Formulation and Evaluation of Orodispersible Tablet with an ... - IJPI
Formulation and Evaluation of Orodispersible Tablet with an ... - IJPI
Formulation and Evaluation of Orodispersible Tablet with an ... - IJPI
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
<strong>Formulation</strong> <strong><strong>an</strong>d</strong> <strong>Evaluation</strong> <strong>of</strong> <strong>Orodispersible</strong> <strong>Tablet</strong> <strong>with</strong> <strong>an</strong><br />
Extended Release Pr<strong>of</strong>ile<br />
Chav<strong>an</strong> Ritesh A.* <strong><strong>an</strong>d</strong> Mayee Rahul<br />
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, Rajasth<strong>an</strong> – 333001<br />
ABSTRACT<br />
Gal<strong>an</strong>tamine is a tertiary alkaloid, selective, competitive <strong><strong>an</strong>d</strong> reversible inhibitor <strong>of</strong> acetyl<br />
cholinesterase. It is used for symptomatic treatment <strong>of</strong> mild to moderately severe dementia <strong>of</strong><br />
the Alzheimer type. Current study was focused on formulation development <strong>of</strong> orodispersible<br />
tablet <strong>of</strong> Gal<strong>an</strong>tamine which disintegrates extended release pellets. Drug coating <strong>of</strong> drug was<br />
done on Celphere CP 203 <strong>with</strong> the help <strong>of</strong> Povidone K30 as a binder. Extended release pellets<br />
were formulated using wurster process. Extended release coating on drug loaded pellets were<br />
done using eudragit NE 30D as a rate limiting polymer. About 30 % extended release coating<br />
<strong>with</strong> eudragit NE 30D showed comparable drug release pattern that <strong>of</strong> <strong>with</strong> marketed<br />
preparation’s pellets <strong>of</strong> Gal<strong>an</strong>tamine ER. Further these pellets were compressed tablets that<br />
were dispersed <strong>with</strong>in 30 seconds, releasing extended release pellets. These formulations<br />
showed ideal drug release comparable to precompressed pellets. It showed no rupture <strong>of</strong><br />
extended release pellets that c<strong>an</strong> hamper the drug release pattern. At accelerated stability<br />
conditions developed formulations were found to be stable for six month.<br />
Keywords – Gal<strong>an</strong>tamine, Extended release orodispersible tablet, extended release pellets,<br />
Eudragit NE 30D, Antialzhimer drug etc.<br />
INTRODUCTION<br />
Orally disintegrating (dissolving) tablets<br />
(ODTs) are solid dosage forms that are<br />
placed in the mouth, rapidly<br />
disintegrate/dissolve when in contact <strong>with</strong><br />
the saliva <strong><strong>an</strong>d</strong> then easily swallowed<br />
<strong>with</strong>out the need for water. The fast<br />
disintegrating behavior <strong>of</strong> the ODT in the<br />
mouth limits the active ingredients that c<strong>an</strong><br />
be incorporated to drugs that exhibit good<br />
taste, stability in gastric conditions <strong><strong>an</strong>d</strong><br />
have long half-life. 1 Bitter tasting drugs<br />
c<strong>an</strong> cause discomfort to patients <strong><strong>an</strong>d</strong><br />
consequently reduce their compli<strong>an</strong>ce,<br />
Volume 3, Issue 3, May − June 2013<br />
whereas incorporating drugs that suffer<br />
from instability in gastric fluids reduces<br />
the efficacy <strong>of</strong> the dosage form<br />
(bioavailability). On the other h<strong><strong>an</strong>d</strong>,<br />
delivering active drugs that have short<br />
half-life in ODTs compromise the<br />
practicality <strong>of</strong> the dosage form as more<br />
frequent administration is required. To<br />
address these issues, a great deal <strong>of</strong> interest<br />
has been directed towards incorporating<br />
multiparticulate drug delivery system in<br />
*Corresponding Author<br />
Chav<strong>an</strong> Ritesh A<br />
55 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
ODT formulations. The multiparticulate<br />
drug delivery system comprises <strong>of</strong> drug<br />
particles encapsulated or coated by one or<br />
more layers <strong>of</strong> polymers that control the<br />
release <strong>of</strong> the drug. The polymer c<strong>an</strong> be<br />
selected to provide extended, delayed or<br />
pulsed drug delivery, allowing the rate <strong>of</strong><br />
release <strong>of</strong> the drug to be tailored as<br />
required. Moreover, they provide m<strong>an</strong>y<br />
adv<strong>an</strong>tages over single-unit dosage forms<br />
because <strong>of</strong> their multiplicity <strong><strong>an</strong>d</strong> small<br />
sizes including reduced risk <strong>of</strong> systemic<br />
toxicity, enh<strong>an</strong>ced bioavailability, reduced<br />
risk <strong>of</strong> local irritation <strong><strong>an</strong>d</strong> reduced patient<br />
to patient variability as a result <strong>of</strong> their<br />
more predictable gastric emptying.<br />
Accordingly, the formulation <strong>of</strong><br />
