DESIGN AND ASSESSMENT OF COLON SPECIFIC DRUG DELIVERY OF CELECOXIB USING PULSINCAP TECHNIQUE
DESIGN AND ASSESSMENT OF COLON SPECIFIC DRUG
DELIVERY OF CELECOXIB USING PULSINCAP TECHNIQUE
Dissertation submitted to
Jawaharlal Nehru Technological University,
Regd. No. (11421S0304)
M. Pharm (Pharmaceutics) IInd year
Under the guidance of
Mr. RAJESH KAZA, M. Pharm., (Ph.D.)
Dept. of pharmaceutics
SRI PADMAVATHI SCHOOL OF PHARMACY
MOHAN GARDENS, TIRUCHANOOR, TIRUPATHI-517503
PULSATILE DRUG DELIVERY SYSTEM
Pulsatile drug delivery system delivers drug in a rapid and burst manner within a
short time period immediately after a programmable lag phase.
Pulsatile drug delivery aims to release drug in a programmed pattern i.e., at
appropriate time and appropriate site of action.
Drug release profile of pulsatile drug delivery system
A: Ideal sigmoidal release
B and C: Delayed release after a lag time
No risk of
Drug adapts to
Rheumatoid arthritis is an autoimmune disorder in
which various joints in the body are inflamed which
leads to swelling, pain, morning stiffness and severe
pain at joints.
It is a chronic disease which initially attacks the
synovium, a connective tissue membrane that lines the
capsule around joints and secretes a lubricating fluid.
In rheumatoid arthritis, an abnormal immune system
response produces destructive molecules that causes
continuous inflammation to the synovium and thereby
narrowing the joint space and eventually damaging the
ETIOLOGY OF RHEUMATOID ARTHRITIS
Treatment FOR RHEUMATOID ARTHRITIS
• Joint replacement surgery
• Unicondylar knee arthroplasty
• Regular exercise
• Managing psychological and
• Mineral baths (Balneotherapy)
• Proper dietary intake
Punitha et al., (2009) have worked on increasing the solubility of poorly water soluble drug celecoxib with solid dispersion
technique using urea as water soluble carrier by physical mixture, solvent evaporation and fusion method. Solid dispersions
were prepared by using 1:1, 1:3 and 1:5 ratios of drug and polymer respectively. The dissolution studies were carried out
using USP paddle type dissolution apparatus. Solid dispersion of drug and polymer in 1:5 ratio prepared by fusion method
showed faster dissolution rate i.e., 79.08% when compared to that of other formulations prepared by physical mixture and
solvent evaporation method. The FT-IR studies revealed that no interaction of drug with carrier. Finally solid dispersions of
drug and polymer in 1:5 ratios respectively prepared by fusion method showed excellent physicochemical characteristics and
was found to be described by first order release kinetics.
Ram Mohan Gupta et al., (2011) carried out an experiment to increase the solubility and dissolution rate of celecoxib by
preparing the spherical crystals of celecoxib using polymers like polyethylene glycol 4000, sodium carboxy methylcellulose,
sodium alginate and polyvinyl pyrrolidone K30 in different ratios i.e., 1:1, 1:2, 1:3 and 1:4 respectively. All the formulations
were characterized for micromeritic properties. FT-IR spectra and differential scanning calorimetry studies revealed that
compatibility between drug and polymer. X-ray diffraction studies revealed the occurrence of decrease in crystallinity of
spherical agglomerates of celecoxib. From the results of dissolution study, spherical agglomerates of celecoxib prepared with
polyvinyl pyrrolidone K30 in 1:4 ratio respectively showed maximum drug release when compared to that of pure drug and
other batches of spherical agglomerates.
Gohel et al., (2002) studied a programmed drug delivery of ketoprofen from hard gelatin capsules containing a hydrophilic
plug made up of polymers like HPMC K15M or guar gum. The significance of factors such as plug thickness and the
formulation of fill material on the release pattern of diltiazem hydrochloride were investigated. In order to accelerate the drug
release after a lag time of 4 hrs, an effervescent blend, sodium bicarbonate and citric acid in the capsules were added. The
plugs of HPMC K15M in tablet form, were used for obtaining immediate drug release after lag time. The results indicated
that the drug release was dependent on the type of swellable hydrophilic agent, HPMC K15M or guar gum for achieving
predetermined lag time.
