floating drug delivery system (RITONAVIR TABLET)

1. By
FOUZEEN KOUSAR 14S61R0050
SYEDA IFFATH QUADRI 14S61R0056
MIR WARID ALI 14S61R0070
SYEDA AYESHA SIDDIQUA 14S61R0083
WAJAHAT AHMED 15S65R0003
Under the joint guidance of
Dr. A. Venkateshwar Reddy Mr. Kanhu Charan Panda
M.Pharm., Ph.D, FICCP M. Pharm. [Ph.D.], FICCP.
Anwarul Uloom College of pharmacy, Mallepally, Hyderabad, A.P.
2018
FORMULATION, DESIGN AND IN VITRO EVALUATION
OF RITONAVIR FLOATING TABLETS
1

2. TOPIC S
INTRODUCTION
OBJECTIVE OF WORK
LITERATURE REVIEW
PLAN OF WORK
DRUG AND POLYMER PROFILE
EXPERIMENTAL
RESULTS AND DISCUSSION
SUMMARY AND CONCLUSION
REFERENCES
2

3. 3

4. FLOATING DRUG DELIVERY SYSTEMS (FDDS): Are aimed to retain the drug in the
stomach and are useful for drugs that are poorly soluble or unstable in intestinal fluids.
These systems have a particular advantage that they can be retained in the stomach and assist in
improving the oral sustained delivery of drugs that have an absorption window in a particular region
of the GIT.
Enalapril is an Angiotensin-converting-enzyme (ACE) inhibitor used in the treatment of hypertension,
diabetic nephropathy, and some types of chronic heart failure. ACE converts the peptide hormone
Angiotensin I to angiotensin II
ENALAPRIL MALEATE
4

5. 5

6. Ritonavir is a antiviral drug appears to undergo first pass
metabolism and it has short half life 3-5hrs
The objective of present investigation is to formulate
and evaluate Ritonavir floating tablets to prolong the
release rate based on gel forming control release
polymers using HPMC K4M, HPMC K 15M, Eudragit
RSPO and ethyl cellulose which will help to retain the
dosage form in the stomach and sodium bicarbonate used
as gas generating agent.
The prepared tablets were evaluated for the
physicochemical parameters such as weight
variation, thickness, friability, hardness, swelling
index ,drug content, in vitro buoyancy studies & in
vitro dissolution studies.
6

7. 7

8. SI. No Author(S) Year Drug Polymers Used Method Used Conclusion
1. Bhaswat
Chakraborty et al
(2013)
Enalapril maleate Hydroxyl propyl
methylcellulose (HPMC K
4M).K15 M
To evaluate the sustained
release matrix tablets of
enalapril maleate by wet
granulation method
The results indicated that the drug
release characteristics from HPMC
polymer matrices follow Higuchi
square root time kinetics and the
mechanism of drug release was both
diffusion and erosion.
2. Azar.Z.F et al (2013) Captopril HPMC K4M,carbomer
934,eudragit rspo as release
retarding polymer, lactose as
filler, sodium bicarbonate
as a gas former by direct
compression
The purpose of this study was
to develop a gastro retentive
controlled release drug
delivery system with swelling
and floating properties.
Statistical analyses of data revealed
that formulation containing HPMC
K4M (42%, w/w), NaHCO3 (8%,
w/w) and Avicel PH 102 (32.35%,
w/w) was the promising system
exhibiting excellent floating
properties and sustained drug release
(12 h) characteristics
3. Ankush Sharma et al
(2011)
Enalapril
Maleate
HPMC, sodium bicarbonate this paper demonstrates
the stability studies of
Enalapril Maleate.
The results observed from the
stability during the storage of
Enalapril Maleate tablets give better
result with alkali compounds e.g.
sodium bicarbonate
4. R. Thakur et al
(2012)
Enalapril
maleate
Hydrophilic polymer
Hydroxy propyl methyl
cellulose (HPMC) with
sodium bicarbonate
oral floating system for
Enalapril maleate with the
objective to enhance the oral
bioavailability of the drug
Among all the formulations, B1F6
showed maximum R2 value i.e.
0.9789 which insured uniform
release profile as compared to other
formulations.
5. Ajay Kumar B et al
(2012)
Enalapril maleate HPMC K15M and sodium
bicarbonate. (NaHCO3) and
citric acid
Enalapril maleate loaded
microspheres to achieve
sustained release action of
Enalapril maleate which is
used in treatment of
hypertension disorder.
The Enalapril maleate microspheres
prepared under optimized conditions
showed good sustained release
characteristics and were stable under
conditions studied
8
Table :1