multiparticulate into ODTs c<strong>an</strong> extend<br />
their application to more challenging drugs<br />
(e.g. acid sensitive) by overcoming<br />
restrictions imposed by the nature <strong>of</strong> these<br />
drugs <strong><strong>an</strong>d</strong> combine the benefits <strong>of</strong> ODTs<br />
<strong><strong>an</strong>d</strong> multiparticulate drug delivery system 2,<br />
3 . The compression <strong>of</strong> multiparticulate into<br />
ODT formulations has attracted subst<strong>an</strong>tial<br />
attention in both academia <strong><strong>an</strong>d</strong> industry<br />
<strong><strong>an</strong>d</strong> resulted in m<strong>an</strong>y scientific<br />
publications <strong><strong>an</strong>d</strong> patent applications.<br />
However, to produce a tablet <strong>with</strong> good<br />
structural integrity, relatively high<br />
compression pressures are required. These<br />
high pressures c<strong>an</strong> cause damage to the<br />
polymer layers <strong>of</strong> the multiparticulate<br />
system, <strong><strong>an</strong>d</strong>, as a result, compromise their<br />
release controlling properties. Peroral<br />
controlled-release multiple unit dosage<br />
forms (e.g., pellets, gr<strong>an</strong>ules or sustained<br />
release pellets, microcapsules,<br />
microparticles) are becoming more <strong><strong>an</strong>d</strong><br />
more import<strong>an</strong>t on the pharmaceutical<br />
market, as they provide several adv<strong>an</strong>tages<br />
Volume 3, Issue 3, May − June 2013<br />
compared to single-unit dosage forms<br />
(e.g., tablets or capsules) 4,5<br />
Gal<strong>an</strong>tamine is a tertiary alkaloid,<br />
selective, competitive <strong><strong>an</strong>d</strong> reversible<br />
inhibitor <strong>of</strong> acetyl cholinesterase. It is used<br />
for symptomatic treatment <strong>of</strong> mild to<br />
moderately severe dementia <strong>of</strong> the<br />
Alzheimer type. Currently available<br />
formulations for gal<strong>an</strong>tamine are in the<br />
form <strong>of</strong> pellets, capsules for extended<br />
release <strong><strong>an</strong>d</strong> conventional tablets for<br />
immediate release 6 . By looking at target<br />
population for Gal<strong>an</strong>tamine, orodispersible<br />
tablet <strong>with</strong> extended release pr<strong>of</strong>ile could<br />
be favorable option that could administer<br />
the dosage form easily. The present work<br />
led to the formulation <strong>of</strong> orodispersible<br />
tablets for oral administration. The<br />
developed formulation which disintegrates<br />
disperses in oral cavity in less th<strong>an</strong> 30<br />
seconds <strong>with</strong>out the need <strong>of</strong> drinking<br />
water; had pleas<strong>an</strong>t mouth feel <strong><strong>an</strong>d</strong><br />
improved patient compli<strong>an</strong>ce particularly<br />
for those who have difficulty in<br />
swallowing 7 .<br />
MATERIALS AND METHODS<br />
Materials<br />
Gal<strong>an</strong>tamine Hydrobromide was selected<br />
as a model drug c<strong><strong>an</strong>d</strong>idate for the<br />
formulation trials aqueous dispersion <strong>of</strong><br />
Eudragit NE 30D was used as a rate<br />
controlling polymer. Talc was used as <strong>an</strong><br />
<strong>an</strong>titacking agent. Celphere CP 203 pellets<br />
from Asahi Kasei Excipients were used as<br />
a core pellets for drug loading. Water <strong><strong>an</strong>d</strong><br />
Meth<strong>an</strong>ol (GR grade) was used as<br />
solvents. Microcrystalline cellulose <strong>of</strong><br />
various grades viz. Ceolus KG 802 <strong><strong>an</strong>d</strong><br />
KG 1000 (Bl<strong>an</strong>ver) were used as a filler<br />
which provides good cushioning effect to<br />
56 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
the pellets. Crosspovidone XL 10 (ISP<br />
chemicals) was used as a disintegr<strong>an</strong>t.<br />
Glyceryl Stearate was used a waxy agent<br />
to promote easy flow <strong>of</strong> pellets. Flavour<br />
(firmenich) was used as a flavour.<br />
Aspartame as a sweetener. Magnesium<br />
Stearate was used as a lubric<strong>an</strong>t.<br />
METHODS<br />
<strong>Formulation</strong> Development<br />
Drug loading<br />
Procedure:-<br />
Refer the table no. 1 for the formula.<br />
Gal<strong>an</strong>tamine Hydrobromide was dissolved<br />
in purified water under continuous stirring<br />
until it gets completely dissolved then<br />
Povidone K30 was added slowly under<br />
continuous stirring in vertex. Stirring was<br />
continued until clear solution obtained.<br />
Finally above drug loading solution so<br />
formed was then subjected for drug<br />
loading over Celphere CP 203 pellets in<br />
Fluidized Bed Equipment (Pam Glatt) <strong>with</strong><br />
bottom spray attachment <strong>of</strong> 1.0 mm spray<br />
gun having fixed column height. After<br />
drug loading, drug loaded pellets were<br />
