FORMULATION AND EVALUATION OF IMMEDIATE RELEASE
TABLETS OF ANTI CANCER DRUG BY USING SIMPLEX
LATTICE DESIGN
M. Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore– 560 041
By
Mr. Chirag R. Patel, B.Pharm
Under the Guidance of
Dr. B. Prakash Rao, M.Pharm, Ph.D
Professor& Head
Department of Industrial Pharmacy
P.G. Department of Industrial Pharmacy,
Acharya & B.M.Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara (Post)
Hesaraghatta Main Road, Bangalore – 560 090
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1
Name of the candidate
and address
Mr. PATEL CHIRAGKUMAR RAMESHBHAI
2,Bahubali society,
Radhanpur Road,
Mehsana – 384002
Gujarat.
2
Name of the Institution
ACHARYA AND B.M. REDDY COLLEGE OF
PHARMACY
Chikkabanavara Post ,
Hesaraghatta Main Road,
Soldevanahalli,
Bangalore-560 090.
3
Course of the study and
subject
M. Pharmacy
(Industrial pharmacy)
4
Date of admission
03/04/ 2009
5
TITLE OF THE PROJECT:FORMULATION AND EVALUATION OF IMMEDIATE RELEASE
TABLETS OF ANTI CANCER DRUG BY USING SIMPLEX LATTICE
DESIGN
1
6
BRIEF RESUME OF INTENDED WORK:-
6.1
NEED FOR THE STUDY:-
Many patients find it difficult to swallow tablets and hard gelatin capsules and
thus not comply with prescription that results in high incidence of non-compliance and
ineffective therapy. Immediate release tablets are gaining prominence as new drug
delivery systems. These dosage forms dissolve or disintegrate in oral cavity within a
minute without the need of water or chewing. In this study, an effort has been made to
formulate immediate release tablets using different disintegrants.
They are also suitable for the mentally ill, the bedridden, and patients who do not
have easy access to water. The benefits, in terms of patient compliance, rapid onset of action,
increased bioavailability, and good stability make these tablets popular as a dosage form of
choice in the current market.
Immediate release tablets remain solid till administration and possess dose
accuracy and stability during storage which transform into liquid form within few
seconds after its administration for easy swallowing. Immediate release tablets have
significant advantages of both solid and liquid dosage forms.
Advantages of this drug delivery system include administration without water,
convenience of administration and accurate dosing as compare to liquids, easy portability,
ability to provide advantages of liquid medication in the form of solid preparation, ideal for
pediatric and geriatric patients and rapid dissolution/absorption of the drug, which may
produce rapid onset of action1.
This study aims to increase aqueous solubility of drug by solid dispersion and then
to formulate such a tablet that disintegrates rapidly and provides rapid dissolution of the drug.
Rapid absorption of a drug requires rapid dissolution, which in turn depends on higher
aqueous solubility.
2
Immediate release tablets are those when put on tounge disintegrate
instantaneously, releasing the drug which dissolve or disperses in the saliva. Faster the
drug in the solution, quicker the absorption and onset of clinical effect. Some drugs are
absorbed from the mouth, pharynx and oesophagus as the saliva passes down in to the
stomach. In such cases, bioavailability of a drug is significantly greater than those
observed from conventional tablet dosage form. The advantages of mouth dissolving
dosage form are increasingly being recognized in both, industry and academia. Their
growing importance was underline recently when European pharmacopoeia adopted the
term “Orodispersible Tablet” as tablet that is to be place in the mouth where it disperses
rapidly before swallowing.
Mycophenolate mofetil is an ester prodrug of the active immunosuppressant
mycophenolic acid. It is a noncompetitive, selective and reversible inhibitor of inosine
monophosphate dehydrogenase, an important enzyme in the de novo synthesis of
guanosine nucleotides in T and B lymphocytes. Mycophenolate mofetil and/or
mycophenolic acid inhibit the proliferation of lymphocytes and the production of
antibodies induced by a variety of mitogens and antigens.
Use of Mycophenolate mofetil (MMF) at induction and introduction of MMF in
the first 3 months post transplantation helps to preserve and restore creatinine levels in
patients with worsened kidney function, and aids in keeping them stable, without
increasing the risk of rejection while optimizing the anti-calcineurin dosage2.
Considering the merits of Mycophenolate mofetil, we are proposing to choose
it as an anti-cancer drug for the present study.
3
6.2
REVIEW OF LITERATURE: Effect of disintegrant on the disintegration behavior of the tablet in the oral cavity
was evaluated. Wetting time prepared from carboxymethylcellulose (NS-300)
having the hardness of 4 kg was 3 s. Tablet containing NS-300 showed fastest
disintegration compared to other formulations. Ethenzamide and ascorbic acid
were added to the formulation, and their disintegration behavior was evaluated.
