gastroretentive DDS gastroretentive DDS.pptx

GASTRORETENTIVE
DRUG DELIVERY
SYSTEMS
BY
DR SUMANT SAINI
M PHARM PHD

INTRODUCTION
• DEFINITION: Gastroretentive drug delivery
systems (GRDDS) are designed to prolong the
residence of drugs in the stomach.
• SIGNIFICANCE:
• Improved therapeutic efficacy for drugs with
short half-lives or narrow therapeutic windows
• Reduced dosing frequency
• Enhanced patient compliance

GASTROINTESTINAL PHYSIOLOGY
•

GASTRIC EMPTYING:
• FOOD COMPOSITION:
• The type and amount of food ingested can significantly affect
gastric emptying.
• High-fat meals, for example, tend to delay gastric emptying,
while carbohydrates and liquids accelerate it.
• GASTRIC MOTILITY: The contractions of the stomach
muscles, known as peristalsis, propel food into the small
intestine. Factors like stress, medications, and certain diseases
can affect gastric motility and, consequently, gastric
emptying.

GASTRIC EMPTYING:
• HORMONAL REGULATION:
• Hormones such as gastrin, secretin, and cholecystokinin
(CCK) play a role in regulating gastric emptying.
• These hormones are released in response to various
stimuli, including the presence of food in the stomach
and the ph of the intestinal contents.
• DISEASE STATES: Certain diseases, such as
gastroparesis (delayed gastric emptying) and irritable
bowel syndrome (IBS), can disrupt gastric emptying.

• DONE TILL HERE ON 5-08-2025

Factors that can slow down
gastric emptying
Factors that can accelerate
gastric
• High-fat meals
• Fiber-rich foods
• Stress
• Certain medications
• Underlying medical
conditions
• Carbohydrates
• Liquids
• Certain medications
• Underlying medical
conditions

IMPORTANCE OF GASTRIC EMPTYING
TIME AND ITS IMPACT ON DRUG
DELIVERY EFFICACY
• Gastric emptying time (GET) plays a crucial role
in drug delivery and absorption.
• It significantly influences the rate at which drugs
reach the small intestine, where most absorption
occurs.
• Understanding the factors affecting GET and its
impact on drug delivery is essential for optimizing
therapeutic outcomes.

FACTORS AFFECTING GASTRIC
EMPTYING TIME (GET)
• Food composition: The type and amount of food
ingested can significantly influence GET. High-fat
meals, for example, tend to delay gastric emptying,
while carbohydrates and liquids accelerate it.
• Gastric motility: The contractions of the stomach
muscles, known as peristalsis, propel food into the
small intestine. Factors like stress, medications, and
certain diseases can affect gastric motility and,
consequently, GET.

EMPTYING TIME (GET)
• Hormonal regulation: Hormones such as gastrin,
secretin, and cholecystokinin (CCK) play a role in
regulating gastric emptying. These hormones are
released in response to various stimuli, including
the presence of food in the stomach and the pH of
the intestinal contents.
• Disease states: Certain diseases, such as
gastroparesis (delayed gastric emptying) and
irritable bowel syndrome (IBS), can disrupt GET.

EMPTYING TIME (GET)
• Drug absorption: GET directly affects the rate at which
drugs reach the small intestine, where most absorption
occurs. Delayed gastric emptying can lead to delayed
drug absorption, potentially reducing therapeutic
efficacy.
• Drug release: some drug delivery systems, such as
enteric-coated tablets or capsules, are designed to
release their contents in the small intestine. If GET is
delayed, these systems may not function as intended,
resulting in suboptimal drug release.

EMPTYING TIME (GET)
• Drug stability: the acidic environment of the stomach
can degrade certain drugs. Delayed gastric emptying
can increase the exposure of these drugs to the acidic
environment, potentially reducing their stability and
effectiveness.
• Therapeutic outcomes: the overall therapeutic
efficacy of a drug can be influenced by its absorption
rate and the concentration of the drug at its target site.
GET plays a critical role in determining these factors.

EMPTYING TIME (GET)
• Formulation modifications: formulating drugs as
immediate-release or sustained-release
preparations can help to manage the impact of
GET on drug delivery.
• Meal timing: administering drugs at specific times
relative to meals can optimize their absorption
based on the known effects of food on get.

• Drug delivery systems: using drug delivery systems
that can overcome the challenges posed by GET, such
as floating or mucoadhesive systems, can improve
drug absorption and therapeutic efficacy.
• Disease management: addressing underlying
diseases or conditions that affect get can help to
optimize drug delivery and improve patient
outcomes.
EMPTYING TIME (GET)

PHYSICOCHEMICAL FACTORS
Pka of the drug
As per the ph-partition hypothesis, the ionization state of a drug depends on its
dissociation constant and the ph of the fluid at the absorption site. Thus, weakly
acidic drugs (pka 2.5-7.5), which remain unionized in the acidic medium are
predominantly absorbed from the stomach.
Solubility
Most drugs are absorbed by passive diffusion in their unionized form. One of the
prerequisites for passive diffusion is that the drug should be in the solubilized state.
Thus, drugs with higher solubility in the acidic medium are predominantly absorbed
from the stomach.
Stability
The ph of the GI segment affects the stability of many drugs. The degradation of the
drug at a particular site retards its absorption, and hence difference in drug
absorption from various regions in the GI tract is observed. Thus, drugs which are
stable in the acidic medium show their absorption window usually in the stomach

• 6.1.2.4 ENZYMATIC DEGRADATION
• Various enzymes present in the particular GI segment can cause drug
degradation, resulting in regional variability during drug
absorption. Thus, the drugs which are not substrates to the enzymes
present in the stomach are absorbed from gastric region.
• 6.1.3 PHYSIOLOGICAL FACTORS
• 6.1.3.1 MECHANISM OF ABSORPTION
• Absorption of certain drugs can be enhanced by local active and
facilitated transport mechanisms present only at a particular site of GI
tract.
• 6.1.3.2 MICROBIAL DEGRADATION
• Degradation of certain drugs by microflora is also responsible for
regional variability in absorption from the GI tract.