then dried at 50 0 C until LOD achieved<br />
NMT 1.5 % w/w. <strong><strong>an</strong>d</strong> then sifted through<br />
ASTM mesh # 60.<br />
Process parameters were set as in table<br />
no.2.<br />
Extended Release Coating<br />
Procedure:-<br />
Refer the table no. 3 for the formula .Talc<br />
was dispersed in purified water under<br />
continuous stirring for 30 min, then<br />
Eudragit NE 30 D was added under<br />
continuous stirring <strong><strong>an</strong>d</strong> Stirred for <strong>an</strong>other<br />
30 minutes more. Finally above extended<br />
release coating solution was then subjected<br />
for enteric coating over drug loaded pellets<br />
Volume 3, Issue 3, May − June 2013<br />
<strong>of</strong> Gal<strong>an</strong>tamine in Fluidized Bed<br />
Equipment (Pam Glatt) <strong>with</strong> bottom spray<br />
attachment <strong>of</strong> 1.0 mm spray gun having<br />
fixed column height. During the process<br />
samples <strong>of</strong> extended release coated pellets<br />
each at 10, 20, 30, 40 <strong><strong>an</strong>d</strong> 50 % extended<br />
release coating, was removed periodically<br />
<strong><strong>an</strong>d</strong> subjected for curing in oven at 50 0 c for<br />
1 hr. Withdrawn samples were then passed<br />
through ASTM mesh #30 <strong><strong>an</strong>d</strong> 50 <strong><strong>an</strong>d</strong><br />
retained pellets on ASTM mesh # 50 were<br />
subjected for dissolution <strong><strong>an</strong>d</strong> subsequently<br />
for further study. Process parameters were<br />
set as in table no.4.<br />
From the in vitro drug release patterns <strong><strong>an</strong>d</strong><br />
curing effects <strong>of</strong> extended release pellets<br />
<strong>of</strong> appropriate coating that matches to in<br />
vitro drug release pr<strong>of</strong>ile <strong>of</strong> marketed<br />
preparation, were selected for further<br />
evaluation <strong><strong>an</strong>d</strong> subsequently compression<br />
process.<br />
Compression <strong>of</strong> Pellets<br />
Procedure<br />
Refer the table no. 5 for the formula<br />
.Ceolus KG 1000 <strong><strong>an</strong>d</strong> 802, Crospovidone<br />
XL 10, Aspartame <strong><strong>an</strong>d</strong> flavor were passed<br />
through mesh # 30 separately. Magnesium<br />
Stearate was passed through mesh # 60.All<br />
ingredients except magnesium Stearate<br />
was blended <strong>with</strong> extended release pellets<br />
were blended in polybag for 5 minutes.<br />
Magnesium Stearate was then lubricated<br />
<strong>with</strong> the above blend for 2 minutes <strong><strong>an</strong>d</strong><br />
subjected for compression <strong>with</strong> 13 mm<br />
biconvex round shaped punch.Compressed<br />
tablets were evaluated for Appear<strong>an</strong>ce <strong><strong>an</strong>d</strong><br />
dimensions, Thickness, Hardness,<br />
Friability, Disintegration, in vitro drug<br />
release <strong><strong>an</strong>d</strong> stability studies 8, 9 .<br />
57 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
<strong>Evaluation</strong> <strong>of</strong> Lubricated Blend <strong><strong>an</strong>d</strong><br />
Pellets<br />
Angle <strong>of</strong> repose<br />
The powder mixture was allowed to pass<br />
through the funnel fixed to a st<strong><strong>an</strong>d</strong> at<br />
definite height. The <strong>an</strong>gle <strong>of</strong> repose was<br />
then calculated by measuring the height<br />
<strong><strong>an</strong>d</strong> radius <strong>of</strong> the heap <strong>of</strong> powder formed.<br />
Then <strong>an</strong>gle <strong>of</strong> repose had been calculated<br />
from below formula<br />
θ = t<strong>an</strong> -1 (h/r)<br />
Where:<br />
θ = Angle <strong>of</strong> repose<br />
h = Height <strong>of</strong> pile in cm<br />
r = radius in cm.<br />
Bulk Density<br />
Accurately weighed qu<strong>an</strong>tity <strong>of</strong> sample,<br />
<strong><strong>an</strong>d</strong> carefully poured into graduated<br />
cylinder. Then after pouring the powder<br />
into the graduated cylinder the powder bed<br />
was made uniform <strong>with</strong>out disturbing.<br />
Then the volume was measured directly<br />
from the graduation marks on the cylinder<br />
as ml. The volume measure was called as<br />
the bulk volume <strong><strong>an</strong>d</strong> the bulk density is<br />
calculated by following formula:<br />
Bulk density = Weight <strong>of</strong> powder /Bulk<br />
volume<br />
Tapped Density<br />
After measuring the bulk volume the same<br />
measuring cylinder was set into tap density<br />
apparatus. The tap density apparatus was<br />
set to 100 taps drop <strong><strong>an</strong>d</strong> operated for 50<br />
taps. Volume was noted as (Va) <strong><strong>an</strong>d</strong> again<br />
tapped for 50 times <strong><strong>an</strong>d</strong> volume was noted<br />
as (Vb). If the difference between Va <strong><strong>an</strong>d</strong><br />
Vb not greater th<strong>an</strong> 2% then Vb is consider<br />
