protected]

Mobile: +919908079758

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

Immediate release tablets are those tablets which disintegrate and release the drug rapidly once it enters

GIT. They are also a tool for expanding markets, extending product life cycles and generating

opportunities. Sorafenib tosylate is approved to treat cancer. The present work involves the formulation

development, optimization and in- vitro evaluation of immediate release Sorafenib tosylate tablets. Direct

compression method was selected for the formulation tablets. Tablets were prepared containing 40%

overages using croscaramellose sodium, crospovidone, pre gelatinized starch and sodium starch glycolate

as disintegrants since tablets containing 10% overages failed to meet the desired specifications. It was

found that the formula G8 containing pregelatinized starch as disintegrant exhibited acceptable

disintegration time, percentage drug content per tablet and in vitro drug release. This formula was scaled up

in two batches out of which one was film coated. Later they were subjected to stability studies after

packing in amber colored PVC-PVDC blister packing which showed acceptable results. So at last it was

concluded that immediate release Sorafenib tosylate tablets containing 40% overages can be prepared using

direct compression which met the required specifications.

Keywords: Immediate release tablets; Sorafenib tosylate; cross carmellose sodium; crosspovidone;

pre gelatinized starch ; sodium starch glycolate.

.

http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45333&version=Patient&language=English




INTRODUCTION

An Oral Dosage Form is the physical form of a dose of a chemical compound used as a drug or

medication intended for administration or consumption by oral route. Common oral dosage

forms are tablets or capsules. Tablets are solid preparations each containing a single dose of one

or more active substances with or without excipients usually obtained by compressing uniform

volumes of particles. The need for new oral drug delivery system continues, due to poor patient

acceptance for invasive methods, need for exploration of new market for drugs and coupled with

high cost of disease management. Developing new drug delivery techniques and utilizing them in

product development is critical for pharma companies to survive this century. An immediate

release dosage form allows a manufacturer to extend market exclusivity, while offering patients a

convenient dosage form or dosage regimen [1].

Immediate Release Tablets are those tablets which are designed to disintegrate and release their

medication with no special rate controlling features, such as special coatings and other

techniques. Recently immediate release tablets have started gaining popularity and acceptance as

a drug delivery system, mainly because they are easy to administer, has quick onset of action is

economical and lead to better patient compliance. They are also a tool for expanding markets,

extending product life cycles and generating opportunities [2,3].

The present work involves the formulation development, optimization and in-vitro evaluation of

immediate release Sorafenib tosylate tablets. To minimize critical process parameters and since

Sorafenib tosylate is moisture and heat sensitive, direct compression method was selected for the

formulation of immediate release Sorafenib tosylate tablets Sorafenib is a small molecular

inhibitor of several tyrosine protein kinases (VEGFR and PDGFR) and Raf kinases (more avidly

C-Raf than B-Raf). [4,5] Sorafenib also inhibits some intracellular serine/threonine kinases (e.g.

C-Raf, wild-type B-Raf and mutant B-Raf).[6] Sorafenib treatment induces autophagy,[7] which

may suppress tumor growth. However, autophagy can also cause drug resistance. [8]

MATERIAL

Sorafenib tosylate drug is obtained from Natco India ltd, and the Excipients that were used used

in the prepareation of the tablets were also obtained from Natco India ltd.

http://en.wikipedia.org/wiki/Enzyme_inhibitor

http://en.wikipedia.org/wiki/Protein_kinase

http://en.wikipedia.org/wiki/VEGFR

http://en.wikipedia.org/wiki/PDGFR

http://en.wikipedia.org/wiki/Raf_kinase

http://en.wikipedia.org/wiki/C-Raf

http://en.wikipedia.org/wiki/BRAF_%28gene%29

http://en.wikipedia.org/wiki/Autophagy

http://en.wikipedia.org/wiki/Sorafenib#cite_note-pmid_.3D_24213221-60

http://en.wikipedia.org/wiki/Sorafenib#cite_note-pmid_.3D_23145926-61




METHOD

The pre formulation studies of the drug were done, like visual inspection, taste, odor, solubility,

loss on drying were done. Then the caliberation curve of the drug was plotted [9,10].