IMPORTANCE OF INCREASED GASTRIC
TRANSIT TIME
•Benefits of prolonged drug residence:
•Increased drug absorption
•Sustained therapeutic levels
•Reduced systemic side effects
•Therapeutic applications:
•Gastrointestinal disorders (e.g., ulcers, gastritis)
•Antibiotic therapy

GASTRORETENTION: DEFINITION AND
MECHANISMS
•Definition: Gastroretention
refers to the retention of a drug
or delivery system in the
stomach for an extended period.

FLOATING SYSTEMS:
UTILIZE LOW-DENSITY MATERIALS TO MAINTAIN BUOYANCY
• In buoyant state in gastric fluids without influencing GRT for extended
periods of time (tamizharasi et al. 2011).
• When the system remains in the flotation state, the drug is released in a slow,
continuous, but controlled fashion (singh et al. 2017).
• After the release of the drug, the residual system gets emptied from the
stomach. This increases GRT, whereby the plasma drug level variability can
be controlled. An FDDS owes its buoyancy either to its lower density than the
stomach contents or due to the gaseous phase formed inside the system after it
comes in contact with the gastric environment (figure 6.6a).
• A floating dds, also known as a hydrodynamically balanced system (hbs),
must comply with three major criteria (bansal et al. 2016b):

NONEFFERVESCENT SYSTEMS
• The floatation of noneffervescent FDDS can be either because of i) low
density due to swelling or ii) inherent low density.
Low density due to swelling
• This type of system involves the admixture of a drug with a gel, which, after
swallowing, swells due to imbibitions of gastric fluid, attaining a bulk density
lower than the outer corona. The entrapped air provides the necessary
floatation to the dosage forms.
• The most commonly used polymers include the gel forming or highly
swellable cellulose type hydrocolloids, matrix- forming materials and
polysaccharides, which also work as bioadhesive polymers such as carbopol
and chitosan This technology involves encasing of a drug reservoir in a
microporous compartment with apertures along its upper as well as lower
walls, as depicted in figure 6.3.

INHERENT LOW-DENSITY SYSTEMS
• The system initially settles down, and then comes to the brim after a specific
lag time, thus poses a plausible risk of premature emptying from the stomach.
Therefore, there is an ardent need of a system that floats immediately as
soon as it comes in contact with gastric fluids.
• This can only be accomplished with the provision of a low-density device since
its inception. Low-density systems are generally made by air entrapment.
• Watanabe et al. (1976) prepared a single-unit FDDS with inherent low
density, consisting of a hollow core (empty, hard gelatin capsule, polystyrene
foam, or pop rice grain) coated with two layers: a subcoat of cellulose
acetate phthalate, and an outer drug-containing coating of ethyl cellulose
(EC)/hydroxypropyl methylcellulose (HPMC). This type of system is very useful
for low-dose drugs but may not be suitable if larger amounts of drug are
needed for an effective therapy.

• 6.2.2.4.1 HOLLOW MICROSPHERES
• HOLLOW MICROSPHERES ARE LOW-DENSITY SYSTEMS THAT
IMMEDIATELY FLOAT AS SOON AS THEY COME IN CONTACT WITH THE
GASTRIC FLUID, CAUSING GASTRORETENTION AND THEREBY
IMPROVING DRUG BIOAVAILABILITY (ALOSHI 2016). FOR INSTANCE,
HOLLOW MICROSPHERES (MICROBALLOONS) CONSISTING OF
EUDRAGIT RS (AN ENTERIC POLYMER) CONTAINING THE DRUG IN THE
POLYMERIC SHELL DEVELOPED HAVE BEEN REPORTED IN THE LITERATURE
(KAWASHIMA ET AL. 1989; BANSAL ET AL. 2016A).

• 6.2.2.4.2 FLOATING BEADS
• DOSAGE FORMS CONTAINING SPHERICAL FLOATING BEADS HAVE BEEN SYNTHESIZED
USING LYOPHILIZED CALCIUM ALGINATE THAT CAN KEEP FLOATING FOR 12 H. FLOATING
BEADS HAVE A PROLONGED GASTRORETENTION TIME OF MORE THAN 5.5 H AS COMPARED
TO SOLID BEADS THAT SHOW A SHORTER GASTRIC RETENTION OF 1 H AS DIAGRAMMATI-
CALLY REPRESENTED IN FIGURE 6.4. BOTH NATURAL AND SYNTHETIC POLYMERIC SYS- TEMS
HAVE BEEN USED IN THE PREPARATION OF MULTIPLE-UNIT FDDS.
• THE FLOATING PROPERTIES OF THE DEVICES STRONGLY DEPENDED ON THE SUBSE- QUENT
DRYING PROCESS. OVEN DRIED BEADS DID NOT FLOAT, WHEREAS LYOPHILIZED BEADS
REMAINED FLOATING FOR >12 H IN HYDROCHLORIDE BUFFER PH 1.5 DUE TO THE PRESENCE
OF AIR-FILLED HOLLOW SPACES WITHIN THE SYSTEM (TALUKDER AND FASSIHI 2004).