as final tapped volume. The tapped density<br />
is calculated by the following Formula:<br />
Tapped Density = Va / Vb<br />
Where<br />
Va = weight <strong>of</strong> the powder<br />
Vb = tapped volume <strong>of</strong> the packing<br />
Compressibility index <strong><strong>an</strong>d</strong> Hausner<br />
ratio:-<br />
Compressibility index <strong><strong>an</strong>d</strong> Hausner ratio<br />
were calculated from bulk <strong><strong>an</strong>d</strong> tapped<br />
density <strong>of</strong> the sample. These parameters<br />
show the flow properties <strong>of</strong> sample.<br />
Compressibility index = [(D T - D B )/ D T ] x<br />
100<br />
Hausner ratio = D T / D B<br />
D T =Tapped density<br />
D B = Bulk density<br />
Friability test<br />
Roche Friabilator was used to measure the<br />
friability <strong>of</strong> the pellets. It was rotated at a<br />
rate <strong>of</strong> 25 RPM. 5 g pellets were weighed<br />
collectively <strong><strong>an</strong>d</strong> placed in the chamber <strong>of</strong><br />
the friabilator. After 100 rotations (4<br />
minutes), the pellets were taken out from<br />
the friabilator <strong><strong>an</strong>d</strong> intact pellets were again<br />
weighed collectively after removing fines<br />
using ASTM sieve # 60 sieve. Permitted<br />
percentage friability limit is 0.8%. The<br />
percent friability was determined using the<br />
following formula.<br />
% friability = [(W 1 – W 2 ) / W 1 ] x 100<br />
Where<br />
W 1 = weight <strong>of</strong> the pellets before test.<br />
W 2 = weight <strong>of</strong> the pellets after test.<br />
Volume 3, Issue 3, May − June 2013<br />
58 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
Drug content (Assay calculation)<br />
This practice was done for the pellets<br />
obtained after drug coating to check the<br />
entrapment <strong>of</strong> the drug in the drug loaded<br />
pellets. Drug loaded pellets equivalent to<br />
24 mg <strong>of</strong> pellets had been dissolved in<br />
diluents, from this solution 1ml was<br />
pipette out in to 10ml volumetric flask <strong><strong>an</strong>d</strong><br />
volume was made up to <strong>with</strong> meth<strong>an</strong>ol 10 .<br />
In vitro drug release<br />
In vitro drug release <strong>of</strong> pellets was carried<br />
out after functional coating to check drug<br />
release pattern <strong>of</strong> the extended release<br />
pellets prior to the compression <strong><strong>an</strong>d</strong> on to<br />
the compressed tablets. Invitro drug<br />
release/ dissolution studies were carried<br />
out using following dissolution conditions.<br />
Dissolution Conditions:-<br />
Dissolution Apparatus = USP type<br />
II (Paddle type).<br />
Dissolution medium = Phosphate<br />
buffer pH 6.8<br />
Temperature = 37 ± 0.5 o C<br />
Paddle rpm = 100.<br />
Time Points =<br />
1,2,3,4,6,8,10,12,14,16,18,20,22,24<br />
hrs.<br />
Accurately weighed pellets were placed in<br />
each flask <strong>of</strong> dissolution apparatus. The<br />
apparatus was allowed to run for 24 hours.<br />
Samples measuring 5 ml were <strong>with</strong>drawn.<br />
Then samples were filtered through 0.45<br />
Millipore filter <strong><strong>an</strong>d</strong> their concentrations<br />
were determined using High Perform<strong>an</strong>ce<br />
Liquid Chromatography System 11<br />
Curing effect:<br />
The pellets were cured in a hot air oven for<br />
24 hours to check the effect <strong>of</strong> curing on<br />
drug release; the cured pellets are<br />
subjected for in vitro release studies 12 .<br />
Volume 3, Issue 3, May − June 2013<br />
EVALUATION OF COMPRESSED<br />
TABLETS:-<br />
Appear<strong>an</strong>ce <strong><strong>an</strong>d</strong> Dimensions:-<br />
The thickness <strong><strong>an</strong>d</strong> diameter <strong>of</strong> the tablets<br />
was determined using a Vernier calliper.<br />
Five tablets from each type <strong>of</strong> formulation<br />
were used <strong><strong>an</strong>d</strong> average values were<br />
calculated. It is expressed in mm.<br />
Weight variation test:-<br />
Twenty tablets were selected r<strong><strong>an</strong>d</strong>omly<br />
from each formulation, weighed<br />
individually <strong><strong>an</strong>d</strong> the average weight <strong><strong>an</strong>d</strong> %<br />
variation <strong>of</strong> weight was calculated.<br />
Hardness<br />
For each formulation, the hardness <strong>of</strong> 3<br />
tablets was determined using the Mons<strong>an</strong>to<br />
hardness tester. The tablet was held along<br />
its oblong axis in between the two jaws <strong>of</strong><br />
the tester. Then const<strong>an</strong>t force was applied<br />
by rotating the knob until the tablet<br />
fractured. The value at this point was<br />
noted.<br />
Friability<br />
For each formulation, the friability <strong>of</strong> 20<br />
tablets was determined using the Roche<br />
friabilator. A sample <strong>of</strong> preweighed 20<br />
tablets was placed in Roche friabilator,<br />
