Formulation Development and
Evaluation of Immediate Release Tablet Dosage form of Sorafenib Tosylate
Dr Y. Krishna Reddy*, D.
Kalpana
Department of Pharmaceutics,
Nalanda College of Pharmacy, Jawaharlal Nehru Technological University,
Hyderabad, Telangana.
*Corresponding Author E-mail: rajinisuralabs1@gmail.com
ABSTRACT:
Immediate release drug
formulation is a novel type of drug delivery system which disintegrates rapidly
and gets dissolved to release the medicaments after administration. Sorafenib
tosylate is kinase inhibitors, used to treat renal cell carcinoma. our work
involves the formulation, optimization and post compressed evaluation studies
of immediate release Sorafenib tosylate tablets. The direct compression method
was employed for formulating tablets. Tablet composition contains Sorafenib
tosylate as a filler. Explotab, Solutab and polyplasdone XL is a
superdisintegrant, mannitol as sweeting agent magnesium stearate as a lubricant,
talc as a anticaking agent. The prepared tablets were evaluated for
physico-chemical properties and post evaluation studies such as drug content
and in vitro dissolution. Further more, Finally, it was concluded that
all the pre-formulation and post compression studies of sorafenib tablet met
with required specifications and also showed comparably a good rate of
dissolution like that of a commercial product. Among all the formulations F6
formulation containing, drug and Solutab showed good result that is 99.56% in
45 min. Hence from the dissolution data it was evident that F6 formulation is
the better formulation.
KEYWORDS: Sorafenib
tosylate, Explotab, Solutab, Polyplasdone XL and Immediate release.
INTRODUCTION:
Oral drug delivery is the most
desirable and preferred method of administering therapeutic agent for their
systemic effects. In addition, the oral medication is generally considered as
the first avenue investigated in the discovery and development of new drug entities
and pharmaceutical formulation, mainly because of patient acceptance,
convenience in administration and cost-effective manufacturing process. For
many drug substances, conventional immediate-release formulation provide
clinically defective therapy while maintain the required balance of
pharmacokinetic and pharmacodynamic profiles with an acceptable level of safety
to the patient.
Immediate release tablets are
those which disintegrate rapidly and get dissolved to release the medicaments.
Immediate release may be provided for by way of an appropriate pharmaceutically
acceptable diluents or carrier , which carrier or diluents does not prolong to
an appreciable extent, the rate of drug relkease and/or absorption . This term
excludes formulations which are adopted to provide for, “modified”,
“controlled”, “sustained”, “prolonged”, “extended”, or “deleyed” release of
drug.
Desired Criteria for Immediate
release Drug Delivery System: 2-5
· In case of the
solid dosage it should dissolve or disintegrate in the stomach within a short
period.
· In case of the
liquid dosage form it should be compatible with taste making.
· Be portable without
fragility concern.
· Have a pleasing
mouth feel.
· It should not leave
minimal or mo residence in the mouth after oral administration.
· Exhibit low
sensitivity to environmental condition as humidity and temperature
· Be manufactured
using conventional processing and packing equipment at low cost
· Rapid dissolution
and absorption of drug, which may produce rapid onset of action.
Merits of
Immediate Release Drug DeliverySystem6-10
·
Improved compliance /added convenience
·
Improved stability, bioavailability
·
Suitable for controlled /sustained release actives
·
Allows high drug loading
·
Ability to provide advantages of liquid medication in the form of solid
preparations.
·
Adaptable and amenable to existing processing and packaging machinery
·
Cost-effective.
·
Improved solubility of the pharmaceutical composition.
·
Decreased disintegration and dissolution times for immediate release
oral dosage forms.
When an immediate release
product is administered, the drug concentration in blood rises rapidly, peaks
soon after administration and then declines. If the peak concentration is too
high, the drug may exhibit undesirable side effects. If the decline in blood
concentration isalso rapi, the product will have to be dosed frequently to
maintain therapeutic blood levels. Such a large fluctuation in the blood
concentration may not be suitable for some drugs, or may 6 require dosing
frequencies that are impractical.
AIM OF WORK
The main aim of the present
study is to Formulation development and evaluation of immediate drug release
tablet dosage form of Sorafenib Tosylate.
OBJECTIVES OF THE WORK
· To formulate
Immediate drug release tablet dosage form of Sorafenib Tosylate for the
improvement of Bioavailability.