Preparation of calibaration curve of sorafenib tosylate

100 mg of Sorafenib tosylate was accurately weighed and transferred to previously dried 100 ml

volumetric flask. Drug was dissolved in 0.1N HCLsolution. The solution was suitably diluted

with 0.1N HCL solution to get standard concentration of 2, 4,6,8,10,12 and 14 µg/ml.

Absorbance was measured at 265 nm using using UV-Visible Spectrophotometer.

Compatibility studies

The drug and the excipients should be compatible with one another to produce stable

efficacious, attractive and easy to administer and safe dosage form. If the excipients are new and

not been used in the formulations containing the active substance, the compatibility studies are of

paramount importance.

Method:-Compatibility study was performed by preparing compatibility blends at different

ratios of different excipients with the drug, based on tentative average weight. These blends were

stored at accelerated condition of 400C/75% RH. Control samples were stored at 40C. The ratio

of drug to excipient was 1:1 and samples were kept in double lined poly-bags. The samples were

evaluated for any change in the physical characteristics with reference to its controlled sample

stored at 4°C for 7, 14 and 30days Chemical stability was confirmed by FTIR spectrophotometry

Manufacturing of immediate release sorafenib tosylate

In the present investigation immediate release Sorafenib tosylate tablets were prepared by two

methods

1. Wet Granulation

2. Direct Compression.

Preparation of Sorafenib tosylate by Wet Granulation:-

All the ingredients were accurately weighed as per formula G1 and dispensed in clean

polythene covers. Sorafenib tosylate, Di calcium phosphate and Croscarmellose sodium were

sifted through sieve no-30. Microcrystalline Cellulose pH-101 and Lactose were passed

through sieve no-20. Magnesium stearate, PVP K 30 and Colloidal silicon dioxide passed

through sieve no-40. After sifting all the above ingredients were transferred into a big

polythene cover and mixed for 30 min. Binder solution was prepared by dissolving




weighed amount of PVP K 30 in required amount of Isopropyl alcohol. The above blend

was taken in a stainless steel container to which the earlier prepared binder solution was

added slowly until a wet mass like substance was formed. The wet mass was passed

through sieve no- 16 to get wet granules which were later dried in a tray drier at 50°c for 1

hour. The dried granules were again passed through sieve no- 16 and thoroughly mixed with

magnesium stearate and colloidal silicon dioxide.

Table 1: Formulae for Preparation of Immediate Release Sorafenib tosylate Tablets with

10% Overages

SL.NO INGREDIENTS G1

(WG)

G2

(DC)

G3

(DC)

G4

(DC) 1. Sorafenib tosylate (10

%overages)

205.5m

g

205.5m

g

205.5

mg

205.5m

g 2. MicrocrystallineCellulose pH- 101 50mg ----- 91.8m

g

-----

3. Microcrystalline Cellulose pH-102 ----- 50mg ----- 91.8mg

4. Lactose 20mg 20mg 20mg 20mg

5. Di calcium phosphate 13.7mg 17.7mg 25mg 25mg

6. Magnesium stearate 1mg 1mg 1.5mg 1.5mg

7. Colloidal silicon dioxide 0.8mg 0.8mg 1.2mg 1.2mg

8. Croscarmellose sodium 5mg 5mg 5mg 5mg

9. PVP K-30 4mg ----- ----- -----

10. Iso propyl alcohol QS ----- ----- -----

Total Tablet Weight 300mg 300mg 350mg 350mg

Preparation of Sorafenib tosylate by Direct Compression:-

All the ingredients were accurately weighed as per formula G2 to G11 and were dispensed

in clean polythene covers. Sorafenib tosylate, Di calcium phosphate and Croscarmellose

sodium were sifted through sieve no-30. Microcrystalline Cellulose pH-101 and Lactose were

passed through sieve no-20. Magnesium stearate and Colloidal silicon dioxide passed through

sieve no-40. Sorafenib tosylate and Di calcium phosphate were mixed in a polythene cover

marked as DC-I. Microcrystalline Cellulose pH-101, Lactose and Croscarmellose sodium

were mixed in polythene cover marked as DC-II. Magnesium stearate and Colloidal silicon

dioxide were mixed in polythene cover marked as DC-III. The covers were mixed thoroughly




for 30 min. Then DC-II and DC-III were added to DC-I and again mixed thoroughly for 30

min.

