Oral Modified-Release Drug Delivery

2023

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References

United States
Pharmacopeia
General Chapters
<1151>,
<711> ,
<1088>

Remington : The Science

and Practice of Pharmacy Modern Pharmaceutics, Controlled Drug Delivery:
20th , 23rd editions 4th Edition Fundamentals and
Banker and Rhodes (eds.) Applications
Robinson and Lee (eds.)

2
Oral modified-release systems
Learning objectives
• Modified release systems - terminology
• Need for extended–release systems
• Biopharmaceutical considerations
• Dose calculations
• Key properties of the active ingredient
• Selected oral controlled-release systems – design, release mechanisms
and release kinetics
• Matrix systems – inert insoluble and hydrophilic matrices
• Reservoir systems (membrane-controlled)
• Osmotic pump delivery systems

3
Terminology

4
USP <1151> Pharmaceutical Dosage forms
Immediate-release (IR) - no deliberate effort has been made to modify the drug
release .
Modified-release (MR)- the location of release or the rate of release of the drug
substance deliberately altered.
Modified-release

Delayed release Extended release

Formulation achieves a delay in the Formulation achieves prolongation of drug
release of the drug for some period of release compared to immediate-release
time after initial administration. dosage form.
• Enteric-coated • Sustained release
• Gastro-resistant • Prolonged release
• Controlled release 5
Drug release behaviour

6
Controlled Release
Controlled release often refers to systems designed to provide precise control over drug
release rate (temporal control; example – zero order release) and /or release location
(spatial control; targeted drug delivery, site specific release).

• Temporal control – provide prolonged drug action by maintaining constant effective

drug levels.
• Localized drug action by placing the controlled-release system adjacent to or in the
diseased tissue. ‘Focal controlled drug delivery systems’ are applied directly to the
diseased site. The drug is delivered over an extended period of time (spatial and
temporal control). For example – drug eluting stents
• Targeted drug delivery – Use of suitable carriers or chemical derivatization to deliver
drug preferentially to particular target cell types.
• Therapeutically based drug delivery system where drug release is determined by the
therapeutic need. Example - insulin pumps adjusting basal insulin delivery rate in
response to continuous glucose monitors. 7
Immediate vs. extended release
Need for extended-release formulations

8
Therapeutic Index Therapeutic Index =
TC50%
EC50%
Therapeutic index - Ratio of maximum drug
concentration that can be tolerated to the
minimum concentration required for
therapeutic effect
The more widely-spaced the “therapeutic
effect” and “toxic effect” dose-response
curves, the higher the therapeutic index and
safer is the drug
Narrow therapeutic index drugs (for example,
warfarin) require therapeutic drug monitoring
during dose titration in clinical use. For
example, therapeutic index is < 10 for drugs
such as warfarin, phenytoin, lithium, digoxin
9
.
Therapeutic window The objective of drug delivery includes
maintenance of drug concentration in
the therapeutic window for the
desired duration, with the aim of
(i) producing and sustaining the
desired therapeutic effect
(concentrations above the minimum
effective concentration)
(ii) minimizing the occurrence and
severity of unwanted side effects
(concentrations below the minimum
toxic concentration)

It is desirable to maintain drug concentrations in the therapeutic window for the entire
duration of treatment, thus avoiding / minimizing concentrations above MTC and below
MEC 10
 Maintenance of blood levels – IV multi-dose therapy
Consider intravenous multi-dose therapy where:
• Same IV bolus dose repeatedly administered intravenously at regular dosing intervals of τ.
• Sharp increase in plasma concentration after each IV bolus (solid lines in graph) followed
by first-order elimination (broken lines in graph) – saw-tooth pattern
If successive doses are administered
before complete elimination of
existing drug, accumulation occurs till
a steady state is attained

At steady state: Within each dosing

interval, the amount of drug added =
amount of drug eliminated.

