Download enclosure – ii

ENCLOSURE – I
6) BRIEF RESUME OF THE INTENDED WORK
6.1)
NEED FOR THE STUDY
Tablets represents the preferred class of pharmaceutical solid oral dosage forms
because of their convenience in terms of self administration, compactness, unit dosage
forms and ease in manufacturing. However, an important variable in any tablet system
is the rate at which the drug substance dissolves and which in turn depends on
disintegration of the dosage after administration. Such tablet fragmentation may be
critical to the subsequent dissolution of the drug and to attainment of satisfactory drug
bioavailability. Thus, the proper choice of disintegrants and its consistency of
performance are of critical importance to the formulation development of such
tablets1. Consequently, tablet disintegration has received considerable attention as an
essential step in obtaining fast drug release by using superdisintegrants as they
promote moisture penetration and dispersion of the tablet matrix.
Superdisintegrants are the substances added to tablet and some encapsulated
formulations to promote the breakup of the tablet and capsule “slugs’ into smaller
fragments in an aqueous environment there by increasing the available surface area
and promoting a more rapid release of the drug substance2. Various superdisintegrants
like cross linked polyvinyl pyrrolidone (crospovidone), cross linked sodium
carboxymethyl cellulose (AcDiSol, solutab), sodium starch glycolate (primogel),
etc., are now frequently used in tablet formulation to ensure quick disintegration and
dissolution of drug from the dosage form3. They are generally used at a low level in
the solid dosage form, typically 1-10% by weight relative to the total weight of the
dosage unit. They may be used alone or in combination with other superdisintegrants.
However, the proper choice of superdisintegrants and its proportion are of significant
importance in the development of tablets. There are three methods of incorporating
disintegrating agents into the tablet: a) Internal addition (Intragranular). b) External
addition (extragranular) and c) Partly internal and external. A disintegrant used in
granulated formulation processes can be more effective if used both “intragranularly”
and “extragranularly” thereby acting to break the tablet up into granules and having
the granules further disintegrate to release the drug substance into solution. However,
the portion of disintegrant added intragranularly (in wet granulation processes) is
usually not as effective as that added extragranularly due to the fact that it is exposed
to wetting and drying (as part of the granulation process) which reduces the activity of
the disintegrant4,5.
Thus, superdisintegrants play an important role to ensure quick disintegration
and high dissolution rates of fast disintegrating drug delivery systems. So, it is
essential to choose proper mode of addition of suitable superdisintegrants in an
optimum concentration during the formulation of tablets. Hence, the aim of the
present study is to develop fast disintegrating tablets of carbidopa which is used to
treat Parkinson’s disease6 using various superdisintegrants. Further to study the effect
of superdisintegrants on the tablet properties as well as to improve the patient
compliance without compromising the therapeutic efficacy.
ENCLOSURE – II
6.2)
REVIEW OF LITERATURE
Kulkarniet al7 formulated and evaluated taste masked fast disintegrating tablets
of lisinopril to improve therapeutic efficacy of the drug. Tablets were evaluated for
weight and thickness variation, disintegration time, drug content, in vitro dissolution,
wetting time and water absorption ratio. The influence of superdisintegrants,
crosspovidone, croscaremellose sodium on disintegration time, wetting time and
water absorption ratio were studied. The in vitro disintegration time of the best fast
disintegrating tablets was found to be within 32 seconds. Tablets containing
crospovidone
exhibit
quick
disintegration
time
than
tablets
containing
croscaremellose sodium. The fast disintegrating tablets of lisinopril with shorter
disintegration time, acceptable taste and sufficient hardness could be prepared using
crospovidone and other excipients at an optimum concentration.
Preetha B et al8 studied the effect of mode of incorporation of superdisintegrants
like croscarmellose sodium, sodium starch glycolate and crospovidone (polyplasdone
XL and XL-10) on dissolution of carbamazepine (poorly soluble), acetaminophen