Ethenzamide did not affect the disintegration property, however, ascorbic acid
prolonged disintegration time. It was suggested that the tablet formulation
containing NS-300 and glycine was highly applicable to water-insoluble drug,
such as ethenzamide.3
 Atenolol was chosen as a model drug because of its poor absorption in the lower
gastrointestinal tract. Three formulations containing 25 mg atenolol, a floating
multiple-unit capsule, a high-density multiple-unit capsule, and an immediaterelease tablet were compared with respect to estimated pharmacokinetic
parameters. The two multiple-unit dosage forms were composed of compressed
minitablets and had sustained release properties. The bioavailability of the two
gastro retentive preparations with sustained release characteristics was
significantly decreased when compared to the immediate-release tablet.4
 Immediate release direct compression tablet formulations require a strict control of
the particle characteristics (i.e. particle size (distribution) and shape) of both the
active pharmaceutical ingredient (API) and the excipients. Comparison with static
image analysis (SIA) and scanning electron microscopy (SEM) data often shows
laser diffraction to generate different size data. However, since laser diffraction
(LD) is fast and frequently shows an adequate precision over a wide particle size
range, the technique is still considered as a valuable analytical tool in the screening
of the particle size distribution of API batches.5
4
 Three
examples
of
immediate
release
products
containing
phenoxymethylpenicillin potassium, glimepiride, and levofloxacin providing
different solubility characteristics are evaluated. The solubility was high in the
case of phenoxymethylpenicillin potassium and levofloxacin and low for
glimepiride according to the biopharmaceutics classification system. The
permeability (10-6 cm/s) of phenoxymethylpenicillin potassium, glimepiride, and
levofloxacin was high. Typically, for immediate release formulations, one limit is
specified for the dissolution to ensure the release of the active ingredient within the
present time period.6
 Melt granulation technique is a process by which pharmaceutical powders are
efficiently agglomerated by meltable binder. The advantage of this technique
compared to conventional granulation is that no water or organic solvents are
needed. Because there is no drying step, the process is less time consuming and
uses less energy than wet granulation. The granules containing oxcarbazepine were
prepared using polyethylene glycol (PEG) 4000 as a melting binder and lactose
monohydrate as hydrophilic filler. The potential of the intragranular addition of
starch as a dissolution enhancer and disintegrative agent was also evaluated.7
 Mycophenolate mofetil significantly inhibited the growth of HepG-2 cells by
inducing the apoptosis of cells and this drug also inhibited the adhesion of HepG-2
cells in a dose-dependent manner. Marked morphological changes characterized in
cell apoptosis were demonstrated through Hoechst33258 staining. In addition,
mycophenolate mofetil decreased the proportion of S phase cells and increased
that of G0/G1 phase cells. [3H]-Thymidine uptake assay indicated that the
application of mycophenolate mofetil at different concentrations significantly
inhibited the cell proliferation.8
5
 Solid dispersions were prepared by the solvent evaporation method at different
drug:polymer ratios (wt/wt). The physical state and drug:carrier interactions were
analyzed by X-ray diffraction, infrared spectroscopy, and scanning electron
microscopy. The dissolution rate of prednisone from solid dispersions was
markedly enhanced by increasing the polymer concentration. The tablets were
prepared from solid dispersion systems using polyethylene glycol (PEG) 6000 as a
carrier at low and high concentration.9
 Diazepam was formulated with polyethylene glycol (PEG-6000) as a solid
dispersion to increase aqueous solubility and dissolution of drug. Croscarmellose
sodium and aerolacR were used in tablet formulation to achieve rapid
disintegration of tablets prepared respectively by wet granulation and direct
compression methods.10
 The poor aqueous solubility of the drug leads to variable dissolution rates. In the
present investigation an attempt has been made to prepare oro-dispersible tablets
of etoricoxib with enhanced dissolution rate. The another purpose of the present
investigation was to evaluate effect of superdisintegrants like Crospovidone
(Polyplasdone XL), Croscarmellose Sodium (Ac-Di-Sol) and Sodium starch
glycolate (Primojel) on dissolution of poorly soluble, selective COX-2 inhibitor in
oro-dispersible tablets. It was concluded that oro-dispersible tablets of etoricoxib
with enhanced dissolution rate can be made using selected superdisintegrants.11
 The biopharmaceutics classification system (BCS) allows biowaiver for rapid
dissolving immediate-release (IR) products of Class I drugs (high solubility and
high permeability). The possibility of extending biowaivers to Class III high
solubility and low permeability drugs is currently under scrutiny. In vivo
bioequivalence data of different formulations of Class III drugs would support
such an extension.12
6

The drug studied was acetaminophen in the form of immediate release (IR)
tablets. The second purpose was to establish a level A in vitro/in vivo correlation
that could predict the bioavailability of a drug instead of using difficult, timeconsuming and expensive in vivo bioequivalence studies. The artificial digestive
system was used to estimate the availability of acetaminophen IR tablets for
absorption in fasted and fed states.13
 Melt granulation with a lipophilic binder (hydrogenated castor oil; Cutina HR®)
improved the stability of the drug, while still maintaining immediate-release
characteristics of the drug product. The drug to binder ratio was shown to impact
the degradation behavior of the drug product. With higher binder levels, the
sensitivity of the drug to degradation under humidity conditions decreased. It is
postulated that the lipophilic binder coated drug particles at the surface protecting
them from the influence of moisture.14
6.3
OBJECTIVE OF THE STUDY:Following are the objectives of the present study :
1. To carry out pre-formulation studies for the possible drug/polymer/excipient
interactions and micromeritic properties.