• 6.2.2.6 EFFERVESCENT SYSTEMS
• 6.2.2.6.1 VOLATILE LIQUID CONTAINING SYSTEMS
• THESE SYSTEMS INCORPORATE AN INFLATABLE CHAMBER CONTAINING A VOLATILE LIQUID, SUCH AS ETHER OR
CYCLOPENTANE, WHICH EVAPORATES AT BODY TEMPERATURE LEAD- ING EVENTUALLY TO INFLATION OF THE
CHAMBER IN THE STOMACH. THESE INFLATABLE GI SYSTEMS CONTAIN A HOLLOW EXPANDABLE AND
DEFORMABLE UNIT THAT CONSISTS OF TWO CHAMBERS SEPARATED BY AN IMPERMEABLE, PRESSURE-RESPONSIVE,
AND MOV- ABLE BLADDER. THE FIRST CHAMBER CONTAINS THE DRUG AND THE SECOND CHAMBER CONTAINS
THE VOLATILE LIQUID. IN THE STOMACH, THE VOLATILE LIQUID EVAPORATES AND INFLATES THE DEVICE, LEADING
TO DRUG RELEASE FROM THE RESERVOIR INTO THE GASTRIC FLUID, AS SHOWN IN FIGURE 6.6A.
• THE DEVICE MAY ALSO CONSIST OF A BIOERODIBLE PLUG MADE UP OF PVA, POLYETH- YLENE, ETC. THAT
GRADUALLY DISSOLVES CAUSING THE INFLATABLE CHAMBER TO RELEASE GAS AND COLLAPSE AFTER A
PREDETERMINED TIME TO PERMIT SPONTANEOUS EJECTION OF THE INFLATABLE SYSTEM FROM THE STOMACH
(RAHIM ET AL. 2015).

• 6.2.2.6.2 GAS GENERATING SYSTEMS
• THESE SYSTEMS INCORPORATE, APART FROM THE DRUG AND THE SWELLING POLY- MERS,
SUCH AS CHITOSAN AND METHYLCELLULOSE, SOME EFFERVESCENT COMPOUNDS, E.G.,
SODIUM BICARBONATE (NAHCO3), TARTARIC ACID (C H O), AND CITRIC ACID (CHO7) THAT
₂ ₂
LIBERATE CO2 WHEN THEY COME IN CONTACT WITH ACIDIC GASTRIC CON- TENTS. AND,
CO IN THIS CASE, GETS ENTRAPPED IN SWOLLEN HYDROCOLLOIDS AND PROVIDES
₂
BUOYANCY TO THE DOSAGE FORMS (MIRANI ET AL. 2016).
• GENERALLY, THE EFFERVESCENT SYSTEMS SUFFER FROM A SPECIFIC DISADVANTAGE THAT
THEY DO NOT FLOAT IMMEDIATELY AFTER SWALLOWING, AS GAS GENERATION TAKES
SOME TIME. THEREFORE, THEY COULD BE CLEARED FROM THE STOMACH BEFORE BECOM-
ING EFFECTIVE.

• 6.2.2.7 LIMITATIONS OF FDDS
• A. THE PERFORMANCE OF LOW-DENSITY, FLOATING DDS IS STRONGLY DEPENDENT
ON THE FED/FILLING STATE OF THE STOMACH. NEVERTHELESS, THIS APPROACH
CAN SUCCESSFULLY PROLONG THE GASTRIC RETENTION TIME AND HAS ALREADY
LED TO THE PRODUCTION OF PHARMACEUTICAL PRODUCTS, WHICH ARE COM-
MERCIALLY AVAILABLE IN THE MARKET (TALUKDER AND FASSIHI 2004).
• B. AN FDDS REQUIRES SUFFICIENTLY HIGH LEVELS OF FLUID IN THE STOMACH TO
FLOAT AND WORK EFFICIENTLY. HOWEVER, THIS CAN BE OVERCOME BY ADMIN-
ISTRATING THE DOSAGE FORM WITH FLUIDS (200-250 ML) AND WITH FREQUENT
MEALS (TARANALLI ET AL. 2015).

• SWELLING SYSTEMS:ABSORB WATER AND EXPAND TO INCREASE
GASTRIC VOLUME

• MUCOADHESIVE SYSTEMS:ADHERE TO THE GASTRIC MUCOSA
THROUGH ADHESIVE PROPERTIES

THEORIES OF BIOADHESION
ELECTRONIC THEORY
• This theory suggests that the formation of a
double layer of electrical charge at the
interface between the bioadhesive and the
biological tissue is responsible for adhesion.
• The interaction of these charges can create a
strong bond.

ADSORPTION THEORY
• This theory posits that bioadhesion is
primarily due to intermolecular forces, such as
van der Waals forces, hydrogen bonding, and
electrostatic attractions.
• These forces act between the molecules of the
bioadhesive and the biological tissue

WETTING THEORY
• According to this theory, the ability of the
bioadhesive to spread and wet the biological
tissue surface is crucial for adhesion.
• A good wetting contact ensures that the
bioadhesive molecules can interact closely
with the tissue

DIFFUSION THEORY
• This theory suggests that the bioadhesive
molecules diffuse into the tissue, creating
interpenetration and entanglement with the
tissue components.
• This interpenetration can lead to strong
adhesive bonds.

FRACTURE THEORY
• This theory focuses on the mechanical
properties of the bioadhesive and the tissue.
• It proposes that the strength of the adhesive
bond depends on the energy required to
fracture the bond.

ADDITIONAL CONSIDERATIONS
• Mechanical Interlocking: In some cases, the
bioadhesive may physically penetrate into the
pores or irregularities of the tissue, creating a
mechanical interlocking effect.
• Dehydration Theory: This theory suggests that the
bioadhesive may cause dehydration of the tissue
surface, leading to closer contact between the
bioadhesive and the tissue.