9. 6
Muthadi Radhika et
al (2013)
Enalapril
maleate
carbopol 934p,HPMC
K15,HPMC K100
was to design oral
controlled release
mucoadhesive tablets
of enalapril maleate by
direct compression
method.
All the formulation followed non-
fickian release mechanism.
Carbopol 934p and HPMC K100
in the ratio of 1:1.5 could be used
to design effective and stable
buccoadhesive tablets maleate
7 Abbas Z et al
(2012)
Enalapril
maleate
crospovidone and sodium
starch glycolate Oral dispersible
tablets of Enalapril
maleate
From the results, it could be
concluded that the
formulation(F-VII) made with
co processed super
disintegrants (1:1) at a
concentration of 5% w/w
revealing a disintegrating time
of 13.2 sec, and 97.84 %
cumulative drug release
emerged as the best
formulation.
8 Md. Asaduzzaman
et al (2014)
Enalapril
maleate
HPMC 50 cps, HPMC 100
cps, HPMC K4M, HPMC
K15M, HPMC K100M,
xanthan gum, carbopol 971
and sodium CMC
Pulsatile drug
delivery of enalapril
maleate preparation
of cross linked hard
gelatin capsules
using formaldehyde
Prepared formulations were
subjected to evaluation of
various physical parameters
and in vitro drug release studies
showed 80% drug release in 8
hours
9
Table :2

10. 10

11.  Design of floating matrix formulation by using wet granulation techniques method using polymers like hydroxy
propyl methyl cellulose, Eudragit rspo & rlpo. sodium bicarbonate, citric acid, carbopol 934p, microcrystalline
cellulose, magnesium stearate, talc
 Evaluation of pre compression parameters
of the formulation:
Angle of repose
Bulk density
Tapped density
% compressibility index
Hausner’s ratio.
 Evaluation of post compression
parameters:
Tablet hardness test,
Friability test,
Weight variation test,
Drug content uniformity,
In vitro buoyancy studies
Swelling index study
In vitro dissolution time
Stability studies
. Characterization of prepared Enalapril maleate tablet:
Fourier Transform Infrared Spectroscopy (FT-IR).
Differential Scanning Calorimetry (DSC).
Assessment of the best
11

12. 12

13.  Ritonavir is an Antiretroviral medicine. It is prescribed for Human
Immunodeficiency Virus HIV Infection.
 Structure
 Mechanism of Action: Ritonavir was originally developed as an inhibitor of HIV
protease. It is one of the most complex inhibitors. It is now rarely used for its own
antiviral activity, but remains widely used as booster of other protease inhibitors.
 Protein Binding : Highly Protein-bound, 98-99%
 Metabolism: Highly metabolized by Cytochrome P450-mediated pathways.
 Half life : 3-5hrs
 Dose and dosage form: tablet 100 mg twice daily, maximum 600 mg BD.

13

14. Polymer profile:
 HYDROXY PROPYL METHYL CELLULOSE:
 Synonyms : HPMC, cellulose hydroxyl propyl methyl ether
 Description : Hypromellose is a solid, white amorphous powder, with no odour and taste
 Functional Categories : lubricant, emulsion stabilizer and gelling agent
 Solubility : Insoluble in anhydrous ethanol ,ethyl ether and acetone
 Applications :
 Use in whole grain breads
 Ophthalmic applications
 Use in construction materials
 Used in food, pharmaceutical and cosmetics
14

15. 
 Eudragit Rspo:
 Synonyms: Eastacryl 30D , Kollicoat MAE 30D, Kollicoat MAE
 Description: EUDRAGIT® RS PO is a copolymer of ethyl acrylate, methyl methacrylate and a low content of
methacrylic acid ester with quaternary ammonium groups. The ammonium groups are present as salts and make the
polymers permeable.