· To perform Drug and
Excipient compatibility studies (FTIR)
· To evaluate pre and
post compression evaluation parameters
· To perform drug
release studies
MATERIALS AND METHODS:
Sorafenib Tosylate Procured from Natco Pharma Ltd. Provided by Sura Labs, Dilsukhnagar, Hyderabad. Explotab,
Solutab and Polyplasdone XL purchased from NATCO pharma. Mannitol and Talc
purchased from Nihar traders Pvt Ltd. MCC purchased from Himedia Laboratories.
Magnesium Stearate purchased from Nice Chemicals Ltd.
METHODOLOGY:
Table 1: Formulation of
Immediate Release tablets
|
INGREDIENTS (mg) |
FORMULATION CODE |
||||||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
|
|
Sorafenib tosylate |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
|
Explotab |
30 |
60 |
90 |
- |
- |
- |
- |
- |
- |
|
Solutab |
- |
- |
- |
30 |
60 |
90 |
- |
- |
- |
|
Poly plasdone XL |
- |
- |
- |
- |
- |
- |
30 |
60 |
90 |
|
Mannitol |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
|
MCC |
146 |
116 |
86 |
146 |
116 |
86 |
146 |
116 |
86 |
|
Magnesium stearate |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
Talc |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
|
Total weight |
400 |
400 |
400 |
400 |
400 |
400 |
400 |
400 |
400 |
RESULTS AND DISCUSSION:
Determination of λ max:
The Prepared stock solution
was scanned between 200-400 nm to determine the absorption maxima. It was found
to be 265 nm.
Calibration curve of Sorafenib
tosylate:
The standard curve of Sorafenib tosylate was obtained and good correlation
was obtained with R2 value of 0.998 the medium selected was pH 6.8
phosphate buffer.
Table 2: Standard graph values
of Sorafenib tosylate at 265 nm in pH 6.8 phosphate buffer
|
Concentration (µg/ml) |
Absorbance |
|
0 |
0 |
|
10 |
0.129 |
|
20 |
0.248 |
|
30 |
0.369 |
|
40 |
0.476 |
|
50 |
0.586 |
Fig 1: Standard curve of
Sorafenib tosylate
Evaluation:
Characterization of
precompression blend:
The pre compression blend of Sorafenib tosylate were characterized with respect to
angle of repose, bulk density, tapped densiy, Carr’s index and Hausner’s ratio.
Angle of repose was less than 29.49, Carr’s index values were less than 25.71
for the pre compression blend of all the batches indicating good to fair
floability and compressibility. Hausner’s ratio was less than 1.34 for all
batches indicating good flow properties.
Evaluation of tablets:
Physical evaluation of
Sorafenib tosylate Immediate release tablets:
The results of the weight
variation, hardness, thickness, friability and drug content of tablets are
given in table 8.3. All the tablets of different batches complied with the
official requirement of weight variation as their weight variation passes the
limit. The hardness of the tablets ranged from (3.1-3.9) kg/cm2 and
the friability values were 0.13 – 0.67% indicating that the tablets were
compact and hard. The thickness of the tablets ranged from 3.12 –3.64 mm. All
the formulations satisfied the content of the drug as they contained 97.36-99.85
% of Sorafenib tosylate and good uniformity in drug content was observed. Thus
all physical attributes of the prepared tablets were found to be practically
within control limits.
Table 3: Physical properties of
precompression blend
|
Formulation code |
Angle of repose (Ө) |
Bulk density (gm/cm3) |
Tapped density(gm/cm3) |
Carr’s index (%) |
Hausner’s ratio |
|
F1 |
25.73 |
0.543 |
0.564 |
16.50 |
1.05 |
|
F2 |
22.45 |
0.543 |
0.731 |
25.71 |
1.34 |
|
F3 |
28.30 |
0.493 |
0.625 |
18.02 |
1.26 |
|
F4 |
27.57 |
0.448 |
0.540 |
17.03 |
1.20 |
|
F5 |
26.68 |
0.561 |
0.735 |
23.67 |
1.31 |
|
F6 |
27.78 |
0.569 |
0.720 |
20.97 |
1.15 |
|
F7 |
24.76 |
0.567 |
0.680 |
13.88 |
1.19 |
|
F8 |
28.84 |
0.555 |
0.740 |
25.00 |
1.33 |
|
F9 |
29.49 |
0.571 |
0.723 |
21.02 |
1.26 |
All the values represent n=3
Table 4: Physical evaluation of
Sorafenib tosylate
|
Formulation code |
Average Weight (mg) |
Thickness (mm) |
Hardness (Kg/cm2) |
Friability (%) |
Content uniformity (%) |
Disintegration time (Sec) |
|
F1 |
398.7 |
3.12 |
3.6 |
0.13 |
97.36 |
38 |
|
F2 |
399.3 |
3.25 |
3.4 |
0.26 |
99.16 |
29 |
|
F3 |
397.5 |
3.54 |
3.8 |
0.54 |
97.52 |
20 |
|
F4 |
398.1 |
3.43 |
3.3 |
0.38 |
98.47 |
52 |
|
F5 |
396.8 |
3.13 |
3.5 |
0.47 |
99.85 |
41 |
|
F6 |
399.6 |
3.24 |
3.9 |
0.25 |
98.33 |
15 |
|
F7 |
397.4 |
3.38 |
3.1 |
0.38 |
96.52 |
35 |
|
F8 |
398.8 |
3.64 |
3.7 |
0.59 |
98.28 |
24 |
|
F9 |
399.7 |
3.45 |
3.3 |
0.67 |
99.14 |
20 |
In vitro release studies:
The drug release rate from
tablets was studied using the USP type ΙΙ dissolution test apparatus.
