3. CLASSIFICATION
HYDRODYNAMICALLY BALANCED
SYSTEMS (HBS)
GAS-GENERATING SYSTEMS
HIGH DENSITY
SYSTEMS MATRIX TABLETS
OILY LIQUID / V
ACUUM CONTAINING
SYSTEMS
FLOATING SYSTEMS
(LOW DENSITY SYSTEMS)
RAFT-FORMING SYSTEMS
HOLLOW MICROSPHERES / BALLOONS
ALGINATE/PECTINATE BEADS
SWELLING SYSTEMS
EXPANDING
SYSTEMS
UNFOLDABLE SYSTEMS
BIO/MUCOADHESIVE
SYSTEM
GRDDS
APPROACHES
3
4. High density systems
Gastric contents have a density close
to water (~1.004).
A density close to 2.5g cm-3 is
necessary for significant prolongation
of gastric residence time.
The commonly used excipients in
high density system includes barium
sulphate, zinc oxide, iron powder, and
titanium dioxide.
The major drawback with such
systems is that it is technically difficult
to manufacture them with a large
amount of drug (>50%) and to achieve
the required density of 2.4-2.8g/cm3. 4
5. B) Floating approach
(Low density approach)
Widely used approach
These have a bulk
density lower than the
gastric content
They remain buoyant in
the stomach for a
prolonged period of time,
with the potential for
continuous release of
drug
5
6. Floating Approach Include:
1. Hydrodynamically balanced systems (HBS)
2. Gas-generating systems
3. Matrix Tablets
4. Oil Liquid/vacuum containing systems
5. Raft-forming systems
6. Hollow Microspheres / Balloons
7. Alginate/Pectinate Beads 6
7. 1. HYDRODYNAMICALLY BALANCED SYSYTEMS
Prepared by incorporating a high level (20-75%w/w) gel-
forming hydrocolloids. E.g.:- Hydoxyethylcellulose,
hydroxypropylcellulose, HPMC & Sod. CMC into the
formulation and then compressing these granules into a
tablets or capsules.g
It maintains the bulk density less than 1.
7
9. 2.
GAS GENERATING SYSTEMS
Carbonates or bicarbonates, which react with
gastric acid or any other acid (e.g., citric or
tartaric) present in the formulation to produce
CO2 , are usually incorporated in the dosage
form, thus reducing the density of the system
and making it float on the media
9
10. 3. MATRIX TABLETS
Single layer matrix tablet is prepared by
incorporating bicarbonates in matrix forming
hydrocolloid gelling agent like HPMC, chitosan,
alginate or other polymers and drug.
Bilayer tablet can also be prepared by gas
generating matrix in one layer and second layer
drug for its SR effect.
with
Triple layer tablet also
swellable floating layer
sustained release layer
prepared having first
with bicarbonates, second
of drug and third rapid
dissolving layer 10
11. 4. Oily Liquid/vacuum containing systems
Mix
Here, air is entrapped in Agar gel
Escape of air is prevented by oil
The tablet contains 2% agar
Warm Agar gel solution
Cool
Pour in a
tablet mould
Drug + Mineral Oil
11
12. raft
5. Raft Forming Systems
The mechanism involved in this
system includes the formation
of a viscous cohesive gel in
contact with gastric fluids,
forming a continuous layer called
raft
Raft systems incorporate
alginate Gels which have
carbonate Component.
Generally, it is used for antacids
and Heart Burn (GERD)
E.G. Liquid Gaviscon
RAFT
12
14. Hollow sphere
Preparation technique (emulsion-solvent
diffusion method)
Process
Formation Formation Generation of
Microballoon
of emulsion of shell gas phase
Mechanism
Rapid diffusion Evaporation and of
EtOH diffusion of CH2Cl2
Current Opinion in Pharmacology
14
15. 7. Calcium alginate/Pectinate beads
Sodium alginate
solution
Calcium Chloride solution
Spherical gel beads
Separate and freeze dry
Calcium
Calcium
Calcium
Pectinate gel beads
Alginate Pectinate Gel beads
Alginate + Chitosan gel beads
IONOTROPIC GELATION METHOD
15
17. Highly porous
Large pore volume
Low inherent density
Granules containing
Drug, HPMC and Calcium
Silicate.
Hydrophobic Lipid
Diff. Grades –
39/01, 43/01
Low Inherent
Density
Melt Granulation
Suitable for SR of
Highly Soluble Drug
GELUCIRE® Granules
Calcium Silicate as
floating carrier
17
18. OIL ENTRAPPED GEL BEADS
Oil – Light weight and Hydrophobic
Pectin has some Emulsification property
Aqueous
Solution of
Pectin
mix
Emulsion
Edible
Veg. OIL
Add
to
Calcium
Chloride
Solution
19. C) Expandable Systems
Also called ‘ PLUG
SYSTEM’
Size of the formulation
is more than Pyloric
sphincter
It should expand for
gastric retention
Should be Collapsed
after lag time
19
22. 4
The basis of mucoadhesion is that
a dosage form can stick to the
mucosal surface by different
mechanisms.