2. To prepare solid dispersion of drug.
3. To carry out estimation of drug in the formulations.
4. To evaluate the formulated dosage forms based on physico-chemical
characterization and in vitro release studies.
5. To carry out short term stability studies on the most satisfactory formulations
as per ICH guidelines at 30 ± 20C (65 ± 5 %RH) and 40 ± 20C (75 ± 5 %RH).
7
7
7.1
MATERIALS & METHODS:SOURCE OF DATA:1) Review of literature from:
a) Journal such as
i) Indian Journal of Pharmaceutical Sciences
ii) European Journal of Pharmaceutical Sciences
iii) Journal of Controlled Release
iv) International Journal of Pharmaceutics
v) AAPS Pharm.Sci.Tech.
vi) Acta Poloniae Pharmaceutica and Drug Research
vii) Asian Journal of Pharmaceutical Sciences
b) World Wide Web.
c) I.I.Sc Library, Bangalore.
d) J-Gate@Helinet.
e) RGUHS Library
8
7.2
METHOD OF COLLECTION OF DATA:-.
1) To carry out preformulation study
A. Drug polymer interaction
B. Micromeritic study
a) Angle of repose
b) Bulk density
c) Porosity
d) Percentage compressibility
2) To develop and formulate immediate release tablets by direct compression/wet
granulation methods using various polymers.
3) Evaluation of the various properties of
the formulated Immediate
release tablets:a) Physical properties:
Diameter and Thickness

Hardness and Friability

Uniformity of Weight and Content
4) In vitro dissolution studies will be carried out in a USP Type-II dissolution
apparatus at 50 rpm in Phosphate buffer pH 1.2 as dissolution media.
5) To carry out short term stability studies on the most satisfactory formulation as per
ICH guidelines at 30 ± 20C (65 ± 5 %RH) and 40 ± 20C (75 ± 5 %RH) for 2 months
6) Statistical analysis of data will be obtained from the results.
9
7.3
DOES THE STUDY REQUIRE ANY INVESTIGATION OR INVESTIGATION
TO BE CONDUCTED ON PATIENT OR OTHER HUMANS OR ANIMALS?
“NO”
7.4
HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION
IN CASE OF 7.3?
“NOT APPLICABLE”
10
8
REFERENCES:1. Barrera-Pulido L, Marin D,
De la Mata M, Lopez-Garrido MA, Gomez-Bravo MA,.
Jimenez M et al. Use of Mycophenolate Mofetil in Liver transplantation: Andalusian Liver
Registry. Transplant Proc 2009;41:2177–80.
2. Ching-Ling Cheng, Lawrence X Yu, Hwei-Ling Lee, Chyun-Yu Yang , Chang-Sha Lue,
Chen-His Chou. Biowaiver extension potential to BCS Class III high solubility-low
permeability drugs: bridging evidence for metformin immediate-release tablet. Eur J Pharm
Sci 2004;22:297-304.
3. Jinichi Fukami, Etsuo Yonemochi, Yasuo Yoshihashi, Katsuhide Terada. Evaluation of
rapidly disintegrating tablets containing glycine carboxymethylcellulose. Int J Pharm
2006;310:101-9.
4. Nathalie Rouge, Eric Alle mann, Marianne Gex-Fabry, Luc Balant, Ewart Cole T, Pierre
Buri et al. Comparative pharmacokinetic study of a floating multiple-unit capsule, a highdensity multiple-unit capsule and an immediate-release tablet containing 25 mg atenolol.