ADVANTAGES
Stability:
• Bioadhesive dosage forms tend to increase
stability of certain drugs by localizing the drug
to an optimal site of its maximal stability.
• Also, these systems by disallowing a proper
contact of drug with food components may
protect the former from attack by the latter

ADVANTAGES
Improved Bioavailability:
• Also, the bioadhesive systems have been
successfully employed to improve the
consistency of the drugs like atenolol by
regulating their drug absorption and reducing
fluctuation of their plasma levels

ADVANTAGES
Peptide Delivery:
• The susceptibility of the peptides to the diverse
pH ranges is known to challenge their efficacy.
The GR systems have been attempted in case of
melatonin to effectively deliver them via an
oral route

ADVANTAGES
Mucosal Protection:
• Bioadhesive dosage forms could protect the
GI mucosa from ulceration caused by NSAIDs

DISADVANTAGES OF BIOADHESIVES
ION-/PH- SENTIVITY
• Polyanionics as polyacrylic acid are highly sensitive to
the ionic environment.
• Thus, the use of polyacrylates in an ion-rich environment
may interfere with the adhesive properties of the polymer.
• Sufficient adhesiveness may be obtained at a specific pH
range only.
• Rheological properties of Carbopol 934 samples were
found to be substantially influenced by the environmental
pH.

HIGH VISCOSITY
• Due to the high viscosity of the polymers, these
systems could impede the delivery of the drug to the
absorbing surface

LOSS OF MUCOADHESIVE ACTIVITY
• An increased wetting of the polymer may lead to
the formation of nonadhesive, slippery mucilage
that may cause loss of mucoadhesive activity.
• Due to this, bioadhesive system may move past
the absorption site.
• Besides, mucoadhesion during the GI transit of
the DDS will be limited by a relatively

CHARACTERIZATION OF GASTRORETENTIVE DOSAGE FORMS
CHALLENGES FACED/ANTICIPATED IN CHARACTERIZATION OF GASTRORETENTIVE
DOSAGE FORMS
• The performance of the GR
formulation is highly dependent
on the physiological conditions
of the stomach.
• A number of factors affect the
gastric retention of the dosage
form and hence the prediction of
drug release profile is difficult.
• The high variability of gastric
emptying time poses major
challenge in determining the GR
behavior of formulations.
• For instance, the presence of
food that extends the GRT is
represented by a higher gastric
emptying time in the fed
condition as compared to the
fasting condition. The in- vitro-
in-vivo correlation (IVIVC)
often becomes difficult as the

IN-VITRO CHARACTERIZATION AND GASTRORETENTION STUDY
• Effective in-vitro characterization plays a crucial role
in ensuring the quality and predicting the clinical
utility of the developed formulations.
• In addition to routine evaluation parameters for final
dosage form, like hardness, friability, general
appearance, assay, uniformity of content, and weight
variation for tablets, the following methods have also
been reported to evaluate peculiar formulation
characteristics accountable for gastric retention.

IN-VITRO CHARACTERIZATION AND GASTRORETENTION STUDY
• The study is performed in USP dissolution apparatus containing 900 mL of
deionized water, 0.1N hydrochloric acid or more preferably simulated
gastric fluid (SGF) as the dissolution medium at a temperature of 37 ± 0.5°C,
with or without stirring.
• For tablet dosage forms, the time required by tablet to start floating
(floating lag time) and the total duration for which the tablet remains
floating (floating time) are often measured.
• For floating mic- roparticulate drug delivery systems, the carrier is
dispersed in continuously stirred testing medium for target duration.
Subsequently, the floating as well as settled fraction of these carriers are
separated and their dry weights (WF and Ws, respectively) are measured to
calculate percent buoyancy as a measure of gastric retention
• Percentage Buoyancy = WF + WS × 100

MUCOADHESION STUDY
• The mucoadhesive property of gastroretentive formulations is evaluated
by measuring the strength, with which the formulation attaches to
mucus lining of biological tissue samples and measuring the force
required to detach the formulation as a measure of mucoadhesive
strength.
• A universal tensile tester is often utilized to sensitively measure the
detachment force for tablets while modified dynamic contact angle
analyser or microtensiometer is utilized for individual microparticles
• Alternatively, an in-vitro wash-off test is also performed for
multiparticulate systems, where the tissue is mounted on a glass slide, a
predefined number of particles are allowed to attach to moistened tissue
and their mucoadhesive strength is challenged by

IN-VITRO DRUG RELEASE
• The paddle or basket type dissolution test apparatus
is commonly utilized for in-vitro drug release Study
using 0.1N HCI, FaSGF (SGF fasted condition) or
FeSGF (SGF fed condition) as a release medium at
37 ± 0.5° C.
• FaSGF contains pepsin, sodium taurocholate, and
lecithin at pH around 1.5, while FeSGF contains milk
or buffer at pH 5, in combination to other ingredients
of FaSGF.

SWELLING INDEX
• The immersion method is used to study the swelling behavior
of a GR systems.
• The method involves immersion of formulation in SGF at 37°C
and the change in dimension, volume, or weight is measured at
predetermined time points as a measure of swelling.
• The percent swelling is calculated by, where Mo and. M are the
₁
measurements recorded initially and at time t, respectively:
• Percent swelling =[(M1-Mo)/Mo] × 100

DENSITY OF THE DOSAGE FORM
• The density of formulation is calculated as
mass to volume ratio.
• For instance, the density of a capsule
shaped tablet is calculated by putting
weight (M), radius (r) and side length (a)
of the tablet,
• Density = M/[(4/3)πr²(r+a)]

DRUG RELEASE KINETIC
MODELING
•

DISSOLUTION CONTROLLED DRUG DELIVERY
SYSTEMS
• A drug with a slow dissolution rate is inherently sustained and for those
drugs with high water solubility, we can decrease dissolution through
appropriate salt or derivative formation.
• The rate limiting step for dissolution of drug is the diffusion across the
aqueous boundary layer. The solubility of the drug provides the source of
energy for drug release which is countered by the stagnant fluid layer.
• The dissolution process at steady state would be described by Noyes-Whitney
equation, dc/dt = K(Cs -Cb)
• Where, dc/dt = Dissolution rate.
• K= Dissolution rate constant.
• Cs = concentration of solution at solid surface
• Cb = The concentration of drug in bulk of the solution