Functional Categories: Film former, tablet binder, controlled release polymer
Applications : Polymethatesaracryl primarily used in oral capsule and tablet formulation as film-coating agents
15

16.  SODIUM BICARBONATE:
 Synonyms: Baking Soda, Sodium Acid Carbonate, Sodium Hydrogen carbonate, Bicarbonate of Soda.
 Functional Category : Cleaning, deodorizing agent and leavening agent
 Description: Odourless white crystals
 Application :
 Used as cleaning agent in fridges, garbage disposals etc.
 Water softner –use in washing machines and for washing dishes
 In the kitchen used as baking agent and in cooking it quickly softens
16

17.  MICROCRYSTALLINE CELLULOSE:
 Nonproprietary Name : Microcrystalline cellulose,USP: Microcrystalline cellulose.
 Synonyms : Cellulose gel, crystalline cellulose, Avicel PH 101, 102
 Functional Category : Tablet and capsule diluent, tablet disintegrant, suspending and/or viscosity increasing agent.
 Chemical Name : Cellulose
 Application: Tablet binder / diluents (wet or dry granulation)- 5 to 20%,tablet disintegrant- 5 to 15% Tablet glidant- 5
to 15%, Anti-adherent- 5 to 20%
 LACTOSE:
 Synonyms: Cellulose, Glucose
 Functional Category: Bulking agent
17

18. MAGNESIUM STEARATE:
 Synonyms: Metallic stearic; Magnesium salt.
 Functional Category: Tablet and Capsule Lubricant.
 Safety : Described as inert or nuisance dust. Dust clouds of magnesium stearate may be explosive.
However, oral consumption of large quantities may result in some laxative effect or mucosal irritation.
 Application: Tablet and capsule lubricant, glidant and antiadherent in the concentration range of
0.25 to 2.0%.
 TALC:
 Nonproprietary Name: USAN: Talc.
 Functional Category : Anticaking agent, Glazing agent, Thickener.
 Chemical Name: Magnesium Silicate, Hydrated Magnesium Silicate.
 Application: It is used in industrial applications because of its lamellar platy nature, softness, whiteness,
hydrophobic features, chemical inertness, and absorption features
18

19. 19

20.  Procedure for direct compression method
20

21. 21
Accurately
weigh quantity
of Ritonavir,
polymers
(HPMC K4M,
HPMC K15
M, Eudragit),
binder PVP
K30 and blend
it in mortar
and pestle.
Then add
sodium
bicarbon
ate
Make up
the total
weight of
tablet by
lactose/mc
c as diluent
Allow it to
pass
through
sieve no 60
then re -
triturate it.
To this
required
amount of
talc and
magnesiu
m stearate
is added .
Then
finally
compresse
d to a
tablet in a
tablet
punching
machine.

22. 22
FORMULATION CHART OF RITONAVIR
FLOATING TABLETS
F1 F2 F3 F4
RITONOVIR 100mg 100mg 100mg 100mg
PVP K-30 2 2 4 4
MCC 50 29 43 20
LACTOSE 20 30 20 30
SOD BICARBONATE 5 5 8.0 10.0
HPMC K-15M 10 20 - -
HPMC K-4M - - 10 20
EUDRAGIT 5 6 7.0 8.0
ETHYL CELLULOSE 5 5 5 5
MAGNESIUM STERATE 2 2 2 2
TALC 1 1 1 1
TOTAL WT OF THE
TABLETS.
200 200 200 200

23. 23
CALIBRATION CURVE OF RITONAVIR
Determination of max
The UV spectrophotometer was set to auto zero and the standard solution was scanned to obtain the
maximum wavelength absorption against blank between wavelength of 200-400nm. The standard solution
was scanned for absorbance maxima against blank. The maximum absorbance was found to be 239 nm in pH
1.2 0.1 Hydrochloric acid buffer which was fixed as a wavelength for Drug analysis.
Procedure for calibration curve:
20 milligrams Ritonavir of was accurately weighed and dissolved in 50 ml of pH 0.1N Hydrochloric acid
buffer to make 400ppm. From this 5,10,15,20 ppm aliquots were prepared and the absorbance was measured
at max of 239nm which follow linearity and obeys Beer-Lambert’s law.
Concentration
(μg/ml)
Absorbance at 239 nm
(mean ± SD)
2 0.551
4 0.675
6 0.946
8 1.45
10 1.26
0
0.5
1
1.5
0 10 20 30 40
ABSORBANCEAT204NM
CONCENTRATION AT PPM
Calibration curve of Ritonavir at
λmax = 239nm in pH 0.1N Hydrochloric acid
buffer
Series1
Y=0.032X+0.15
5
R²=0.999