At steady state, the plasma

concentration - time curves after each
dose are roughly superimposable.
11
 Maintenance of blood levels – IV multi-dose therapy

• At steady state, the drug concentration stays consistent, fluctuating between a

maximum (Cpss (max)) and minimum (Cpss (min)) steady state concentration.
• The dosing regimen may be established to obtain average steady state concentrations
in the therapeutic window.
• Depending on the dosing regimen employed and the therapeutic window of the drug,
the peak concentrations may exceed the minimum toxic concentration and the trough
concentrations may fall below the minimum effective levels. 12
Maintenance of blood levels – IV multi-dose therapy

For example, consider:

• Repeated IV bolus administrations of a fixed dose (say 100 mg) of a drug – see graph
• Dosing interval = half-life (τ = t½).
• Drug accumulation would occur.
• The plasma concentrations would achieve:
o ~ 97% of steady state levels in 4 - 5 half-lives
o > 99% of steady state levels in 6 - 7 half-lives. 13
Maintenance of blood levels – Oral multi-dose treatment
Example:
Consider a drug with an elimination half-life
of 12 h

An oral tablet of the drug with dose D is

administered every 24 h (τ = 24 h).

The plasma profile over the first 4 dosing

periods (a total of 8 half-lives) are shown.

By Alfie↑↓© (Helmut Schütz) - Own work, CC BY 3.0,

https://commons.wikimedia.org/w/index.php?curid=14784996

Similar to repeated IV administration, oral multi-dose treatment at regular intervals,

where successive doses are administered before complete elimination of the previously
administered drug, will result in drug accumulation till steady state is achieved.
14
Steady State
Steady State concentration depends on: Example:
Higher steady state levels can be achieved with
Clearance ↑ Css ↓ higher doses and / or with more frequent
dosing
Dosing frequency ↑ (τ ↓) Css ↑
Steady state levels can be affected when
Dose ↑ Css ↑ clearance is affected by hepatic or renal
impairment

AUCss for one dosing interval

Average steady state concentration =
τ

The time to reach steady-state is independent of the dose and dosing interval (τ).
On repeated dosing, at regular intervals, steady-state levels (> 97%) are achieved in 4-5
half-lives. 15
Limitations of multi-dose therapy
For drugs with short half life, frequent dosing will be needed

Risk of patient non-compliance is higher for multiple dosing.

If dosing intervals are not appropriate for the half-life of a given drug, large peaks and
valleys in the drug concentration will result.

During the early doses, concentrations may not be in the therapeutic range – a higher
loading dose may be needed to quickly achieve therapeutic levels

16
Maintenance of blood levels – loading dose + maintenance dose

An IV loading dose may be used to quickly

attain a therapeutic drug level
(A higher initial oral dose may also be
employed a a loading dose).

This may be followed by repeated

maintenance dosing by the oral route
Example – antibiotics

The maintenance dose can also be

administered as a constant IV infusion.

17
Oral extended- release systems

18
Oral extended- release systems
Oral extended-release systems
prolong the release of drug from the
dosage form - deliver drug to the
absorption sites in the intestine, over
a longer period of time. This prolongs
drug absorption and sustains blood
levels in the therapeutic range.

Extended-release products may be

designed to achieve lower peak to
trough ratios at steady state compared
to multi-dose therapy with
immediate-release formulations.

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Oral extended- release systems

Advantages
1.Reduction in frequency of administration leads to better patient
compliance
2. Employs less total drug for the same duration of treatment – reduced local
and systemic side effects
3. Better disease-state management due to controlled therapeutic levels
4. Reduction in hospitalisation / treatment time - economical

20
Oral extended- release systems

Limitations
1. Difficult to adjust dose of drug in renal or hepatic impairment or adjust for
patient age.
2. Breaking extended-release tablets to administer a fraction of the dose will
influence release profile.
3. Quick termination of therapy is difficult.
4. Higher unit cost due to expensive excipients, more sophistication in design
and manufacturing processes.

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Oral extended- release systems
Kinetic Processes in oral drug delivery
Dosage Systemic
Dissolved drug at Elimination
form Circulation /
absorption site
Release rate Absorption rate Target Area Elimination rate
constant, kr constant ka constant ke

Immediate release systems

➢ kr (drug release / dissolution rate constant) >>> ka
Drug release / drug dissolution is relatively fast. Absorption (transport of the drug molecules
across the intestinal barrier) is the slower step.