DISSOLUTION AND DIFFUSION
CONTROLLED DRUG RELEASE SYSTEM
• Drug encased in a partially soluble
membrane (Ethyl cellulose & PVP
mixture)
• Pores are created due to dissolution of
soluble parts of membrane.
• It permits entry of aqueous medium into
core & drug dissolution take place.
• Diffusion of dissolved drug out of
system.
• Example-mixture of ethyl cellulose and
PVP they get dissolve in water and
create pores of insoluble ethyl cellulose
membrane

MATHEMATICAL MODELLING
• The mathematical modeling of drug delivery has a
significant potential to facilitate product development
and help to understand release behavior of complex
pharmaceutical dosage forms.
• The models are based on the main factors which affect
the drug release such as the particle size distribution,
the physical state and the concentration profile of the
drug inside the polymeric particles, the viscoelastic
properties of the polymer–penetrant system and the
dissolution–diffusion properties of the loaded drug.
• Any one particular theory cannot be made applicable
to any drug delivery system as the systems may also
involve combination of models.

FACTORS AFFECTING THE DRUG RELEASE
KINETICS
DRUG RELATED FACTORS
• DRUG SOLUBILITY
• DOSE OR DRUG CONTENT
• MOLECULAR WEIGHT AND SIZE
• PARTICLE SIZE AND SHAPE
• DIFFUSION IN POLYMER AND
MEDIA
FORMULATION
VARIABLES
• FORMULATION
GEOMETRY (SIZE & SHAPE)
• FORMULATION
EXCIPIENTS
• ADDITIVES QUANTITIES
AND THEIR ROLES
Polymer related factors
An increase in polymer proportion increases the viscosity of the gel and,
thereby, increases the diffusional path length. Hence diffusion coefficient
decreases and rate of drug release falls.

ZERO ORDER RELEASE KINETICS
• IT REFERS TO THE PROCESS OF CONSTANT DRUG RELEASE
FROM A DRUG DELIVERY DEVICE INDEPENDENT OF THE
CONCENTRATION. ZERO ORDER RELEASE CAN BE
REPRESENTED AS
Q = Q + K T
₀ ₀
Where Q is the amount of drug released
or dissolved
Q is the initial amount of drug in
₀
solution, K is the zero order release
₀
constant.
Graphical representation of fraction of
drug dissolved verses time will be
linear.
The slope of the curve gives the value
of K in zero order release kinetics

Osmotic
pumps
Transderma
l systems
Slow
release
matrix
systems
Matrix
tablets with
coated
forms
ZERO ORDER RELEASE KINETICS IS MAINLY
EXPRESSED BY

FIRST ORDER RELEASE KINETICS
• The first order equation describes the release from system where
release rate is concentration dependent, it is expressed by the
equation:
Dc / dt = - kt
• Where K is first order rate constant.
• This equation can be expressed as:
Log c’= log c – k t / 2.303
₀
• Where, c is the initial concentration of drug and c’ is the
₀
concentration of drug in solution at time t.
• The equation predicts a first order dependence on the
concentration gradient (co – c’) between the static liquid layer next
to the solid surface and the bulk liquid.

• The plot made: log cumulative of % drug remaining vs time
which would yield a straight line with a slope of –K/2.303.
• The dosage forms containing water soluble drug in porous
matrices follows this profile.

HIGUCHI MODEL
• The first example of a mathematical model aimed to describe drug release from a
matrix system was proposed by Higuchi in 1963.
• This model is applicable to study the release of water soluble and low soluble drugs
incorporated in semisolid and solid matrices, transdermal patches or films for oral
controlled drug delivery
• Model expression is given by the equation:
Q= [d.Ε/τ. (2a-εcs)cst]1/2
• Where Q is the amount of drug released in time t per unit area A
• Ε is the porosity of matrix,
• Τ is the capillary tortuosity factor
• C is the initial amount of drug contained in the dosage form
• Cs is the solubility of active agent in the matrix medium
• D is the diffusion coefficient in the matrix medium

• Simplified higuchi model describes the release of drugs
from insoluble matrix as a square root of time
dependent process
Q= kht1/2
• The data obtained were plotted as cumulative
percentage drug release versus square root of time. The
slope of the plot gives the higuchi dissolution constant
KH

HIXSON CROWELL CUBE ROOT LAW
• It was first proposed as a means of representing dissolution rate that is
normalized for the decrease in solid surface area as a function of time.
• It describes the release from systems where there is a change in surface area
and diameter of particles or tablets. Provided there is no change in shape.
• As a suspended solid dissolves, its surface decreases as the two-thirds power
of its weight
• The cube root law can be written as:
Qo
1/3
- qt
1/3
= khct
Where, qt denotes the remaining weight of solid at time t
Qo is the initial weight of solid at time t = 0,
KHC represents the dissolution rate constant

• The graphical plot of the cubic root of the unreleased fraction of the
drug verses time should yield a straight line.
• This model is used by assuming that release rate is limited by the drug
particles dissolution rate and not by the diffusion.
• The assumptions made for the validity of the law by hixson and crowell
can be summarized as follows:
(1)The law is claimed to be more suitable for monodispersed systems.
(2)The dissolution takes place normal to the surface. The difference in
rates at different crystal faces is considerably less and the effect of
agitation of the liquid against all parts of the surface remains same.
(3)The liquid is agitated intensely to prevent stagnation in the nearest
places of the dissolving particle thus resulting in a slow rate of
diffusion.