24.  1. Angle of Repose :
 Angle of repose was determined by fixed
height method to characterize the flow
property of powder. It is calculated from the
average radius using the following formula.
θ = tan1 (h/r}
Where,
θ = Angle of repose.
h = Height of the pile.
r = Average radius of the powder cone e radius of
the powder cone was measured.
 2. Bulk Density
Bulk density of determined by The volume
occupied by the sample in graduated cylinder.
is recorded. Bulk density was calculated.
Bulk density (g/ml) = weight of sample
volume occupied by the sample
 3. Tapped Density
The tapped density was determined by
Volume occupied by the sample after tapping
was recorded
Tapped density [g/ml] = weight of sample
volume of sample occupied
 4. Compressibility (% )
It is also one of the sample methods to
evaluate flow property of a powder by
comparing the bulk density and tapped
density. A useful empirical guide in given by
the Carr’s index
Carr’s Index = taped density- bulk density x 100
taped density
 5. Hausner ratio
It provides an indication of the degree of
densification which could result from vibration
of feed hopper.
Hausner ratio = taped density/ bulk density
24

25. 1. Weight Variation
 It was determined as per IP 1996. Twenty
tablets were selected randomly from each
formulation, weighed individually and the
average weight and % variation of tablet
weight was calculated.
 2. Friability
 Twenty tablets were weighed and placed in
the Roche friabilator test apparatus, the
tablets were exposed to rolling and repeated
shocks, resulting from free falls within the
apparatus. After 100 revolutions, the tablets
were dedusted and weighted again. The
friability was determined as the percentage
loss in weight of the tablets.
Friability (%)
 3. Hardness
 Hardness of tablets were measured using the
Monsanto hardness tester.
 4. Drug Content
 Weigh accurately the powder equivalent to 100mg of
verapamil hydrochloride and it was shaken with
150ml of 0.1M hydrochloric acid to produce 200 ml
volume. From this 10ml of the filtrate was collected
and it was diluted to 100 ml with distilled water and
the absorbance was measured at 278nm
spectrophotometrically.
 In vitro Buoyancy Studies
 The buoyancy studies were performed by placing the
tablet in a 250 ml glass beaker, containing 200 ml of
0.1N HCl with tween-20 (0.02% w/v), pH 1.2,
maintained at 37 ± 0.5°C in a water bath. Their
physicalstate was observed for 24 h. The time
between introduction of the dosage form and its
buoyancy on the 0.1N HCl (buoyancy lag time) and
the time during which the dosage form remains
buoyant (total buoyancy time) were determined
visually.
= 100
testbeforetabletsofWeight
after testtabletsofWeight
1 






25

26.  Swelling study
 Gastro retentive tablet was weighed
individually (W1) and placed separately
in glass beaker Containing 200 ml of 0.1N
HCl and incubated at 37ºC ± 1ºC. At
regular 1h time intervals until 24h, the
tablet was removed from beaker and the
excess surface liquid was removed
carefully using the filter paper. The
swollen tablet was then re-weighed (W2)
and swelling index (SI) was calculated
using the following formula
 SI = (W2 – W1)/W1
 Stability testing.
 Stability studies on the promising formulation
(F6) were carried out by storing the tablets in the
desiccator containing saturated solution of
sodium chloride, which gave a relative humidity
of 75 5%. The desiccator was placed in the hot
air oven maintained at 402ºc for one month. At
intervals of one week, the tablets were visually
examined for any physical changes, and changes
in drug content.
 In-vitro dissolution studies
 The In vitro release rates of verapamil Hcl
floating matrix tablets were determined using
USP type II basket apparatus using 900 ml of
simulated gastric fluid (pH1.2) at 50 rpm and at
a constant temperature of 37±0.50C
26

27. 27

28. 28
Parameters F1 F2 F3 F4
ANGLE OF
REPOSE
23 24 21 24
BULK DENSITY 0.571 0.509 0.427 0.45
TAPPED DENSITY 0.666 0.636 0.47 0.562
HAUSNER’S
RATIO
1.166 1.249 1.10 1.24
COMPARESSIBIL
ITY INDEX
14.26 19.96 9.14 19.92