Extended-release systems
➢ kr <<< ka
Drug release is the rate limiting step and determines the rate of absorption
22
Oral extended- release systems – influence of drug release rate
EXAMPLE
Consider a drug with a first order elimination rate constant (ke) of 0.2 h-1 and a volume of distribution of 10 L.
The drug is administered at a dose D of 100 mg.
Formulations are designed to release the drug at varying rates with first order release rate constant (kr) of 0.05,
0.1, 0.15, 0.3 and 0.5 h-1.
If absorption is rapid and complete, drug release rate determines the rate of absorption.
The plasma concentration – time profiles after a single dose, are influenced by drug absorption (release) and
elimination rate constants and can be expressed by the following equation:

D kr
Cp = e−ke t − e−krt
Vd (kr − ke )

Cp - plasma concentration at time t, Vd - volume of distribution,

kr - first order release rate constant for drug release from an oral formulation,
Ke - first order elimination rate constant
23
Oral extended- release systems – influence of drug release rate
D kr
Cp = e−ke t − e−krt
Vd (kr − ke )

Graph includes the predicted plasma concentration -time

profiles for formulations with different drug release rates.
As release rate constant (kr) decreases, peak drug
concentration (Cmax) decreases, time required for peak
concentration (tmax) is prolonged, and drug levels are
sustained longer (see graph).
Thus, drug release profiles can be modified to target
desired plasma concentration profiles.
When the release rate constants are increased and
exceed the elimination rate constants (see profiles for kr =
0.3 and 0.5 h-1), the slopes of the elimination phase
become independent of the release rates and equal to
the elimination rate constant. 24
Oral extended- release systems – Zero order release

Consider a single dose of a formulation that delivers drug at the absorption site in a zero-
order fashion.
Drug released at a constant rate (rate constant = k0) is absorbed → drug accumulation in
the body occurs.
If k0 << ka, for an extended-release formulation, the plasma concentration profile for this
accumulation phase can be expressed as follows:
k0
Cp = 1 − e−ke t
Vd ke

Once the zero-order drug delivery ends (the dosage form is depleted of drug), the plasma
concentration decreases (first-order elimination) 25
Oral ER systems – Zero-order release EXAMPLE – Single dose
Consider a single extended-release dose of 120 mg
Drug zero-order release rate 10 mg hr-1.
The formulation thus releases with constant rate over 12 h.
Two scenarios:
1. ke = 0.087 h-1 (t½ = 8 h)
2. ke = 0.35 h-1 (t½ = 2 h)

During the accumulation phase: the amount of absorbed drug in

the body (A = Cp Vd)
k0
A = Cp Vd = 1 − e−ke t
ke
Drug accumulation over 12 h and subsequent first order
elimination are plotted in graph, for both scenarios

Same drug-release profile (and same absorption rates) can result

in different drug level profiles due to different elimination rates.

For the same drug release rate, shorter half-life results in lower
peak concentrations. 26
Oral ER systems – Zero-order release EXAMPLE – repeat dosing
For both elimination rates (t1/2 = 2 h and 8 h), let
us consider repeat dosing of the ER formulation
12 hours
at dosing intervals of 12h (B and C).

Here successive doses are administered as soon

as all the drug is released from the previous
dose. Therefore, there is continuous release of
drug, at a constant rate, over the repeated dosing
periods

Broken lines - the absorbed drug levels in the

body due to each individual dose
Solid lines - resulting cumulative amount of drug.

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Oral ER systems – Zero-order release EXAMPLE – repeat dosing
When the same dose (120 mg) is administered
as a zero-order release formulation with the
same release rate (10 mg/h), at the same dosing
12 hours
interval (12 h)
1. Steady state is attained sooner in the
scenario where the half-life is shorter (Panel
C)
2. The steady-state concentration achieved is
higher in the scenario where the half-life is
longer (slower clearance) (Panel B)

When zero-order releasing formulations are

administered at intervals (τ) corresponding to
the release duration of each dosage unit, they
are analogous to a constant-rate IV infusion.
Successive doses continue delivering drug at the
same constant rate and the result is a constant
plasma level at steady state. 28
Extended-release dose calculations