PEPPAS MODEL (POWER LAW)
• Ritger and peppas, korsmeyer and peppas developed an empirical equation
to analyze both fickian and non-fickian release of drug from swelling as well
as non swelling polymeric delivery systems.
MT/MΑ= KTN
ALSO CAN BE WRITTEN AS: LOG[MT/MΑ] =LOG[K] + NLOG[T]
• WHERE MT/M∝ is fraction of drug released at time T
• N is diffusion exponent indicative of the mechanism of transport of drug
through the polymer
• K is kinetic constant incorporating structural and geometric characteristics of
the delivery system.
• THE power law model is useful for the study of drug release from polymeric
systems when the release mechanism is not known or when more than one
type of phenomenon of drug release is involved..

• THE “N” VALUE IS USED TO CHARACTERIZE DIFFERENT RELEASE
MECHANISMS.
• PEPPAS AND SAHLIN DEVELOPED A RELEASE KINETICS MODEL AND
THE EQUATION IS APPLICABLE TO SWELLABLE SYSTEMS.
MT/MΑ= KTM
+ KT2M
• CONSIDERING THE RIGHT SIDE OF THE EQUATION, THE FIRST TERM
REPRESENTS THE FICKIAN DIFFUSIONAL CONTRIBUTION, F, WHEREAS
THE SECOND TERM REPRESENTS THE CASE II RELAXATIONAL
CONTRIBUTION, R.

 BIOAVAILABILITY OR BIOEQUIVALENCE STUDIES
the european agency provides biowaivers for the
immediate release formulation of highly water-
soluble drug releasing more than 85% drug within
first 15 min, where gastroretentive dosage forms
(GRDFS) don't fit due to controlled or sustained drug
release.
 USFDA maintains the database of the biowaiver
reports on approved federally compliant products
that are used to prepare bioequivalence procedures
as biowaivers; generating the relationship between
the in-vitro and in-vivo data as IVIVC.
This might aid in surmounting the problems associated with
the biowaiver principles. In particular, a Level A correlation
suits the best for extended release systems like GRDF, as it
involves point to point comparison of dissolution data directly
with plasma drug concentration-time profile to provide better
prediction of in-vivo performance.

In-vivo Pharmacokinetics
• The GI tract demonstrates varying absorption
characteristics based on its region-specific differences
in physiology and anatomy.
• Thus, drug delivery to different regions of the gl tract
significantly impacts the corresponding
pharmacokinetic profiles
• As discussed earlier, the GRDF approach aims at
providing continuous delivery of drugs to the upper
part of the GL tract via overcoming the natural gastric
activities responsible for evacuation of its content into
the intestine
• The major approaches utilized so far for GRDF
includes low-density systems that float in gastric fluid,
high-density systems that sink

• MAGNETIC SYSTEMS:UTILIZE MAGNETIC PROPERTIES TO BE RETAINED
IN THE STOMACH

Bioadhesive systems:
•Adhere to biological tissues through specific interactions

• COMBINATION APPROACHES:UTILIZE MULTIPLE MECHANISMS FOR
ENHANCED GASTRORETENTION

DESIGN AND DEVELOPMENT OF
GRDDS
FORMULATION CONSIDERATIONS:
•Drug solubility and release rate
•Excipient selection
•GRDDS design and fabrication

MATERIALS AND EXCIPIENTS:
• POLYMERS (E.G., CHITOSAN, ALGINATE)
• FLOATABLE MATERIALS (E.G., MICROBUBBLES,
HOLLOW SPHERES)
• MUCOADHESIVE AGENTS (E.G., CARBOMER,
HYALURONIC ACID)
• MAGNETIC PARTICLES (E.G., MAGNETITE)

FABRICATION TECHNIQUE
•Hot melt extrusion
•Spray drying
•3D printing

EVALUATION OF GRDDS
• IN VITRO EVALUATION:
• DISSOLUTION STUDIES
• SWELLING STUDIES
• MUCOADHESION STUDIES
• FLOATING STUDIES

• IN VIVO EVALUATION:
• ANIMAL MODELS (E.G., RATS, DOGS)
• HUMAN STUDIES

• MARKETED GRDDS AND APPLICATIONS
• EXAMPLES OF COMMERCIALLY AVAILABLE GRDDS:
• [PRODUCT NAMES AND DESCRIPTIONS]
• THERAPEUTIC APPLICATIONS:
• GASTROINTESTINAL DISORDERS
• ANTIBIOTIC THERAPY
• HORMONE REPLACEMENT THERAPY

EVALUATION OF GASTRORETENTION
USING IMAGING TECHNIQUES
•X-RAY IMAGING:
• PRINCIPLES AND TECHNIQUES
• APPLICATIONS IN GRDDS EVALUATION
• [X-RAY IMAGES OF GRDDS IN THE
STOMACH]

EVALUATION OF GASTRORETENTION
USING IMAGING TECHNIQUES
• POSITRON EMISSION TOMOGRAPHY (PET):
• PRINCIPLES AND TECHNIQUES
• APPLICATIONS IN GRDDS EVALUATION
• [PET IMAGES OF GRDDS IN THE STOMACH]

POLYMERS FOR GASTRORETENTIVE
SYSTEMS
 Hydrocolloids hydrocolloids are gel-forming agent,
which swells in contact with gastric fluid and
maintains a relative integrity of shape and bulk
density less than the gastric content e.G., Acacia,
pectin, agar, alginates, gelatin, casein, bentonite,
veegum, methylcellulose (MC), HPMC,
ethylcellulose (EC), HPC, hydroxyethyl cellulose,
and carboxy methylcellulose sodium (na CMC).