Table 2: Formulae for Preparation of Immediate Release Sorafenib tosylate Tablets

with 40% Overages

SL.NO INGREDIENTS G5 G6 G7 G8 G9

1. Sorafenib tosylate(40

%overages)

207mg 207mg 207mg 207mg 207mg

2. MicrocrystallineCellulose pH-

102

91mg 91mg 91mg 91mg 92mg

3. Lactose 20mg 20mg 20mg 20mg 22.3m

g 4. Di calcium phosphate 24.3m

g

24.3m

g

24.3m

g

24.3m

g

25mg

5. Magnesium stearate 1.5mg 1.5mg 1.5mg 1.5mg 1.7mg

6. Colloidalsilicon dioxide 1.2mg 1.2mg 1.2mg 1.2mg 2mg

7. Croscarmellose sodium 5mg -- -- -- --

8. Crosspovidone -- 5mg -- -- --

9. Sodium starch glycolate. -- -- 5mg -- -

10. Pre gelatinized Starch -- -- -- 5mg --

Total Tablet Weight 350mg 350mg 350mg 350mg 350mg

Procedure for Scale up of Sorafenib tosylate Tablets:-

Scale up was done by following the same procedure as given for direct compression.

Mixing was carried out in a Double cone blender for 15 min. This blend is then subjected to

direct compression on a Double Rotary Compression Machine (27 station) at 100 rpm to

yield Sorafenib tosylate tablets.

Table 3: Formulae for Scale Up Batch Immediate Release Sorafenib tosylate Tablets

SL.NO INGREDIENTS G10 G11

1. Sorafenib tosylate (40 % overages) 207mg 207mg

2. Microcrystalline Cellulose pH-102 91mg 91mg

3. Lactose 20mg 20mg

4. Di calcium phosphate 24.3mg 24.3mg

5. Magnesium stearate 1.5mg 1.5mg

6. Colloidal silicon dioxide 1.2mg 1.2mg

7. Pre gelatinized Starch 5mg 5mg

Total Tablet Weight 350mg 350mg




Preparation of Coating Solution:-

All the ingredients were accurately weighed as per formula and dispensed. Ferric oxide Red

and Ferric oxide Yellow were dissolved in PEG-6000. HPMC-6cps and titanium di oxide were

dissolved in water. Both the solution were mixed together and stirred for 45 min to get

a homogenous solution. The appearance, average weight, thickness of tablets, disintegration

and drug release etc were also checked.

Table 4: Formulae for Preparation of Film Coating Solution for G11

Sl.no Ingredients Quantity

1. Hpmc-6cps 100 gm

2. Peg- 6000 26gm

3. Ferric oxide - yellow 0.2gm

4. Ferric oxide - red 0.4gm

5. Titanium di oxide 20gm

6. Water 600 ml

Evaluation of tablets

After the formulation of the granules they were evaluated for various pre compression

parameters like bulk density. Tapped density, angle of repose, porosity, carr’s index and

hausners ratio. Then the granules were compressed and then they were compressed to form

single unit dosage forms i.e., tablets. These tablets were evaluated for various tests which are as

follows.

Thickness:

Thickness was measured using calibrated venire calipers. Six tablets of each formulation were

picked randomly and thickness was measured individually and average thickness was reported.

Friability:

Previously weighed 10 tablets were taken in a Roche friabilator and the friability was checked

at 25 rpm for 4 minutes. Then the tablets were dusted and reweighed and the percentage of

powder eroded during 4 minutes was recorded. Friability was than calculated using the

following equation. Friability of tablets less than 1% was considered acceptable.




(W initial) - (W final)

F = X 100

(W initial)

where W initial = Initial weight of tablets, W final = Final weight of tablets.

Disintegration Time:

The disintegration time was determined using disintegration test apparatus at 37° C±2° C. A

tablet was placed in each of the six tubes of the apparatus and one disc was added to each tube.