Pharmaceutica Acta Helvetiae 1998;73:81-7.
5. Tinke AP, Vanhoutte K, Vanhoutte F, Smet De M, Winter De H. Laser diffraction and
image analysis as a supportive analytical tool in the pharmaceutical development of
immediate release direct compression formulations. Int J Pharm 2005;297:80-8.
6. Annke Frick, Helga Moller, Ehrenfried Wirbitzki. Biopharmaceutical characterization of
oral
immediate
release
drug
products.
In
vitro/in
vivo
comparison
of
phenoxymethylpenicillin potassium, glimepiride and levofloxacin. Eur J Pharm Biopharm
1998;46:305-11.
7. Patel Nirav V, Chotai Narendra P, Patel Mayur P. Formulation design of oxcarbazepine
fast-release tablets prepared by melt granulation technique. Asian J Pharm 2008:22-5.
8. Chu Yankui, Lu Jianguo, Yin Jikai, Cai Liang, Liu Yi. Inhibitory effect of mycophenolate
mofetil on human hepatocellular carcinoma cell line HepG-2. Journal of Medical Colleges
Of PLA 2009;24:208-14
.
11
9. Darío Leonardi, María Gabriela Barrera, María Celina Lamas,Claudio Javier Salomon.
Development of Prednisone:Polyethylene Glycol 6000 Fast-Release Tablets From Solid
Dispersions: Solid-State Characterization, Dissolution Behavior, and Formulation
Parameters. AAPS Pharm Sci Tech 2007;8(4):E1-8.
10. Tapan Giri K, Parimal Jana, Biswanath Sa. Rapidly disintegrating fast release tablets of
diazepam using solid dispersion: devolpment and evaluation. J Sci Ind Res 2008;67:436-9.
11. Shahi SR, Agrawal GR, Shinde NV, Shaikh SA, Shaikh SS, Somani VG et al. Formulation
and in vitro evaluation of oro-dispersible tablets of etoricoxib with emphasis on comparative
functionality evaluation of three classes of superdisintegrants. Rasayan J Chem 2008;2:292300.
12. Patel Biraju, Patel Dhaval, Parmar Ramesh, Patel Chirag, Serasiya Tejas, Sanja SD.
Development and in vitro evaluation of fast dissolving tablets of glipizide. Int J Pharm
Pharm Sci 2009;1:145-50.
13. Sabah Souliman, Stephanie Blanquet, Eric Beyssac, Jean-Michel Cardot. A level A in
vitro/in vivo correlation in fasted and fed states using different methods: Applied to solid
immediate release oral dosage form. Eur J Pharm Sci 2006;27:72-9.
14. James Kowalski, Oskar Kalbb, Joshi Yatindra M, Serajuddin, Abu TM. Application of melt
granulation technology to enhance stability of a moisture sensitive immediate-release drug
product. Int J Pharm 2009;381:56-61.
15. Aleksandra Dukic-Ott, Jean Paul Remon, Paul Foreman, Chris Vervaet. Immediate release
of poorly soluble drugs from starch-based pellets prepared via extrusion/spheronisation. Eur
J Pharm Biopharm 2007;67:715-24.
16. Radke RS, Jadhav JK, Chajeed M R. Formulation and evaluation of Orodispersible
tablets of baclofen. Int. J ChemTech Res 2009;1(3):517-21.
17. Mario Giorgi, ChemD, Sara Del Carlo, PhD, Micaela Sgorbini, DVM et al.
Pharmacokinetics of Tramadol and Its MetabolitesM1, M2, and M5 in Donkeys after
Intravenous and Oral Immediate Release Single-Dose Administration J Equine Vet Sci
2009;29(7):569-74.
12
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10
11
SIGNATURE OF THE
CANDIDATE
REMARKS OF THE GUIDE
NAME AND DESIGNATION OF:
11.1 GUIDE
Dr. B. Prakash Rao
Professor& Head
Dept of Industrial Pharmacy
11.2 SIGNATURE
11.3 CO-GUIDE
---
11.4 SIGNATURE
---
11.5 HEAD OF THE
DEPARTMENT
Dr. B. Prakash Rao
Professor& Head
Dept of Industrial Pharmacy
11.6 SIGNATURE
12
12.1 REMARKS OF THE PRINCIPAL
12.2 NAME OF THE PRINCIPAL
Dr. DIVAKAR GOLI
Principal,
Acharya & B.M. Reddy College of
Pharmacy
Soldevanahalli,
Bangalore-90
12.3 SIGNATURE
13