29. 29
Formul
ation
Batch
Weight
variatio
ns
Hardnes
s
kg/cm2
%friabil
ity
Swelling
Index(%)
Invitro
Lag
time
Buoyancy
Time
(hr)
Drug
content
F1 200±4.5 3.0 0.89 6.7 13sec 22.83 97.23±0.21
F2 200±3.2 3.5 0.78 7.8 15sec 23.74 98.56±0.89
F3 200±1.5 3.0 0.52 12.4 0.4sec 26.48 97.34±0.83
F4 200±1.2 3.5 0.46 92.46 0.9sec 28.42 98.23±0.28

30. 30
At zero time At 1st
h At 6th
h At 12th
h
IN-VITRO BUYONACY STUDIES OF ENALAPRIL MALEATE FLOATING
MATRIX TABLET OF FORMULATION F4

31. 31
Photographs showing swelling of floating tablet formulation F4
in pH 0.1N HCl buffer

32. COMPARATIVE DISSOLUTION PROFILES OF FORMULATIONS F1 TO F4
32
Time in
(hours)
% CDR
F1 F2 F3 F4
1 12.31 11.46 9.82 6.86
2 18.42 16.53 12.64 10.12
3 21.24 19.42 14.98 12.12
4 29.35 27.33 21.62 17.46
5 38.96 35.42 29.83 24.95
6 56.24 49.81 39.65 32.12
7 68.72 62.36 52.12 49.19
8 79.48 74.89 69.64 65.46
9 98.96 83.69 78.46 76.48
10 98.49 97.84 93.69 95.26
11 98.57 98.63 99.19 98.29
12 98.63 98.74 99.09 99.46

33. 33
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14
%CDR
TIME IN HR
IN VITRO DRUG RELEASE STUDY FROM
FORMUALTION F1 TO F4
F1
F2
F3
F4

34. FT-IR-spectroscopy:
34
Figure: FTIR spectra of Ritonavir Figure: FTIR of optimized
formulation F4

35. 35
DIFFERENTIAL SCANNING CALORIMETRY

36. 36
FORMULATION OF RITONAVIR FLOATING MATRIX TABLETS
Ritonavir tablets were prepared by using different polymers and excepients such as HPMC
(K4M),HPMC(K15), ,Eudragit RSPO, microcrystlline cellulose, sodium bicarbonate, magnesium
state and talc. 100 mg of ritonavir drug was taken for the formulation. F1-F4.
COMPATIBILITY STUDIES BY FTIR AND DSC ANALYSIS
From the FTIR and DSC studies it was found that there was no drug and polymer interactions.
PRECOMPRESSION PARAMETER STUDIES
From the studies it was found that powders showed excellent flow properties.
POST COMPRESSION PARAMETER STUDIES
From the studies it was found that all the formulation from F1-F4 complying pharmacopoeial
limits.
INVITRO DRUG RELEASE STUDIES
From the studies it was found that the formulation of F4 showed 99.46% of drug release up to
12hrs with a predetermined rate and predictable manner as comparison to other formulations

37. 37

38. 38
 FDDS is a promising approach to achieve in vitro buoyancy.
 The objective of present investigation was to prepare and evaluate floating tablets of
Ritonavir to prolong the release rate.
 Based on gel forming polymers using hydroxyl propyl methyl cellulose K4M , hydroxyl
propyl methyl cellulose K15M, and Eudragit rspo and sodium bicarbonate which will
helped to retain the dosage form in the stomach.
 Tablets were prepared by direct compression technique.
 The pre and post compression parameters were evaluated and found within the acceptable
pharmacopieal limits. Tablets containing gel-forming polymers and gas-generating agent
sodium bicarbonate showed short buoyancy lag time, total floating time more than 12 h.
which was controlled release characteristics.
 From the in vitro drug release study the formulation F4 showed highest 99.46 of drug
release with a predetermined rate and predictable manner among all other formulations up
to 12 h; this may be due to suitable blend of polymers.
 However, further pre-clinical and clinical studies are recommended to assess the utility of
this system for patients suffering from HIV.

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40. 40