The time taken for complete disintegration of the tablet with no palpable mass in the apparatus

was noted.

Percentage Drug Content: [11,12]

Principle: This method is based on the reaction of Sorafenib tosylate with formaldehyde to

yield a colored product having absorption maxima at 360nm.

Reagents:

Preparation of 1 N sulphuric acid: 54 ml of sulphuric acid was added to 1000ml water.

Preparation of 0.1 N HCL solution: 0.4gm of HCL was dissolved in 1000ml to give

0.01 N Sodium Hydroxide solutions.

Preparation of standard solution: 100mg of Sorafenib tosylate was dissolved in 100 ml 0.1N

HCL solution. From this 1ml solution was taken and diluted to 10ml with 0.1N HCL to get 100

µg/ml which was taken as standard.

Preparation of sample solution: Ten tablets were powdered in a mortar and powder

equivalent to 5 mg of Sorafenib tosylate was taken and extracted with 25 ml of 0.1N HCL

solution by shaking for 15 min. It was filtered and diluted to 50 ml with water.

Procedure: To each 10 ml of sample and standard; 13 ml of 1 N Sulphuric Acid and 3 ml of

formaldehyde were added which were then heated for 1 hour and cooled. The cooled solution

was diluted to 25 ml with water and absorbance was measure at 360nm against reagent blank.

Invitro Dissolution Studies: [13]

Dissolution test was carried out in USp Electro labs XXIII paddle type apparatus. The

dissolution medium was distilled water and the volume is 500ml. The temperature was

maintained at 37 °±0.5° C and the paddle speed was at 50rpm. The drug samples of 5ml were




taken at regular intervals of 5min (5, 10, 15, 20, 25, 30, 35, 40 and 45 minutes) and the same

amount of volume was replaced by dissolution media. The samples were taken till 45min. The

absorbance was measured at 265nm.

Limit – Not less than 75% of labeled amount of Sorafenib tosylate was dissolved in 45 min.

Stability studies

Stability of a drug has been defined as the ability of a particular formulation in a specific

container, to remain within its physical, chemical, therapeutic and toxicological specifications.

The purpose of stability study is to provide evidence on the quality of a drug substance or drug

product which varies with time under the influence of a variety of environmental factors such as

temperature, humidity and light. Recommended storage conditions, re-test periods and shelf-

lives are to be established.

Method: The scaled up formulations G10 and G11 were subjected to accelerated stability studies

and parameters like hardness, disintegration time, drug content and in vitro drug release were

analyzed after storing them at 40±20C / 75±5% RH for 2 months.

RESULT & DISCUSSION

Table 5: Characterization of Sorafenib tosylate

Test Specification / limits Observations

Color Yellow to orange yellow powder Yellow to orange yellow powder

Taste Tasteless Tasteless Odor Odorless Odorless

Losson drying Not more than 0.2 % 0.14%

Table 6: Solubility of Sorafenib tosylate

Quantity of Sorafenib

tosylate Quantity of solvents Inference

100 mg

100 mg

100 mg

100mg

30 ml of Water 100 ml of

Methanol

100 ml Hydrochloric acid

100ml 0.01NSodium

hydroxide solution

Practically insoluble

Insoluble

Soluble

Soluble




Table 7: Standard Calibration Curve of Sorafenib tosylate at 265 nm.

Concentration

(µg/ml)

Absorbance Average

Absorbance Trial1 Trial2 Trial3

0 0 0 0 0 2 0.127 0.125 0.126 0.126 4 0.237 0.236 0.237 0.236 6 0.346 0.345 0.344 0.345 8 0.451 0.451 0.450 0.450 10 0.553 0.553 0.554 0.553 12 0.662 0.662 0.665 0.663 14 0.765 0.764 0.760 0.763

Fig. 1: Standard Calibration Curve of Sorafenib tosylate at 265 nm

Table 8: Compatibility Studies

Sl.

no. Drug+ Excipients Ratio Initial color

Condition (400C/75%RH)