(sparingly soluble) and cetrizineHCl (soluble) tablet formulations prepared by wet
granulation. The disintegrants were incorporated extragranularly or intragranularly or
distributed equally between the two phases. The results indicated that crospovidone in
general was effective in improving the dissolution of the drugs used in the study and
generally extragranular mode of addition seemed to be the best mode of
incorporation, irrespective of the solubility of the main tablet component.
Shirsand SB et al9 designed fast disintegrating tablets of prochlorperazine
maleate with a view to enhance patient compliance by direct compression method. In
this method, crospovidone (up to 3% w/w) and croscarmellose sodium (up to 5%
w/w) in combination were used as superdisintegrants. Then tablets were further
evaluated for hardness, friability, drug content uniformity, in vitro dispersion time,
wetting time and water absorption ratio. Based on in vitro dispersion time
(approximately 12 s), one promising formulation was tested for in vitro drug release
pattern in phosphate buffer pH 6.8 and short-term stability (at 40 degrees /70% RH
for 3 mo), drug-excipient interaction (IR spectroscopy) were studied. Among the
formulations tested, formulation DCPC(4) containing 5% w/w of croscarmellose
sodium and 3% w/w of crospovidone as superdisintegrant, emerged as the overall best
(t(50%) 7.0 min) based on drug release characteristics in pH 6.8 phosphate buffer
compared to commercial conventional tablet formulation (t(50%) 17.4 min). Shortterm stability studies on the promising formulation indicated that there were no
significant changes in drug content and in vitro dispersion time (p<0.05).
Amit Modi et al10 formulated and evaluated fast dissolving tablets of Diclofenac
sodium using different superdisintegrants by direct compression method. It was
concluded that the batch which was prepared by using combination of crosspovidone
and sodium starch glycolate as a superdisintegrant shows excellent disintegration
time, enhance dissolution rate, taste masking and hence lead to improve efficacy and
bioavailability of drug.
Shirsand SB et al11 successfully prepared fast dissolving tablets of Clonazepam
by direct compression method by using crospovidone, croscarmellose sodium and
mannitol. They concluded that the formulation which was prepared by using
10%crospovidone and 35%w/w microcrystalline cellulose is the best formulation
(t50% - 1.8 minutes).
Arul Kumaran KSG et al12 prepared a levodopa- carbidopa combination of orally
disintegration tablet by direct compression method and evaluated results were
compared with marketed tablets. Effect of superdisintegrants (such as microcrystalline
cellulose, sodium starch glycolate and crospovidone) on wetting time, disintegration
time, drug content, in vitro release and stability parameters has been studied. Taste
evaluation (palatability studies) was done for the formulation with the peppermint oil
and evaluated for its better compliance than the other flavors used in the formulation.
Taste and disintegration of optimized formulation (F5&F7) were found to be better
than the marketed product. Drug release rate was more or less same as that of the
marketed product.
Patil C and Das S et al13 developed an orally disintegrating tablet (ODT) of
lamotrigine and evaluated the effect of various superdisintegrants on its disintegration
time and release profile. Tablets were prepared by direct compression technique using
sodium starch glycolate, croscarmellose sodium and crosspovidone XL-10 in
combinations to achieve optimum release profile, disintegration time and hardness.
Direct compression process was selected for this formulation of ODT tablets, because
porous nature is more in direct compression blend than wet granulation blend, so it
will give faster disintegration. Microcrystalline cellulose was used as diluent and
mannitol, mint flavor and sodium saccharin was used to enhance the organoleptic
properties of tablets. The tablets were evaluated for weight variation, hardness,
friability, in-vitro disintegration time and drug release characteristics. Hardness and
friability data indicated good mechanical strength. The results of in-vitro
disintegration time indicated that the tablets dispersed rapidly in mouth within 8 s.
Dissolution study revealed release rate of drug from the tablets was comparable with
marketed tablet formulation of lamotrigine. It was concluded that superdisintegrants
addition technique is a useful method for preparing orally disintegrating tablets by
direct compression method.