which was then operated for 25 RPM for 4<br />
minutes. A loss <strong>of</strong> less th<strong>an</strong> 1% in weigh in<br />
generally considered acceptable. Percent<br />
friability (% F) was calculated as follows,<br />
% friability = [(W 1 – W 2 ) / W 1 ] x 100<br />
Whereas W 1 = weight <strong>of</strong> tablets before<br />
test.<br />
W 2 = weight <strong>of</strong> the tablets after test.<br />
In vitro disintegration test<br />
The process <strong>of</strong> breakdown <strong>of</strong> a tablet into<br />
smaller particles is called as disintegration.<br />
The in-vitro disintegration time <strong>of</strong> a tablet<br />
59 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
was determined using disintegration<br />
apparatus as per USP specifications.<br />
In vitro drug release<br />
Same as in vitro drug release testing <strong>of</strong><br />
pellets.<br />
Stability Studies<br />
Stability studies were conducted according<br />
to ICH guidelines by using optimized<br />
formulation at 40°C/75±5% RH or a<br />
period <strong>of</strong> 6 months. The samples were<br />
<strong>with</strong>drawn at 1, 3 <strong><strong>an</strong>d</strong> 6 month <strong><strong>an</strong>d</strong><br />
<strong>an</strong>alyzed for drug content, <strong><strong>an</strong>d</strong> dissolution<br />
study as given in in-vitro release<br />
dissolution studies by <strong>an</strong> HPLC method.<br />
Drug content (Assay calculation)<br />
Twenty tablets were weighed <strong><strong>an</strong>d</strong><br />
powdered. The blend equivalent to 24 mg<br />
<strong>of</strong> Gal<strong>an</strong>tamine was weighed <strong><strong>an</strong>d</strong><br />
dissolved in sufficient qu<strong>an</strong>tity <strong>of</strong> PH 6.8<br />
phosphate buffer. The solution was filtered<br />
through Whatm<strong>an</strong>n filter paper (no.41),<br />
suitably diluted <strong>with</strong> pH 6.8 phosphate<br />
buffer <strong><strong>an</strong>d</strong> assayed.<br />
RESULT AND DISCUSSION<br />
Drug loading<br />
Drug solution <strong>of</strong> Gal<strong>an</strong>tamine hydro<br />
bromide was loaded on Celphere CP 203<br />
pellets Due to low viscous solution drug<br />
loading process was done <strong>with</strong>out <strong>an</strong>y<br />
process issues. Further drug loaded pellets<br />
were evaluated.<br />
Moisture Content<br />
Loss on drying was measured using<br />
moisture <strong>an</strong>alyzer at 105 0 c <strong><strong>an</strong>d</strong> was found<br />
to be 1.13 %w/w.<br />
Assay content<br />
130 mg <strong>of</strong> drug loaded Pellets equivalent<br />
to 24 mg <strong>of</strong> Gal<strong>an</strong>tamine was subjected for<br />
assay determination by HPLC which was<br />
Volume 3, Issue 3, May − June 2013<br />
found to be 98.93 % which shows effective<br />
drug loading on inert pellets.<br />
Friability<br />
Friability <strong>of</strong> drug loaded pellets was found<br />
to be 0.361 which showed enough strength<br />
to <strong>with</strong>st<strong><strong>an</strong>d</strong> <strong>an</strong>y pellets breaking issues<br />
during pelletisation.<br />
EXTENDED RELEASE COATING<br />
Extended release coating was done on drug<br />
loaded pellets. Due to low glass tr<strong>an</strong>sition<br />
temperature <strong>of</strong> eudragit NE 30D, process<br />
was done using slow rate <strong>of</strong> spray rate.<br />
Also it was found that increasing spray<br />
rate triggers the sticking <strong>of</strong> pellets which<br />
was not ideal condition for rate controlling<br />
issue. Parameters observed during<br />
extended release coating were as below.<br />
Samples were <strong>with</strong>drawn at different<br />
coating levels <strong><strong>an</strong>d</strong> then subjected for<br />
curing at 50 0 c for 1 hr. Cured pellets were<br />
then passed through ASTM mesh # 30 <strong><strong>an</strong>d</strong><br />
50. Pellets retained on ASTM mesh #50<br />
was subjected for dissolution to check<br />
drug release pattern <strong>of</strong> the extended release<br />
pellets <strong><strong>an</strong>d</strong> drug release was found to be<br />
as in table no. 6 <strong><strong>an</strong>d</strong> graph no.1.<br />
It was found that coated 30% extended<br />
release coated pellets were found to be<br />
comparable <strong>with</strong> marketed extended<br />
release pellets. So these were chosen for<br />
further studies as below.<br />
Moisture Content:-<br />
Loss on drying was measured using<br />
moisture <strong>an</strong>alyzer at 105 0 c <strong><strong>an</strong>d</strong> was found<br />
to be 0.89 %w/w.<br />
Friability<br />
Friability <strong>of</strong> extended release pellets was<br />
found to be 0.453 at 300 RPM which<br />
showed enough strength to <strong>with</strong>st<strong><strong>an</strong>d</strong> <strong>an</strong>y<br />
60 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
pellets breaking issues during<br />
compression.<br />
Effect <strong>of</strong> Curing on extended release<br />
pellets.<br />