INERT FATTY MATERIALS
• EDIBLE, PHARMACEUTICAL INERT FATTY MATERIAL, HAVING A SPECIFIC
GRAVITY

RELEASE RATE ACCELERANTS
• THE RELEASE RATE OF THE MEDICAMENT FROM THE FORMULATION
CAN BE MODIFIED BY INCLUDING EXCIPIENT LIKE LACTOSE AND/OR
MANNITOL. THESE MAY BE PRESENT FROM ABOUT 5% TO 60% BY
WEIGHT. E.G., LACTOSE, MANNITOL, ETC.

RELEASE RATE RETARDANTS
• INSOLUBLE SUBSTANCES SUCH AS CALCIUM PHOSPHATE, TALC, AND
MAGNESIUM STEARATE DECREASED THE SOLUBILITY AND HENCE,
RETARD THE RELEASE OF MEDICAMENTS. E.G., DICALCIUM PHOSPHATE,
TALC, MAGNESIUM STEARATE, ETC.

BUOYANCY INCREASING AGENTS
• MATERIALS LIKE EC, WHICH HAS BULK DENSITY

EFFERVESCENT AGENTS
• THESE ARE THE AGENTS WHICH GENERATE CARBON DIOXIDE AFTER
REACTING WITH GASTRIC ACIDIC MEDIUM. E.G., SODIUM
BICARBONATE, CITRIC ACID, TARTARIC ACID, DI-SODIUM GLYCINE
CARBONATE, CITROGLYCINE, ETC.[15,16]

ON THE BASIS OF ORIGIN
• 1. NATURAL POLYMERS LIKE, CHITOSAN, SODIUM ALGINATE, ETC.
• 2. SEMI-SYNTHETIC POLYMERS LIKE, EC, HPMC, ETC.
• 3. SYNTHETIC POLYMERS LIKE, ACRYLIC ACID DERIVATIVES, LACTIC
ACID DERIVATIVES, ETC.

CHITOSAN
• CHITOSAN (OBTAINED BY ALKALINE DEACETYLATION OF CHITIN) IS A SWELLABLE,
NATURAL LINEAR BIOPOLYAMINOSACCHARIDE. CHITIN IS A STRAIGHT HOMOPOLYMER
COMPOSED OF -(1,4)-LINKED N-ACETYL-GLUCOSAMINE UNITS, WHILE CHITOSAN
COMPRISES OF COPOLYMERS OF GLUCOSAMINE AND N-ACETYL-GLUCOSAMINE.
• THE EMULSION CROSS-LINKING AND THE IONOTROPIC GELATION ARE MOST PREFERRED
AND WIDELY USED METHODS FOR THE PREPARATION OF FLOATING MICROSPHERES. IN
BOTH METHODS, CROSS-LINKING IS REQUIRED DUE TO ITS IONIC NATURE.
• DIFFERENT GRADES OF CHITOSAN ARE AVAILABLE ON THE BASIS OF THEIR DEGREE OF
DEACETYLATION AND MOLECULAR WEIGHT, AND THEIR SOLUBILITY CAN ALSO VARY
BETWEEN SLIGHTLY ACIDIC MEDIUM TO THE AQUEOUS MEDIUM.[17

SODIUM ALGINATE
• ALGINATE IS A POLYSACCHARIDE THAT IS ABUNDANT IN NATURE, AS IT IS
SYNTHESIZED BY BROWN SEAWEEDS AND SOIL BACTERIA.[40] IT IS WIDELY
EMPLOYED IN THE FOOD PROCESSING INDUSTRY, OFTEN AS A THICKENER OR
EMULSIFION STABILIZER AND IN THE PHARMACEUTICAL INDUSTRY SINCE IT IS THE
FIRST BYPRODUCT OF ALGAL PURIFICATION.[41,42] SODIUM ALGINATE CONSISTS
OF -L-GULURONIC ACID RESIDUES (G BLOCKS) AND -D-MANNURONIC ACID
Α Β
RESIDUES (M BLOCKS), AS WELL AS SEGMENTS OF ALTERNATING GULURONIC AND
MANNURONIC ACIDS (GM BLOCKS). THE GULURONATE RESIDUE BLOCKS ALLOW
ALGINATE FIBRES TO FORM GELS BY BINDING CA2+ IONS AND STOMACH H+
IONS, WHICH CROSS-LINK THE FIBERS INTO A VISCOUS POLYMER MATRIX.[43]

CALCIUM PECTINATE
• PECTIN IS AN INEXPENSIVE, NONTOXIC POLYSACCHARIDE EXTRACTED FROM
CITRUS PEELS OR APPLE POMACES, AND HAS BEEN USED AS A FOOD
ADDITIVE, A THICKENING AGENT AND A GELLING AGENT. IT ALSO HAS
BIOADHESIVE PROPERTIES TOWARD OTHER GASTROINTESTINAL TISSUES,
WHICH CAN BE USED AS A DRUG DELIVERY DEVICE ON A SPECIFIC SITE FOR
TARGETED RELEASE AND OPTIMAL DRUG DELIVERY DUE TO INTIMACY AND
DURATION OF CONTACT. PECTIN HAS A VERY COMPLEX STRUCTURE, WHICH
DEPENDS ON BOTH ITS SOURCE AND THE EXTRACTION PROCESS. NUMEROUS
STUDIES CONTRIBUTED TO ELUCIDATE THE STRUCTURE OF PECTIN. BASICALLY,
IT IS A POLYMER OF A-D-GALACTURONIC ACID WITH 1-4 LINKAGES