Examples of Materials commonly
used for bioadhesion are
poly(acrylic acid) (Carbopol®,
polycarbophil), chitosan, Gantrez®
(Polymethyl vinyl ether/maleic
anhydride copolymers),
cholestyramine, tragacanth,
sodium alginate
D) Bio/Muco adhesive Systems
22
23. Here, the drug is incorporated with bio/Muco-
adhesive agents, enabling the Device to adhere to the
stomach walls, thus resisting gastric emptying
However, the mucus on the walls of the Stomach is in
a state of constant renewal, resulting in
unpredictable adherence.
Thus, this approach is not widely used.
23
25. •
•
•
Hydration-mediated adhesion
Bonding-mediated adhesion
Receptor-mediated adhesion
• Rapid removal of mucus
• We are not sure weather the DF will adhere
to the mucus or epithelial cell layer
• DF may adhere to esophagus resulting in
drug induced injuries
Problem of muco adhesive system:
Mechanism of bioadhesion:
25
26. Evaluation of GRDDS
• Total Floating Time
• Resultant Weight
• Bioadhesion
• Buoyancy/Floating Lag time
• Specific Gravity/ Density
• Swelling Index
• Raft Strength
• Appearance
• Hardness
• Friability
• Drug Content
• Content Uniformity
• Weight Variation
• Drug Release
Tests for Gstroretention
Routine Tests
26
27. 1) For floating system
• Buoyancy/Floating Lag Time (FLT)
It is determined in order to assess the time taken
by the dosage form
dissolution medium,
medium
Total Floating Time
The time for which
to float on the top of the
after it is placed in the
• (TFT)
the dosage form continuously
floats on the dissolution media is termed as total
floating time
These tests are usually performed in Simulated
oC
Gastric Fluid (SGF) maintained at 37
These tests can be performed as a part of
dissolution test
27
28. 1) For floating system
• Specific
Density
method
Gravity/Density
can be determined by the displacement
using Benzene as displacement medium
• Resultant Weight
Only single determination of density is not
sufficient to describe the buoyancy because
density changes with change in resultant weight
as a function of time
For E.g. matrix tablet with bicarbonate and
matrixing polymer floats initially by gas
generation but after some time, some drug is
released and simultaneously some outer part of
28
29. 1) For floating system
The magnitude and direction of force/resultant
weight (up or down) is corresponding to its
buoyancy force (Fbuoy) and gravity force (Fgrav)
acting on dosage form
F = Fbuoy - Fgrav = Df g V- Ds g V = (Df -Ds) g V
Where, F = Resultant weight of dosage form
Df = Density of Fluid
Ds = Density of Dosage Form
= M/V = Mass of DF/ Volume of DF
g = Gravitational Force
So when Ds is lower, F force is +ve giving buoyancy
and when it is higher, F will be –ve showing sinking
29
30. 2) For Bio/muco-adhesive system
The bioadhesive strength of a polymer can
determined by…
be
Measuring the force required to separate
polymer specimen sandwiched between the
of either an artificial (e.g., cellophane) or
the
layers
biological (e.g., rabbit stomach tissue) membrane
This force can be measured by using modified
precision balance or an automated texture
analyzer and recorded in gram force/unit area
30
32. 3) For swelling system
Swelling Index
After immersion of swelling dosage form into SFG at 37 oC,
dosage form is removed out at regular time intervals and
dimensional changes are measured in terms of increase in
tablet thickness/diameter with time
Water uptake / Weight gain (WU)
It is indirect measure of swelling property
Dosage form is removed out at regular time intervals and
weight changes are determined with respect to time
WU = (Wt – Wo) * 100 / Wo
Where, Wt = Weight of DF at time t
Wo = Initial weight of DF at time zero
32
34. 4) For Raft Forming System
Raft strength measurement
A tablet powder/ liquid equivalent to unit dose is
transferred to 150 mL of 0.1 N HCl maintained at 37°C
in a 250 mL glass beaker
Raft is allowed to form around an L-shaped wire probe
(diameter: 1.2 mm) held upright in the beaker
throughout the whole period (30
development
Raft strength is estimated using
method
Water is added drop wise to the
min) of raft
the modified balance
pan and the weight of
water required to break the raft is recorded
34
35. 4) For Raft Forming System
A double pan
dispensing
balance is
modified for
raft strength
measurement
One pan of the
dispensing
balance is
replaced with
an L-shaped
wire probe
35
36. In Vitro dissolution test is generally done by using USP
apparatus with paddle and GRDDS is placed normally as
for other conventional dosage forms in SGF
The drawbacks faced by the conventional USP apparatus
2 for testing floating drug delivery systems are:
The volume of dissolution medium (900 mL) is very high
as compared to stomach content
Adherence of dosage form on the shaft
Problem in sample collection (overdriven arrangement)
The test does not mimic the release of acid from
stomach lining & gastric emptying through pylorus
opening
1.
2.
3.
4.