The dissolution medium was 500 ml of pH 6.8 phosphate buffer at 50 rpm at a
temperature of 37±0.5 ˚C. Samples of 5 ml were collected at different time
intervals up to 1 hr and has analyzed after appropriate dilution by using UV
spectrophotometer at 265nm.
Table 5: In vitro data
for formulation F1-F3
|
TIME (MIN) |
% DRUG RELEASE |
||||||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
|
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
5 |
16.25 |
21.15 |
32.56 |
26.62 |
32.91 |
28.32 |
21.91 |
21.62 |
18.85 |
|
10 |
23.12 |
35.29 |
45.82 |
38.11 |
47.56 |
48.33 |
34.15 |
30.42 |
36.54 |
|
15 |
38.56 |
47.36 |
57.94 |
49.24 |
52.36 |
53.75 |
42.56 |
46.35 |
44.92 |
|
20 |
47.28 |
66.48 |
69.65 |
56.25 |
58.10 |
65.85 |
55.38 |
59.57 |
52.12 |
|
25 |
53.4 |
74.56 |
82.13 |
68.34 |
63.54 |
72.56 |
69.86 |
66.30 |
65.63 |
|
30 |
69.56 |
83.26 |
85.5 |
71.84 |
78.36 |
84.25 |
83.45 |
75.52 |
72.96 |
|
45 |
76.78 |
88.92 |
94.54 |
78.35 |
86.56 |
99.56 |
94.23 |
84.83 |
82.85 |
Fig 2: In vitro
dissolution data for formulation F1-F9
Among all the formulations F6
formulation containing drug and Solutab showed good result that is 99.56 % in
45 minutes, at the concentration of 90 mg. Hence from all the formulations it
is evident that F6 formulation is the better formulation.
Drug-Excipient compatibility
studies by FTIR studies:
Sorafenib tosylate was mixed
with various proportions of excipients showed no colour change at the end of
two months, providing no drug –excipient interactions.
Fig 3: FTIR spectra of pure
drug
Fig 4: FTIR spectra of
optimized formulation
CONCLUSION:
In the present work, an
attempt was made to formulate and in vitro evaluation of immediate
release Sorafenib tablets. Various compositions were formulated by changing the
ratios of excipients. All formulations were prepared by the direct compression
method. Preformulation studies include API characterization, Bulk density,
Tapped density, Carr’s index, Hausner’s ratio and drug-excipient compatibility
studies were conducted to know the drug characteristics and developing the
final formulation. The best formulation (F6) was optimized.
The finished tablets were
subjected to post compression studies include disintegration time, percentage
drug content, dissolution studies etc. The trail F6 shows 99.56% drug release
in 45 min is comparably equal to marketed preparation and also shown good
disintegration time (15sec) with sufficient hardness. Finally, it can be
concluded that a good generic pharmaceutical and stable formulation of
Sorafenib tablets was optimized and all the pre and post compression studies of
Sorafenib tablet met with required specifications and also showed comparably a
good rate of dissolution like that of a commercial product.
АCKNOWLEDGEMENT:
The Authors arе thankful
to Sura Labs, Dilshukhnagar, Hydеrabad for providing thе necessary
facilities for the research work.
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Received on 17.02.2020
Modified on 25.02.2020
Accepted on 29.02.2020 ©Asian Pharma Press
All Right Reserved
Asian J. Pharm.
Tech. 2020; 10(1):38-42.
DOI: 10.5958/2231-5713.2020.00008.2