GUAR GUM
• GUAR GUM IS A NATURAL NONIONIC POLYSACCHARIDE DERIVED FROM THE
SEEDS OF CYAMOPSIS TETRAGONOLOBUS (FAMILY LEGUMINOSAE). IN
PHARMACEUTICALS, GUAR GUM IS USED IN SOLID DOSAGE FORMS AS A
BINDER, DISINTEGRANT, AND AS A POLYMER IN THE FLOATING DRUG
DELIVERY SYSTEM.[80,81] GUAR GUM MAINLY CONSISTING OF
POLYSACCHARIDES OF HIGH MOLECULAR WEIGHT (50,000-8,000,000)
COMPOSED OF GALACTOMANNANS, MANNOSE: GALACTOSE RATIO IS
ABOUT 2:1. IT CONSISTS OF LINEAR CHAINS OF (1-4)-B-D-
MANNOPYRANOSYL UNITS WITH A-D-GALACTOPYRANOSYL UNITS
ATTACHED BY (1-6) LINKAGES

XANTHAN GUM
• XANTHAN (A WELL-KNOWN BIOPOLYMER) IS AN EXTRACELLULAR HETEROPOLYSACCHARIDE
PRODUCED FROM BACTERIUM XANTHOMONASCAMPESTRIS WHICH IS A NATURAL,
BIOSYNTHETIC, EDIBLE GUM, AND AN EXTRACELLULAR ANIONIC POLYSACCHARIDE.
• XANTHAN GUM CONSISTS OF GLUCOSE, MANNOSE, AND GLUCURONIC ACID, AND IS USED IN
DIFFERENT FOODS AS THICKENER AND STABILIZER.[88]
• XANTHAN IS A LONG-CHAINED POLYSACCHARIDE WITH A LARGE NUMBER OF TRISACCHARIDE
SIDE CHAINS (COMPOSED OF TWO MANNOSE UNITS AND ONE GLUCURONIC ACID UNIT) AND
CONSISTS OF A B-(1, 4)-D-GLUCOSE BACKBONE. THIS GUM DEVELOPS A WEAK STRUCTURE IN
WATER, WHICH CREATES HIGH-VISCOSITY SOLUTIONS AT LOW CONCENTRATION.
• VISCOSITY REMAINS FAIRLY CONSTANT FROM 0°C TO 100°C

• THERE ARE VARIOUS EXCIPIENTS SUCH AS SURFACTANTS (SODIUM
LAURYL SULFATE, POLY VINYL ALCOHOL, ARLACEL-60, TWEENS, SPANS
ETC.), GAS GENERATING AGENTS (SODIUM BICARBONATE, CALCIUM
CARBONATE), AND PORE FORMING AGENTS (CITRIC ACID, SILICATES)
ARE USED IN THE FORMULATION OF FLOATING DRUG DELIVERY
SYSTEM.

CASE-STUDY
• Darandale, S.S. And vavia, P.R., 2012.
Design of a gastroretentive mucoadhesive
dosage form of furosemide for controlled
release. Acta Pharmaceutica Sinica
B, 2(5), pp.509-517.

DESIGN OF A GASTRORETENTIVE
MUCOADHESIVE DOSAGE FORM OF
FUROSEMIDE FOR CONTROLLED RELEASE
• EVALUATION-1 in vitro bioadhesion. Bioadhesion of the CR layer of the film to
stomach mucosa
• Double beam physical balance as described previously8.
• Briefly, the stomach mucosa of wistar rats was excised, washed with tyrode’s solution
and tied tightly (mucosal side upwards) using a thread to the end of a cylindrical
teflon block.
• The cylinder was placed into a glass container which was then filled with either
aqueous hydrochloric acid ph 1.2 or ph 4.5 acetate buffer at 3771 1C until the fluid just
reached the surface of the mucosal membrane.
• This was placed below the left arm of the balance. The moist film was then brought
into contact with a film (CR layer downwards) attached to the lower surface of
another teflon cylinder suspended from the left arm of the balance by removing a 5 g
weight from the right pan of the balance.
• The balance was kept in this position for 3 min after which weights were added
slowly to the right pan until the film separated from the mucosal surface.
• The excess weight on the pan (total weight minus 5 g) is the bioadhesive strength
required to separate the film from the mucosa. The force of adhesion was calculated
using the formula:

IN VITRO RESIDENCE TIME.
• The in vitro residence time was determined in triplicate as described
previously9.
• The CR side of a film was applied to freshly prepared rat stomach
mucosa fixed to a glass slide with cyanoacrylate glue and suspended
from a reciprocating motor.
• The slide was suspended in a beaker filled with 800 ml aqueous
hydrochloric acid ph 1.2 or ph 4.5 acetate buffer and moved vertically
in and out of the medium by switching on the motor.
• The experiment was continued until the film detached or eroded from
the mucosa.

SWELLING BEHAVIOR.
• Swelling of films was examined in triplicate in
simulated gastric fluid (pH 1.2) and pH 4.5
acetate buffer according to the following
procedure.
• After recording the initial weight of a film (W1),
it was immersed in medium maintained at
37±1ºC for 360 min and then weighed again (W2).
• The swelling ratio was determined as
(W2-W1)/W1.

MECHANICAL PERFORMANCE.
• Mechanical properties of films free of physical defects
were determined in triplicate using a universal testing
machine (UTM, LLOYD) as previously described.
• Rectangular samples of film (30 mm 5 mm) were
subjected to analysis based on ASTM D-882. The films
were carefully placed between the two vertical grips of
the tester and the movable grip then driven upward at
5 mm/min until the film ruptured.
• From the recorded load-extension profile, the tensile
strength, percent elongation at break and Young’s
modulus were calculated

IN VITRO DRUG RELEASE
• In vitro dissolution of optimized formulation F9 was
studied in media of different ph using the procedure
described in section 2.3.2.
• Dissolution of the marketed formulation, lasix retards
60 mg, was also determined in aqueous hydrochloric
acid ph 1.2 for comparison.
• In vitro release profiles were fitted to different kinetic
models including zero order, first order, korsmeyer–
peppas model, higuchi model and hixson–crowell
model and the correlation coefficients of the fits
compared

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