In Vitro Dissolution
36
37. But sometimes as the vessel is large and
paddles are at bottom, there is much lesser
paddle force acting on floating DF which
generally floats on surface of media
As floating DF does not rotate, may not
give proper & reproducible results
Similar problem occur with swellable DF, as
they are hydrogel may stick to surface of
vessel or paddle and give non-reproducible
results
In Vitro Dissolution
37
38. In order to prevent such problems, various
types of modifications in dissolution
assembly made are as follows:
A) To prevent sticking at vessel or paddle
and to improve movement of DF, method
suggested is to keep paddle at surface and
not too deep inside dissolution medium
B) Floating unit can be made fully
submerged by attaching some small, loose,
non-reactive material such as few turns of
wire helix around dosage form
However this method can inhibit three
dimensional swelling of some dosage form
and also affects drug release
In Vitro Dissolution
38
39. C) Other
unit fully
assembly
modification is to make floating
submerged under ring or mesh
and paddle is just over ring that
gives better force for movement of unit
D) Other method suggests placing DF
between two ring/ meshes
However this method can inhibit three
dimensional swelling of some dosage form
and also affects drug release
E) Another method suggests the change in
dissolution vessel that is indented at some
above place from bottom and mesh is
placed on indented protrusions, giving more
area for movement of DF
In Vitro Dissolution
39
40. In spite of the
various modifications
done to get the
reproducible results,
none of them showed
correlation with the
in vivo conditions
So test apparatus
called Rossett-Rice
test was proposed by
Rossett and Rice
It is used for
antacids and anti
reflux formulations
In Vitro Dissolution
40
41. Novel dissolution test apparatus with Modified Rossett-Rice
test was proposed by Gohel et.al which mimic the in vivo
conditions
In the proposed method, a side arm is provided at the
bottom of the beaker to mimic gastric emptying
phenomenon
The test also tries to simulate the conditions of a flow-
through cell with respect to availability of fresh dissolution
medium around the dosage form
High stirring rate (300 rpm) is used in the Rossett-Rice
test as compared to the current practice of low speed
stirring (50–100 rpm) in the USP paddle apparatus
In Vitro Dissolution
41
42. In short, the modified test tries to mimic the gastric
volume (70 ml), gastric acid secretion rate (2 ml/min) and
emptying of liquid through pylorus opening
In Vitro Dissolution
42
43. Radiology:
X-ray is widely used for examination of internal body
systems
Barium Sulphate is widely used Radio Opaque Marker
So, BaSO4 is incorporated inside the dosage form and
images are taken at various intervals to view GRDF
X-ray
Its major advantages as compared to -Scintigraphy are
simplicity and cost
However, use of X-ray experiment in biopharmaceutical
studies involving healthy volunteers
Barium sulphate high concentration: e.g. 40%
Aluminum thread contrast medium can also be used
In Vivo Evaluation
43
44. -Scintigraphy:
A small amount of a stable isotope e.g. Samarium [152Sm] is
compounded into the DF during its preparation
Prior to the study the DF is irradiated in a neutron source
to convert the isotope into a -emitting material e.g. 153Sm
99Tc
Widely used emitting material is Technetium
In Vivo Evaluation
44
45. Gastroscopy:
It is generally used for diagnosis purpose
Used with fiber optic or video systems
No adverse effect
and endoscopy
Magnetic Marker Monitoring:
Magnetically marked DF by magnetic source
Therefore require very sensitive biomagnetic
instrument
No radiation
Completely safe
measurement
In Vivo Evaluation
45
46. Brand Name Drug (dose) Company
Madopar® Levodopa (100 mg),
Benserazide (25 mg)
Roche, USA
Valrelease® Diazepam (15 mg)
Hoffman LaRoche,
USA
Liquid Gaviscon® Al(OH)3 + MgCO3
GlaxoSmithKlein,
India
Topalkan® Liquid Al – Mg antacid
Pierre Fabre Drug,
France
Almagate
Flotcoat® Al – Mg antacid
Conviron® Ferrous sulfate Ranbaxy, India
Cifran OD® Ciprofloxacin (1 g) Ranbaxy, India
Cytotec® Misoprostal (100/200 g) Pharmacia, USA
46
47. o S. P. Vyas, Roop K. Khar, CONTROLLED
DRUG DELIVERY – Concepts &
Advances, Vallabh Prakashan, Page
No. 196-217
o N. K. Jain, Progress in Controlled &
Novel Drug Delivery Systems, 1st
edition 2004, CBS Publishers, Page No.
76-97
o D. M. Patel, D. G. Patel, C. N. Patel.
Formulation and Optimization of
Raft Forming Chewable Tablet
Containing Lafutidine. International
Journal of Pharmaceutical Sciences
and Drug Research 2015, 7(3), Page
No: 229-234
REFERENCE
47
48. GTU QUESTIONS
• What type of drug is suitable for GRDDS and mention merits and
demerits of GRDDS.
• Explain in vivo evaluation method for GRDDS.
• Gives the different approaches for GRDDS.
• Discuss evaluation parameters for GRDDS.
• Discuss the non effervescent type of floating systems.
• Explain expandable systems in detail.
48