The pellets were cured in a hot air oven for<br />
24 hours at 60 o c to check the effect <strong>of</strong><br />
curing on drug release. Periodically pellets<br />
were sampled <strong><strong>an</strong>d</strong> then subjected for in<br />
vitro drug release studies <strong><strong>an</strong>d</strong> compared<br />
<strong>with</strong> previous initial results. It had been<br />
found that there is no drastic effect on drug<br />
release after curing for long time. This<br />
shows the promising stability <strong>of</strong> extended<br />
release coating. In vitro drug release was<br />
found to be as in table no.7 <strong><strong>an</strong>d</strong> graph<br />
no.2.<br />
Further Extended release pellets were<br />
evaluated for precompression parameters<br />
as Angle <strong>of</strong> Repose, Bulk density, Tapped<br />
density, Compressibility index, Hausner<br />
ratio as below which showed good flow<br />
property as statedin table no.8.<br />
Further these pellets were subjected for<br />
blending <strong><strong>an</strong>d</strong> lubrication <strong>with</strong><br />
extragr<strong>an</strong>ular ingredients<br />
Compression<br />
Lubricated blend was then subjected for<br />
preformulation studies to check flowability<br />
<strong><strong>an</strong>d</strong> compressibility properties as stated in<br />
table no. 10. Then lubricated blend was<br />
compressed into tablets by using 13.0 mm<br />
biconvex round shaped punch. In process<br />
compression parameters as followed in<br />
table no. 11.<br />
Since disintegration was achieved on the<br />
above parameters hence tablets were<br />
compressed <strong><strong>an</strong>d</strong> subjected for dissolution<br />
to check that if there was <strong>an</strong>y ch<strong>an</strong>ce <strong>of</strong><br />
rupturing extended release pellets during<br />
the compression, as in table no. 12.<br />
Volume 3, Issue 3, May − June 2013<br />
It had been observed that there was no<br />
impact on dissolution pr<strong>of</strong>ile <strong>of</strong><br />
compressed tablets <strong><strong>an</strong>d</strong> extended release<br />
pellets, also on this hardness there was no<br />
rupture <strong>of</strong> pellets during compression <strong>with</strong><br />
enough tablet friability.<br />
Stability study<br />
Stability studies were conducted according<br />
to ICH guidelines by using optimized<br />
formulation at 40°C/75±5% RH or a<br />
period <strong>of</strong> 6 months. The samples were<br />
<strong>with</strong>drawn at 1,3 <strong><strong>an</strong>d</strong> 6 month <strong><strong>an</strong>d</strong><br />
<strong>an</strong>alyzed for drug content, <strong><strong>an</strong>d</strong> dissolution<br />
study as given in in-vitro release<br />
dissolution studies by <strong>an</strong> HPLC method as<br />
in Table no. 13,14 <strong><strong>an</strong>d</strong> graph no. 4.<br />
REFERENCES<br />
1. Akbari B.V., Dholakiya R.B.,<br />
Shiy<strong>an</strong>i B.G., Lodhiya D.J. Design,<br />
development <strong><strong>an</strong>d</strong> characterization<br />
<strong>of</strong> mouth dissolving tablets <strong>of</strong><br />
cinnarizine using superdisintegr<strong>an</strong>ts.<br />
International journal<br />
<strong>of</strong> pharmtech research . Vol.2,<br />
no.1, pp 97-105 J<strong>an</strong>-Mar 2010<br />
2. Aulton, M.E.,Kh<strong>an</strong>, K.A., The<br />
strength <strong><strong>an</strong>d</strong> compaction <strong>of</strong><br />
millispheres. The design <strong>of</strong> a<br />
controlled-release drug delivery<br />
system for ibupr<strong>of</strong>en in the form <strong>of</strong><br />
a tablet comprising compacted<br />
polymer-coated millispheres. Drug<br />
Dev. Ind. Pharm., 20, 3069-3104,<br />
1994.<br />
3. Bechgaard H., Nielsen G.H.<br />
Controlled-Release Multiple-Units<br />
<strong><strong>an</strong>d</strong> Single-Unit Doses a Literature<br />
Review. Drug Development <strong><strong>an</strong>d</strong><br />
Industrial Pharmacy 4, 53 – 67,<br />
1978.<br />
61 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
4. Bodmeier, R., <strong>Tablet</strong>ing <strong>of</strong> pellets.<br />
Europe<strong>an</strong> Journal <strong>of</strong> Pharmaceutics<br />
<strong><strong>an</strong>d</strong> Biopharmaceutics . 1997.<br />
5. Dashevsky, A., Kolter, K.,<br />
Bodmeier, R., Compression <strong>of</strong><br />
pellets coated <strong>with</strong> various aqueous<br />
polymer dispersions. Int. J. Pharm.<br />
279 (1-2), 19-26. 2004.<br />
6. http://www.drugb<strong>an</strong>k.ca/drugs/DB<br />
00674<br />
7. Joh<strong>an</strong>sson, B., Nicklasson, F.,<br />
Alderborn, G., Effect <strong>of</strong> pellet size<br />
on degree <strong>of</strong> deformation <strong><strong>an</strong>d</strong><br />
densification during compression<br />
<strong><strong>an</strong>d</strong> on compactability <strong>of</strong><br />
microcrystalline cellulose pellets.<br />
Int. J. Pharm., 163, 35-48. 1998.<br />
8. Joh<strong>an</strong>sson, B., Wikberg, M., Ek,<br />