Putta Rajesh Kumar et al., (2012) developed the pulsatile drug delivery system for verapamil hydrochloride to release the
drug after a predictable lag time. The verapamil hydrochloride pulsincaps were prepared by physical mixture with lactose by
varying drug to polymer ratio and evaluated for percentage yield, drug content, IR and in vitro drug release studies. Sodium
alginate and xanthan gum were used as hydrogel plugs to maintain a suitable lag period. The in vitro drug release studies
were carried out by using buffer of pH 1.2 for a period of 2 hrs, phosphate buffer of pH 7.4 for a period of 4 hrs and
phosphate buffer of pH 6.8 for a period of 6 hrs simultaneously. Results showed that the optimized formulation containing
guar gum as hydrogel plug releases 94.5% of drug at 12 hrs with 4 hrs lag time. Thus programmable pulsatile drug release
has been achieved from optimized formulation over a period of 12 hrs and is consistent with the demands of pulsincap drug
AIM OF the WORK
The aim of present work is to
improve the solubility of celecoxib
by rapid solvent change method and
the prepared microcrystals were
used for the development of
pulsatile drug delivery using
OBJECTIVEs OF THE WORK
• To enhance the solubility of celecoxib by rapid solvent change method .
• To synchronize the drug delivery to the circadian rhythms of rheumatoid arthritis.
• To provide maximum drug release when sharp increase of symptoms of rheumatoid arthritis occurs .
• To bypass the gastric degradation and first pass metabolism of drug.
• To minimize the frequency of drug administration
• To improve the patient compliance.
• Category: Selective COX-2
• Bioavailability: 25-30%
• Half life: 7.5-8 hrs
• Solubility: It is freely
ethanol, PEG 400, DMSO
and acetone. It is poorly
soluble in water and nonpolar hydrocarbons.
• Melting point: 1571580C
• Dose: 100-200 mg
Used for the
NAME OF THE
Tablet binder and
In colonic drug delivery
Used in cosmetics, food
Tablet film former in
aqueous film coating.
Carrier to increase the
viscosity of solutions.
Osmolarity regulator for
Tablet binder and
NAME OF THE
HPMC K100 M
Controlled release agent
Sustained release agent
Tablet and capsule
Dry powder inhaler
Used in oral, ophthalmic,
nasal and topical pharmaceutical formulations.
Suspending agent in
topical gels and ointments
Tablet and capsule diluent
PLAN OF WORK
• Preparation of
• Preparation of
• Evaluation of
• Preparation of
• Evaluation of
• Preformulation studies for drug
• Drug-excipient compatibility
studies by FT-IR
Preparation of celecoxib microcrystals BY
RAPID SOLVENT CHANGE METHOD
Drying at 500C
for 1 hr
EVALUATION OF microcrystals
CHARACTERIZATION OF microcrystals
Preparation of celecoxib pulsincaps
Separation of cap and
bodies of capsules.
Treatment of capsule
bodies with 15% v/v
for 12 hrs in dessicator.
Drying for a period of
3 hrs at 50 C.
ratios (1:1, 1:2, 1:3
and 1:4) of HPMC
and guar gum
Subject to direct
using 6 mm punches
and dies on rotary
Sealing and coating
200mg of optimized
Joint of capsule body and
cap was sealed with a
small amount of 3% ethyl
To this, add
of sodium starch
Coating of capsules with
3% ethyl cellulose
ethanolic solution by dip
Filling of above
mixture in capsule
Coating was repeated until
8-12% increase in total
weight of capsule was
Composition of pulsincaps
Weight taken (per capsule)
Optimized microcrystal formulation (mg)
Equivalent to 200 mg of drug (w/w)
Sodium starch glycolate (mg)
Quantity sufficient (q.s)
Total weight (mg)
Composition of different formulations of hydrogel plug
Guar gum (mg)
Total weight (mg)
evaluATION OF pulsincaps
In vitro drug
EVALUATION OF hydrogel plugs
RESULTS AND DISCUSSION
Standard curve of celecoxib
Preformulation studies of celecoxib
• White crystalline
Drug-excipient compatibility study by FT-IR .
Same peaks of N-H, C-N, C-F and S=O bonds were present as that of pure
drug without much shifting in the spectra of celecoxib microcrystals suggested
that no chemical interaction between the drug and stabilizing agent.