7 14 30 Conclusion

1 Sorafenib tosylate + Microcrystalline

1:1

WHITE

** ** ** compatible cellulose pH 102

2 Sorafenib tosylate + Lactose. 1:1 ** ** ** compatible

3 Folic acid + Dicalcium

phosphate. 1:1 ** ** ** compatible

4 Sorafenib tosylate + Croscarmellose

sodium. 1:1 ** ** ** compatible

5 Folic acid + Magnesium

stearate. 1:1 ** ** ** compatible

6 Sorafenib tosylate + Colloidal silicon

di oxide. 1:1 ** ** ** compatible

7 Sorafenib tosylate + Crosspovidone 1:1 ** ** ** compatible

8 Sorafenib tosylate + Pre gelatinized

starch. 1:1 ** ** ** compatible

9 Folic acid + Sodium starch

glycolate 1:1 ** ** ** compatible

10 Sorafenib tosylate final blend ------ ** ** ** compatible




Figure 2: IR Spectra of Sorafenib tosylate Figure 3: IR Spectra of Sorafenib tosylate +

Pre gelatinized starch

Figure 4: IR Spectra of Sorafenib tosylate Figure 5: IR Spectra of Sorafenib tosylate +

Croscarmellose sodium + Crosspovidone

Figure 6: IR Spectra of Sorafenib tosylate Figure 7: IR Spectra of Sorafenib

+ Magnesium stearate tosylate + Microcrystallinecellulose





+ Lactose tosylate + Di calcium phosphate


+ Colloidal silicon di oxide tosylate final blend

Table 8: Evaluation of Pre-Compression Parameters

Fo

rmu

lati

on

Co

de Evaluation of pre compression Parameters

Bu

lk

Den

sity

(g/c

c)

Ta

pp

ed

Den

sity

(g/c

c)

Po

rosi

ty (

%)

Ca

rr’s

In

dex

(%)

Ha

usn

er’s

Ra

tio

An

gle

of

Rep

ose

(θ)

G1 0.571 0.740 0.229 18.84 1.21 29.49

G2 0.555 0.714 0.222 18.31 1.22 28.86

G3 0.465 0.540 0.139 13.88 1.16 24.87

G4 0.454 0.526 0.136 13.68 1.15 26.15




G5 0.488 0.571 0.146 14.54 1.17 26.38

G6 0.465 0.540 0.140 13.88 1.16 28.13

G7 0.512 0.625 0.179 18.08 1.22 27.75

G8 0.526 0.588 0.105 10.54 1.11 22.45

G9 0.434 0.526 0.174 17.50 1.22 31.02

G10 0.526 0.588 0.105 10.54 1.11 22.48

G11 0.512 0.571 0.102 10.40 1.12 22.50

Table 9: Evaluation of Post-Compression Parameter

Form

ula

tion

Cod

e

Evaluation of post compression Parameters

Hard

nes

s of

tab

lets

*

(kg/c

m2)

Fri

ab

ilit

y

of

tab

lets

*(

%)

Wei

gh

t

vari

ati

o

n (

mg)

Per

cen

ta

ge

dru

g

con

ten

t

per

tab

let*

(%)

Dru

g

con

ten

t

per

tab

let*

(mg)