R., Alderborn, G., Compression<br />
behaviour <strong><strong>an</strong>d</strong> compactability <strong>of</strong><br />
microcrystalline cellulose pellets in<br />
relationship to their pore structure<br />
<strong><strong>an</strong>d</strong> mech<strong>an</strong>ical properties. Int. J.<br />
Pharm., 117, 57-73. 1995.<br />
9. Juslin, M., Turakka, L.,<br />
Puumalainen, P., Controlled<br />
release tablets. Part 1: The use <strong>of</strong><br />
pellets coated <strong>with</strong> a retarding<br />
acrylate plastic in tabletting.<br />
Pharm. Ind., 42, 829-832, 1980.<br />
10. Satyakala G<strong>an</strong>ti. Development <strong>of</strong><br />
HPLC Methods For<br />
Pharmaceutically Relev<strong>an</strong>t<br />
Molecules; Method Tr<strong>an</strong>sfer To<br />
UPLC. Comparing Methods<br />
Statistically For Equivalence.<br />
Temple University Graduate<br />
Board. J<strong>an</strong>uary 2011.<br />
11. T. Jagadeesh, R. Bala Ramesha<br />
Chary. Development <strong>of</strong> Oral Multi<br />
Particulate Drug Delivery System<br />
<strong>of</strong> Gal<strong>an</strong>tamine Hydrobromide by<br />
Using Extrusion Spheronization<br />
technique. International Journal <strong>of</strong><br />
Pharmacy & Technology. IJPT |<br />
June-2011 | Vol. 3 | Issue No.2 |<br />
2633-2643<br />
12. Korber, M., V. H<strong>of</strong>fart, et al.<br />
(2010). "Effect <strong>of</strong> unconventional<br />
curing conditions <strong><strong>an</strong>d</strong> storage on<br />
pellets coated <strong>with</strong> Aquacoat<br />
ECD." Drug Development <strong><strong>an</strong>d</strong><br />
Industrial Pharmacy 36(2): 190-<br />
199.<br />
Volume 3, Issue 3, May − June 2013<br />
62 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
Table No. 1 Formula for drug loading<br />
Sr. No. Ingredients % w/w<br />
1 Gal<strong>an</strong>tamine Hydrobromide (Eq. to 24 mg <strong>of</strong> Gal<strong>an</strong>tamine) 23.66<br />
2 Polyvinyl Pyrrolidone (Povidone K30) 2.37<br />
3 Celphere CP203 73.97<br />
4 Purified water 107.69<br />
Table No. 2 Set Parameters <strong>of</strong> drug loading.<br />
Parameters<br />
Set value<br />
Inlet temperature ( 0 C) 50<br />
Product temperature ( 0 C) 45<br />
Exhaust temperature ( 0 C) 45<br />
Atomisation Air (bar) 0.8-0.9<br />
F<strong>an</strong> speed 20-50<br />
Peristaltic Pump Speed (RPM) 1-10<br />
Table No. 3 Formula for extended release coating.<br />
Sr. No. Ingredients % w/w<br />
1 Eudragit NE 30 D * 50.00<br />
2 Talc 50.00<br />
3 Purified water q.s.<br />
*Solid content.<br />
Table No. 4 Set Parameters <strong>of</strong> drug loading.<br />
Parameters<br />
Set values<br />
Inlet temperature ( 0 C) 25<br />
Product temperature ( 0 C) 20-25<br />
Exhaust temperature ( 0 C) 20-25<br />
Atomisation Air (bar) 0.9-1.0<br />
F<strong>an</strong> speed 30-75<br />
Peristaltic Pump Speed (RPM) 1-5<br />
Volume 3, Issue 3, May − June 2013<br />
63 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
Table No. 5 Formula for blending <strong><strong>an</strong>d</strong> lubrication <strong>of</strong> extended release pellets.<br />
Sr. No. Ingredients % w/w<br />
1 Extended Release Pellets 42.25<br />
2 Ceolus KG 1000* 24.55<br />
3 Ceolus KG 802 18.45<br />
4 Glyceryl Stearate 2.50<br />
5 Crospovidone XL 10 10.00<br />
6 Or<strong>an</strong>ge Flavor 0.50<br />
7 Aspartame 0.50<br />
8 Magnesium Stearate 1.25<br />
<strong>Tablet</strong> weight<br />
400.00 mg<br />
*To be adjusted in accord<strong>an</strong>ce <strong>with</strong> extended release pellets weight<br />
Table- 6 In vitro drug release pr<strong>of</strong>ile <strong>of</strong> extended release pellets at different coating levels.<br />
Time<br />
(Hours)<br />
Marketed<br />
sample<br />
Percentage <strong>of</strong> drug released<br />
10 % 20 % 30 %<br />
ERC ERC ERC<br />
40 %<br />
ERC<br />
50 %<br />
ERC<br />
0 0 0 0 0 0 0<br />
1 28 48 38 26 23 14<br />
2 40 62 51 38 31 20<br />
3 52 72 60 47 39 31<br />
4 60 81 69 57 50 38<br />
6 74 92 83 70 63 52<br />
8 81 99 89 79 73 68<br />
10 85 100 95 84 79 75<br />
12 89 100 96 87 83 79<br />
14 90 99 99 88 86 84<br />
16 92 100 100 91 90 88<br />
18 95 100 99 94 92 89<br />
20 97 99 100 96 93 92<br />
22 99 98 100 98 96 93<br />
24 100 99 99 99 98 95<br />
F2 Value 35.24 50.52 74.40 50.99 36.71<br />
ERC= Extended release coating<br />
Volume 3, Issue 3, May − June 2013<br />
64 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
Table-7 In vitro drug release pr<strong>of</strong>ile <strong>of</strong> cured extended release pellets at different time<br />
intervals<br />
Percentage <strong>of</strong> drug released<br />
Time<br />
Cured pellets Cured pellets Cured pellets<br />
(Hours)<br />
(Initial) for 12 hrs. for 24 hrs.<br />
0 0 0 0<br />
1 26 24 23<br />
2 38 36 35<br />
3 47 45 43<br />
4 57 55 54<br />
6 70 68 67<br />
8 79 77 75<br />
10 84 82 81<br />
12 87 85 84<br />
14 88 86 84<br />
16 91 90 88<br />
18 94 92 89<br />
20 96 93 92<br />
22 98 96 94<br />
24 99 98 97<br />
F2 Value 74.40 64.16 59.20<br />