Dissolution profile of celecoxib microcrystals
From the results, it was revealed that the enhancement in the dissolution rate
of microcrystals occurs due the presence of stabilizing agent, which has the ability
to reduce the crystallinity of drug by adsorption onto the specific faces of the
growing crystal surface of crystalline drug which results in the passage of solvent
towards the faces and interiors of drug particles and leads to increased solubility
and subsequent dissolution.
From DSC thermograms, the melting point of pure celecoxib,
microcrystals containing guar gum, maltodextrin and PVP K30 showed a
sharp melting endothermic peak at 170.01, 163.08, 161.70 and 162.370C
Melting endotherm is not appreciably changed in celecoxib
microcrystals prepared in the presence of hydrophilic stabilizing agents
i.e., guar gum, maltodextrin and PVP K30 but with a slight reduction that
did not seem to be significant.
This observation confirmed the absence of chemical interaction of drug
with stabilizing agents during crystallization process.
Characteristic peaks appeared in the XRD for celecoxib showed sharp
intensity peaks at 2θ values of 10, 22, 27, 29, 31, 36, 41, 46, 49, 54 and 74.
In case of celecoxib microcrystals containing guar gum, sharp intensity
peaks were exhibited at 25, 31, 36, 39 and 46. In case of celecoxib
microcrystals containing maltodextrin, sharp intensity peaks were exhibited
at 41, 53, 59 and 74. In case of celecoxib microcrystals containing PVP K30,
sharp intensity peaks were exhibited at 31, 41, 49 and 74.
The lack of numerous distinctive peaks of the drug in case of celecoxib
microcrystals indicates the reduced crystallinity when compared to that of
This may be due to partial conversion of the drug to amorphous state from
crystalline state and thus enhances the solubility
SEM of celecoxib
SEM of celecoxib microcrystals
Microcrystals containing maltodextrin as stabilizing agent at
0.1% w/v concentration with 1:6 ratios of solvent to anti-solvent
(v/v) respectively (F6 formulation) showed small platy crystals
with particle size of 28µm diameter.
From the results, it was observed that the particle size of drug
decreases three folds by rapid solvent change method. This may
be due to face specific adsorption of stabilizing agent alters the
growth rate of the crystal faces where adsorption takes place and
thus changes the morphology of the crystal.
Modification of crystal habit can improve the dissolution rate
by promoting the growth of more hydrophilic faces or inhibiting
the growth of more hydrophobic faces.
Evaluation of celecoxib pulsincaps
Physico-chemical characterization of capsules:
Untreated capsules without
capsules without coating
capsules with coating
Solubility and disintegration time:
Untreated capsules without coating
Whole capsule-≤15 min
Whole capsule-3 min
Formaldehyde treated capsules
Evaluation of hydrogel plugs
Passes the test.
Passes the test.
Passes the test.
Passes the test.
Dissolution profile of celecoxib pulsincap formulations
% Cumulative drug release
Out of four pulsincap formulations prepared (PH1-PH4), PH4
formulation showed highest percentage drug release i.e., 87.89% at the
end of 8th hr and maximum lag time of 6 hrs when compared to other
Lag time profile of celecoxib pulsincap formulations
Lag time (hrs)
Increase in lag time of pulsincap formulation with increased
concentration of guar gum occurs may be due to the presence of high
viscosity for guar gum which further retards the release of drug by
increasing the erosion time of hydrogel plug.
Therefore, in case of PH4 pulsincap formulation, due to the presence of
higher amount of guar gum in hydrogel plug, plug possesses high viscous
nature and takes more time for complete erosion. Hence it maintains a
maximum lag time of 6 hrs when compared to other pulsincap
Celecoxib microcrystals were prepared by rapid solvent change method using guar gum, maltodextrin and
PVP K30 as a hydrophilic stabilizing agents. 1:6 ratio of solvent to antisolvent (methanol/water) and 0.1%
stabilizing agent were optimum parameters for microcrystallization of celecoxib.
The optimized microcrystals were exploited in the development of pulsincaps. Amongst the pulsincap
formulations prepared (PH1-PH4), PH4 formulation containing hydrogel plug made of HPMC and guar
gum in 1:4 ratio respectively was considered as optimized formulation in which percentage drug release
was found to be 87.89% at the end of 8th hour and maximum lag time of 6 hrs when compared to that of
other pulsincap formulations.
The studies have clearly indicated that pulsatile drug release of celecoxib from time dependent pulsincaps
can be helpful for chronomodulated therapy for treating rheumatoid arthritis as well as declining the
frequency of dose administration by preventing the drug from gastric degradation and first pass metabolism.
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