Th

ick

ne

ss

of

tab

lets

*

(mm

) D

isin

teg

rati

o

n

tim

e

(min

)*

G1 5.6 1.470 2.97 76.70 3.835 2.95 4.26

G2 5.3 1.503 2.95 77.14 3.857 2.93 4.30

G3 4.8 0.644 1.54 80.06 4.003 2.55 3.17

G4 4.7 0.628 1.43 82.34 4.117 2.54 3.31

G5 4.3 0.789 1.89 111.92 5.600 2.53 3.53

G6 4.4 0.854 1.76 109.95 5.490 2.54 3.53

G7 4.7 0.590 1.10 111.02 5.501 2.56 4.18

G8 4.5 0.545 1.05 112.85 5.642 2.55 2.53

G9 4.9 1.276 2.19 107.69 5.385 2.54 6.48

G10 4.6 0.539 1.04 112.82 5.641 2.53 2.54

G11 4.5 0.540 1.02 112.93 5.646 2.57 2.55




Table 10: In-Vitro Drug Release Study of Various Formulations

% Cumulative drug release*

Formulatio

ns

5 min 10min 15mi

n

20min 25min 30min 35min 40mi

n

45min

G1 40.10 42.40 48.80 52.67 56.32 59.51 63.07 66.19 68.05

G2 42.48 43.69 48.21 55.60 57.05 59.11 64.87 67.88 69.10

G3 52.97 55.30 58.92 61.77 64.23 67.19 69.05 70.44 72.69

G4 50.97 54.36 57.29 61.66 65.08 68.27 70.12 72.21 73.57

G5 55.35 59.96 65.11 71.80 76.00 81.61 86.37 89.03 91.13

G6 56.04 58.41 64.98 72.16 78.80 82.88 87.51 90.81 92.79

G7 58.18 55.99 65.00 74.31 76.19 81.95 87.87 89.01 90.09

G8 55.28 59.03 66.25 73.42 80.17 84.67 88.79 91.77 93.20

G9 10.47 19.18 28.47 35.98 40.65 47.22 50.77 53.66 55.10

G10 55.93 60.10 66.01 73.39 81.27 85.00 89.00 91.76 93.24

G11 53.81 61.37 66.56 70.82 76.99 81.01 84.15 87.70 89.45

Table 11: Results of Stability Studies of Selected Formulations (G10 and G11)

Formulation G10 Formulation G11

Time

(days)

Hardness Disintegration

Time

% Drug

Content

Hardness Disintegration

Time

% Drug

Content

0 4.6 2.54 112.82 4.5 2.55 112.93

15 4.6 2.54 112.82 4.5 2.55 112.93

30 4.6 2.53 112.80 4.5 2.54 112.93

45 4.6 2.53 112.80 4.5 2.54 112.92

60 4.6 2.53 112.78 4.5 2.54 112.92

Table 12: In-Vitro Drug Release Study of G10

Days 5 min 10min 15mi

n

20mi

n

25mi

n

30min 35min 40mi

n

45min

0 55.93 60.10 66.01 73.3

9

81.27 85.00 89.00 91.7

6

93.24

15 55.90 59.89 65.91 72.6

1

80.35 84.55 88.77 91.6

5

93.20

30 55.91 58.77 65.34 71.7

7

79.26 86.19 89.01 90.8

7

92.91

45 55.87 59.06 66.10 71.6

9

78.99 81.07 86.19 91.0

4

92.88

60 4.98 58.50 64.88 0.84 80.12 83.50 87.20 90.6

6

92.85




Table 13: : In-Vitro Drug Release Study of G11 .

Day

s

5 min 10min 15min 20min 25min 30min 35min 40min 45min

0 53.81 61.37 66.56 70.82 76.99 81.01 84.15 87.70 89.45

15 53.77 61.19 65.97 70.50 76.88 80.80 83.64 88.04 89.40

30 52.91 60.64 64.70 68.55 75.20 81.12 83.50 86.15 88.88

45 52.89 59.79 64.85 67.89 75.30 80.66 84.54 86.03 88.50

60 51.77 58.69 63.44 67.10 74.45 81.21 85.09 87.48 88.48

CONCLUSION

The present work involves the formulation development, optimization and in-vitro evaluation of

immediate release Sorafenib tosylate tablets. To minimize critical process parameters and since

Sorafenib tosylate is moisture and heat sensitive, direct compression method was selected for the

formulation of immediate release Sorafenib tosylate tablets. Under the pre formulation studies

API characterization and drug-excipient compatibility studies were carried out. The API

characterization showed compliance with the drug characteristics. The polymers and other

excipients were selected based on the satisfying results produced during drug- excipient

compatibility studies to develop the final formulation. The final suitable formulation (G8) was

achieved fruitfully by the direct compression technique using pre gelatinized starch as

disintegrant which exhibited acceptable disintegration time (2.53 min), percentage drug content

per tablet (112.85%) and in vitro drug release (93.20%). The best formulation was later subjected

to scale up in two batches containing 30,000 tablets each (G10 and G11) which were later

subjected to stability studies after packing in amber colored PVC-PVDC blister packing. One

batch of scale up was film coated for following reasons-

Reduce influence of moisture.

Avoid dust formation.