Table No 8 Precompression parameters <strong>of</strong> extended release pellets<br />
Sr. No. Parameters Results Remark<br />
1 Bulk Density 0.720 g/ml<br />
2 Tapped Density 0.810 g/ml<br />
3 Hausners ratio 1.12 Good flow<br />
4 Compressibility index 10.62 % Good flow<br />
5 Angle <strong>of</strong> repose 13.24 o Good flow<br />
Volume 3, Issue 3, May − June 2013<br />
65 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
Table No. 9 Formula for blending <strong><strong>an</strong>d</strong> lubrication <strong>of</strong> extended release pellets<br />
Sr. No. Ingredients % w/w<br />
1 Extended Release Pellets 42.25<br />
2 Ceolus KG 1000* 24.55<br />
3 Ceolus KG 802 18.45<br />
4 Glyceryl Stearate 2.50<br />
5 Crospovidone XL 10 10.00<br />
6 Flavor 0.50<br />
7 Aspartame 0.50<br />
8 Magnesium Stearate 1.25<br />
<strong>Tablet</strong> weight 100.00<br />
Table No.10 Preformulation parameters <strong>of</strong> lubricated blend.<br />
Sr. No. Parameters Results Remark<br />
1 Bulk Density 0.660 g/ml<br />
2 Tapped Density 0.760 g/ml<br />
3 Hausners ratio 1.15 Good flow<br />
4 Compressibility index 12.88 % Good flow<br />
5 Angle <strong>of</strong> repose 13.24 o Good flow<br />
Table No. 11 In process compression parameters<br />
Sr. No. Parameters Results Remark<br />
1 Uniformity <strong>of</strong> weight ( mg) 394-205<br />
2 Weight variation 2.25 % deviation<br />
Within Limit<br />
3 Thickness (mm) 2.50±0.16 mm<br />
4 Hardness (kP) 2.9-3.5<br />
5 Friability ( for 100 revolutions) 0.451 Within Limit<br />
6 In-vitro disintegration time (sec) 18-28 Within Limit<br />
Volume 3, Issue 3, May − June 2013<br />
66 | P a g e<br />
http://www.ijpi.org
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
Table No. 12 Comparative dissolution pr<strong>of</strong>ile <strong>of</strong> Extended release pellets <strong><strong>an</strong>d</strong><br />
compressed tablets.<br />
Time (Hours)<br />
Percentage <strong>of</strong> drug released<br />
Extended Release Pellets Compressed tablets<br />
0 0 0<br />
1 26 24<br />
2 38 36<br />
3 47 45<br />
4 57 55<br />
6 70 68<br />
8 79 77<br />
10 84 82<br />
12 87 85<br />
14 88 86<br />
16 91 90<br />
18 94 92<br />
20 96 93<br />
22 98 97<br />
24 99 98<br />
F2 Value 74.40 64.16<br />
Table No. 13 Drug content according to stability conditions.<br />
Sr.No. Stability Conditions Drug content<br />
1 Initial 99.93 %<br />
2 40 o c/75% RH, 1 month. 99.27<br />
3 40 o c/75% RH, 2 month. 98.69<br />
4 40 o c/75% RH, 3 month. 98.21<br />
Volume 3, Issue 3, May − June 2013<br />
67 | P a g e<br />
http://www.ijpi.org
% Drug released<br />
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
Table No. 14 In vitro drug release pattern <strong>of</strong> stabilised formulations.<br />
Time<br />
(Hours)<br />
Initial<br />
Percentage <strong>of</strong> drug released<br />
40 o C/75% RH,<br />
1 month<br />
40 o C/75% RH<br />
2 month<br />
40 o C/75% RH,<br />
3 month<br />
0 0 0 0 0<br />
1 24 23 21 22<br />
2 36 34 35 33<br />
3 45 44 42 41<br />
4 55 56 55 53<br />
6 68 68 66 65<br />
8 77 75 73 74<br />
10 82 82 81 80<br />
12 85 84 83 82<br />
14 86 84 83 83<br />
16 90 88 86 85<br />
18 92 91 91 89<br />
20 93 93 94 92<br />
22 97 97 95 94<br />
24 98 98 97 98<br />
F2 values 74.40 61.01 56.46 54.42<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
Marketed sample<br />
10 % Extended release coating<br />
20 % Extended release coating<br />
30 % Extended release coating<br />
40 % Extended release coating<br />
50 % Extended release coating<br />
0 2 4 6 8 10 12 14 16 18 20 22 24<br />
Time (Hours)<br />
Graph-1 In vitro drug release pr<strong>of</strong>ile <strong>of</strong> extended release pellets at different coating levels<br />
Volume 3, Issue 3, May − June 2013<br />
68 | P a g e<br />
http://www.ijpi.org
% Drug released<br />
% Drug released<br />
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
0 2 4 6 8 10 12 14 16 18 20 22 24<br />
Time (Hours)<br />
Cured pellets (Initial)<br />
Cured pellets for 12 hrs.<br />
Cured pellets for 24 hrs.<br />
Graph -2 In vitro drug release pr<strong>of</strong>ile <strong>of</strong> cured extended release pellets at different time intervals<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
0 2 4 6 8 10 12 14 16 18 20 22 24<br />
Time (Hours)<br />
Extended Release Pellets<br />
Compressed tablets<br />
Graph - 3 Comparative dissolution pr<strong>of</strong>ile <strong>of</strong> Extended release pellets <strong><strong>an</strong>d</strong> compressed tablets.<br />
Volume 3, Issue 3, May − June 2013<br />
69 | P a g e<br />
http://www.ijpi.org
% Drug released<br />
INTERNATIONAL JOURNAL OF<br />
RESEARCH ARTICLE<br />
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
0 2 4 6 8 10 12 14 16 18 20 22 24<br />
Time (Hours)<br />
Initial<br />
40oc/75% RH, 1 month.<br />
40oc/75% RH, 3month.<br />
40oc/75% RH, 6 month.<br />
Graph - 4 In vitro drug release data <strong>of</strong> stabilised formulation<br />
Volume 3, Issue 3, May − June 2013<br />
70 | P a g e<br />
http://www.ijpi.org