Sarasija S et al14 prepared and evaluate mouth dissolving tablets of salbutamol
sulphate. Fast dissolving tablets of salbutamol sulphate were prepared using
sublimation ingredients. Selection of the filler also had an important role in deciding
the disintegration time. Evaluation of the tablets showed that all the tablets were
found to be within official limits and the disintegration time for the formulations
ranged from 5 s to 40 s. amongst all, the formulation containing microcrystalline
cellulose and ammonium bicarbonate showed the least disintegration time of 5
seconds.
Chakraborty S et al15 studied on comparative effect of natural and synthetic
superdisintegrants in the formulation of fast dissolving tablets. The effect of a natural
superdisintgrant vis-a-vis isolated mucilage of Plantago ovata and synthetic
superdisintegrants like sodium starch glycolate (SSG) and croscarmellose sodium
(Ac-Di-Sol) were compared in the formulations of fast dissolving tablets. Fast
dissolving tablets of Aceclofenac (modal drug) were prepared by direct compression
method using microcrystalline cellulose as direct compressible vehicle. The present
study revealed that this natural superdisintegrants Plantago Ovata mucilage showed
better disintegrating property than the most widely used synthetic super disintegrants
like SSG and Ac-Di-Sol in the formulation of fast dissolving tablets.
Gudas GK et al16 prepared formulation and evaluation of fast dissolving tablets
of Chlorpromazine HCL. The tablets were prepared with five superdisintegrants like
sodium starch glycolate, crospovidone, croscarmellose, L-HPC, pregelatinised starch.
The blend was examined for angle of repose, bulk density, tapped density,
compressibility index and Hausners ratio. The tablets were evaluated for hardness,
friability, disintegration time, dissolution rate, drug content. It was concluded that the
fast dissolving tablets with proper hardness, rapidly disintegrating with enhanced
dissolution can be made using selected superdisintegrants.
Tayebi H and Mortazavi SA17 prepared a novel matrix-type buccal fast
disintegrating ibuprofen tablet formulation using special polymers, water soluble
excipients, super-disintegrants and quickly soluble granules. For this purpose different
tablet formulations of ibuprofen were prepared. Eight groups of formulation were
prepared (A-H series), accounting for a total number of 45 formulations. Formulations
prepared were examined in terms of different physicochemical tests including
powder/granule flowability, appearance, thickness, uniformity of weight, hardness,
friability and disintegration time. Results of formulation F22a (in series F), was found
to be acceptable, making it the chosen formulation for further studies. Then, by
adding various flavorants and sweeteners to this formulation, complementary series of
formulations, named G and H, were prepared. Following the comparison of their taste
with each other through asking 10 volunteers, the most suitable formulation regarding
the taste, being formulation F22s, was chosen as the ultimate formulation. This
formulation had PVP, ibuprofen and croscarmellose as the intra-granular components
and xylitol and saccharin as the extra-granular ingredients. Formulation F22s was
found to be acceptable in terms of physicochemical tests conducted, showing quick
disintegration within the buccal cavity, appropriate hardness and rather low friability.
Hence formulation F22s was selected as the final formulation.
Tapan KG et al18 developed tablets of diazepam-hydroxypropyl-β-cyclodextrin
inclusion complex that disintegrate within 3 minutes and release 85% of drug within
30 minutes to provide rapid action of the drug through oro-mucosal route. Tablets of
diazepam were prepared by direct compression method that disintegrated quickly (in
13.3 seconds) and released 85% drug rapidly (in 8.98 minutes).
Comoglu T and Unal B19 developed new solution to incorporate higher doses of
a model hydrophobic drug; meloxicam, without affecting the fast disintegrating
properties of the formulation. In order to enhance the solubilization of meloxicam in
fast disintegrating tablet (FDT) formulations, β cyclodextrin inclusion complex of the
drug is prepared and FDTs containing meloxicam--β cyclodextrin inclusion complex
(F1 A and F2 A) were compared and evaluated with the FDTs containing pure
meloxicam (F1 and F2) by means of in vitro quality control tests.
ENCLOSURE – III
6.3) OBJECTIVES OF THE STUDY
The proposed work is planned with the following objectives:

To carry out preformulation studies of drug and selected excipients.

To formulate fast disintegrating tablets of carbidopa using various
superdisintegrants
like
cross
linked
poly
vinyl
pyrrolidone
(crospovidone), cross linked sodium carboxymethyl cellulose (AcDiSol,
solutab), sodium starch glycolate (primogel) etc., by adopting wet
granulation method.

To carry out pre-compression and post-compression evaluation of the
prepared formulations.

To
investigate
the
effect
various
superdisintegrants
and
their
concentrations on release profile of the drug from carbidopa tablets.

To investigate the effect of mode of addition of superdisintegrants on the
tablet properties.

To carry out in vitro disintegration and dissolution studies of prepared
formulations.
ENCLOSURE – IV
7) MATERIALS AND METHODS
7.1) SOURCE OF DATA: The primary data will be collected by conducting
various experimental work and investigations in the laboratory and recording the
observations. The secondary data will be collected by referring various national
and international journals, books, Pharmacopoeia’s and professional websites like
Helinet,Pubmed etc.
ENCLOSURE –V
7.2) METHOD OF COLLECTION OF DATA
1) The physico-chemical parameters of the model drug will be determined in our
laboratory using standard methodology.
2) Instruments like disintegration apparatus, friabulator, dissolution apparatus
and UV spectrophotometer will be used to record the observations.
3) Compatibility between the drug and excipients will be studied using
techniques such as DSC, FT-IR etc.
4) Tablets of carbidopa will be formulated by adopting suitable technique.
5) Tablets shall be evaluated for pre-compression parameters like bulk
density, tapped density, Hausner’s ratio, Caurr’s index, particle size
distribution (PSD) and post-compression parameters like thickness, weight
variation, hardness, friability, drug content, in vitro disintegration and in
vitro dissolution studies.
6) In vitro drug release profiles will be studied and data shall be analyzed
statistically and kinetics of drug release shall be studied.
7) To carry out short term stability studies of tablet formulations as per ICH
guidelines at 30 ± 2C (65 ± 5 %RH) and 40 ± 2C (75 ± 5 %RH).
7.3) Does the study require any investigations to be conducted on patients/ humans/
animals?
NO
ENCLOSURE –VI
8) LIST OF REFERENCES:
1. Na Zhao and Augsburger LL. Functionality comparison of 3 classes of
superdisdintegrants in promoting aspirin tablet disintegration and dissolution.
AAPS PharmSciTech 2005;6:E634-E640.
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Delivery System, First Edition, 1998, 78.
3. Shangraw R, Mitrevej A, Shah M. New era of tablet disintegrants.
PharmTechnol 1980;4:49-57.
4. Lachman L, Liberman HA. Theory and Practice of Industrial Pharmacy, Third
Edition, 1990, 293-294.
5. Caramella C, Colombo P, Conte U, Ferrari F, La Manna A, Van Kamp HV,
Bolhuis GK. Water uptake and disintegrating force measurements: towards a
general understanding of disintegration mechanisms. Drug Dev Ind Pharm
1986;12:1749-1766.
6. Block G, Liss C, Reines S, Irr J, Nibbelink D. Comparison of immediaterelease and controlled release Carbidopa/Levodopa in Parkinson's disease. A
multicenter 5-year study. The CR First Study Group. Eur Neurol 1997;37:
23-27.
7. Kulkarni SV, Ranjit Kumar P, Basavaraj, SomeshwaraRao B, Ramesh B,
Ashok Kumar P. Effect of superdisintegrants on formulation of taste masked
fast disintigratinglisinopril tablets. Int J Curr Pharm Res 2011;3(1):11-14.
8. Preetha B, Pandit JK, Rao VU, Bindu K, Rajesh YV, BalasubramaniamJ.
Comparative Evaluation of Mode of Incorporation of Superdisintegrants on
Dissolution of Model drugs from wet granulated tablets. Acta Pharmaceutica
Sciencia 2008;50: 229-236.
9. Shirsand
SB, Suresh
S, Swamy
PV, Para
MS, Nagendra
Kumar
D.
Formulation design of fast disintegrating tablets using disintegrant blends.
Indian J Pharm Sci 2010;72(1):130-3.
10. Amit M, Vandana S, Arun G, Ashish A. Formulation and Evaluation of Fast
Dissolving Tablets of Diclofenac Sodium Using Different Superdisintegrants
by Direct Compression Method. Int J Pharm Biol Arch 2012; 3(4):10031007.
11. Shirsand SB, Sarasija S, Swamy PV, Nagendra KD, Rampure MV. Design
and Evaluation of Fast Dissolving Tablets of Clonazepam. Indian J Pharm
Sci 2008; 11:791-795.
12. Arul Kumaran KSG, Sreekanth J, Palanisamy S. Formulation development
and evaluation of Levodopa-Carbidopa orally disintegration tablets J Chem
Pharm Res 2011;3(3):169-175.
13. Patil C and Das S. Effect of various superdisintegrants on the drug release
profile and disintegration time of Lamotrigine orally disintegrating tablets.
African Journal of Pharmacy and Pharmacology 2011;5(1):76-82.
14. Sarasija S, Pandit V, Joshi HP. Preparation and evaluation of mouth
dissolving tablets of salbutamol sulphate. Ind J Pharm Sci 2007;69(3):467469.
15. Chakraborty S, Khandai M, Singh SP, Patra NC, Int J Green Pharmacy 2008;
2(1), 22-25.
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Tech 2010;2(1):99-102.
17. Tayebi H, Mortazavi SA. Formulation and evaluation of a novel matrix-type
orally disintegrating Ibuprofen tablet. Iran J Pharm Res 2011;10(3):469-79.
18. Tapan KG, Biswanath Sa. Preparation and Evaluation of Rapidly
Disintegrating
Fast
Release
Tablet
of
Diazepam-Hydroxypropyl-β-
Cyclodextrin Inclusion Complex. Pharmacology & Pharmacy 2010;1:18-26.
19. Comoglu T, Unal B. Preparation and evaluation of an orally fast
disintegrating tablet formulation containing a hydrophobic drug. Pharm Dev
Technol 2013;Dec 3 [Epub ahead of print].