Improve drug stability and prolong shelf life.

For brand differentiation and consumer recognition

Considering the results of scaled up batches containing pre gelatinized starch as disintegrant it

can be concluded that the formulation G10 and G11 were meeting the desired in vivo and in vitro

correlation limits provided by the company




The formula G10 and G11 were subjected for cost evaluation and marketing department

approval for costing and patient compliance respectively, and a positive feedback was received

for formulation G10 and G11. It was also observed that direct compression was the best suitable

method used for producing immediate release tablets Sorafenib tosylate tablets. Based on all the

above considerations these formulas will be subjected for bio availability studies and if it

complies to all the requirement of those studies the same formula will be commercialized.

Further improvement in these formulations can be achieved by optimizing the film

coating given to Sorafenib tosylate tablets

REFERENCE

1. Banker GS, Anderson SN. Modern pharmaceutics. 4rd ed. New York: Taylor & Francis

Group;2005.

2. Allen LV, Nicholas GP, Howard CA. Ansel’s pharmaceutical dosage forms & drug

delivery systems. 8th ed. New Delhi: Lippincott Williams & Wilkins; 2005.

3. Rudman A. Guidance for industry-Immediate release solid dosage forms. CDER 1995

Nov; 59(83): 48754-59..

4. Keating GM, Santoro A (2009). "Sorafenib: a review of its use in advanced

hepatocellular carcinoma". Drugs 69 (2): 223–40. doi:10.2165/00003495-200969020-

00006. PMID 19228077.

5. Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P,

Elder DE, Wang Y, Nathanson KL, Herlyn M (January 2009). "CRAF inhibition induces

apoptosis in melanoma cells with non-V600E BRAF mutations". Oncogene 28 (1): 85–

94. doi:10.1038/onc.2008.362. PMC 2898184. PMID 18794803.

6. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (October 2008).

"Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and

VEGF and PDGF receptor tyrosine kinase signaling". Mol. Cancer Ther. 7 (10): 3129–

40. doi:10.1158/1535-7163.MCT-08-0013. PMID 18852116.

7. Zhang Y (Jan 2014). "Screening of kinase inhibitors targeting BRAF for regulating

autophagy based on kinase pathways.". J Mol Med Rep 9 (1): 83–90. PMID 24213221.

http://en.wikipedia.org/wiki/Digital_object_identifier

http://dx.doi.org/10.2165%2F00003495-200969020-00006

http://dx.doi.org/10.2165%2F00003495-200969020-00006

http://en.wikipedia.org/wiki/PubMed_Identifier

http://www.ncbi.nlm.nih.gov/pubmed/19228077

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898184



http://dx.doi.org/10.1038%2Fonc.2008.362

http://en.wikipedia.org/wiki/PubMed_Central





http://dx.doi.org/10.1158%2F1535-7163.MCT-08-0013



http://www.spandidos-publications.com/mmr/9/1/83

http://www.spandidos-publications.com/mmr/9/1/83






8. Gauthier A (Feb 2013). "Role of sorafenib in the treatment of advanced hepatocellular

carcinoma: An update..". Hepatol Res 43 (2): 147–154. doi:10.1111/j.1872-

034x.2012.01113.x. PMID 23145926

9. James JD, Braunstein M, Kraig, Hartshorn. A guide to drug interactions. Mc Graw Hill;

1992:521-529

10. British Pharmacopoeia. Department of health, Scottish home and health department,

Welsh Office, 2000 ed; Volume I &II

11. Indian Pharmacopoeia. Government of India, Ministry of health and family welfare,

Published by the controller of publications, Delhi, 2007; Volume I &II.

12. Augustin J, Klein BP, Becker DA, Venugopal PB. Methods of vitamin assay. 4th ed. Mc

Graw Hill; 2001

13. Sethy PD. Quantitative analysis of drugs in pharmaceutical formulations. 3rd ed: 591-593


http://dx.doi.org/10.1111%2Fj.1872-034x.2012.01113.x

http://dx.doi.org/10.1111%2Fj.1872-034x.2012.01113.x



international journal of innovative pharmaceutical ... · t.bindu*, 2p.prem kumar , 3y ......

Documents