29
Oral extended- release systems – dose calculations – zero order release
As an ideal goal, to maintain constant drug levels, the formulation should release drug for
absorption at the same rate as drug elimination.
For a constant drug level, this implies drug delivery at a constant rate over time (independent
of the amount of dug remaining in the dosage form; zero-order)
Rate in = Rate out
k0r = ke . Vd . Cd
Where k0r is zero order rate constant for drug release; ke = first order rate constant for overall drug elimination
(time-1 ); Cd = desired drug level in the body (amount/volume); Vd = volume of distribution (volume)
1. Assumes that all released drug is transported to the system circulation (F=1), rate in = k0r
2. ke . Vd . Cd are determined from appropriately designed single dose PK studies and from concentration-
efficacy and concentration-toxicity relationships
3. Required release rate (k0r ) can be calculated. z

If the desired zero-order release rate is known and the desired release duration is known (Td ), the extended-
release dose, De can be calculated.
De = (required release rate) × (duration over which extended release desired)
De = (k0r) × (Td) = (ke Vd Cd ) Td = (CL Cd ) Td
30
Loading dose
Since desired drug level Cd may not be achieved quickly from an extended-release formulation,
a loading dose may be required.

Loading dose
The loading dose (Di) should be made immediately available to achieve therapeutic levels
quickly.

For a loading dose administered as an IV bolus

Di = Vd × Cd
z
For a loading dose administered orally, released immediately (IR) and rapidly absorbed

Di = (Vd × Cd ) / F
F is the fraction of the administered dose reaching the systemic circulation; oral bioavailability
Vd is the volume of distribution
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Dosage form containing both loading (Di) and maintenance (De) doses
EXAMPLE
Consider a single dosage unit designed to quickly achieve target drug levels (loading dose)
and sustain levels over the desired duration (maintenance dose)

Total dose W = immediate release loading dose (Di) + extended-release maintenance dose (De)
W = Di + De

If both the loading and maintenance doses start releasing drug at t =0, a correction is required to
account for the drug released by the extended-release component in the early stages.

W = (Di - k0rTp )+ k0rTd

k0rTp = correction factor (= amount of drug provided from the maintenance dose during the period t=
0 to the peak drug level Tp)

While formulations may include both loading dose and maintenance dose components, it is often
more practical to use an immediate release product to achieve target blood levels quickly and a
separate extended-release product to subsequently maintain blood levels. 32
Oral extended-release (zero order) systems – dose calculation
A drug can be administered intravenously to quickly provide therapeutic plasma levels.

The drug is rapidly and completely absorbed on oral administration. An oral maintenance dose regimen
is needed to replenish eliminated drug and maintain the target plasma concentrations. An ER zero-
order release profile can be achieved from a selected formulation approach.
Target plasma concentration Cd = 1 mg/L; Volume of distribution Vd = 50 L; Clearance CL = 8 L/h
Desired maintenance dosing interval = 8 h

IV bolus loading dose =

Di = Vd × Cd = (50 L x 1 mg/L) = 50 mg

For a zero-order release system, required release rate =

k0r = (ke . Vd . Cd ) = (CL Cd) = (1 mg/L x 8 L/h) = 8 mg/h

For a dosing interval ( drug release duration, Td ) = 8 h

De = k0r x Td = 8 h x 8 mg/h = 64 mg
An extended-release formulation with a strength of 64 mg, releasing drug at 8 mg/h, dosed every 8 h will
maintain the desired plasma levels of the drug 33
Oral extended- release systems – dose calculations
More generalized equations for oral products may be written as follows.
For an orally dosed drug product with a dose D, a bioavailable fraction F, and a dosing interval
(τ), the average rate of drug input into the systemic circulation =

𝐷𝑜𝑠𝑒
Rate in = 𝐹. ( )
𝜏

At steady state, (average steady state concentration = Css), rate of elimination =

F.Dose
Rate out = Css ke Vd = CL Css = C𝑠𝑠
AUC
F Dose 𝐴𝑈𝐶
Therefore, average steady state concentration = Css = =
CL τ 𝜏
Css depends on dose, dosing frequency, bioavailability and clearance
Note similarity with
Cssτ ke Vd Cssτ CL expression for De on slide 30
Drug dose per unit (product strength) = =
F F
For a target plasma concentration, the dose / dosing frequency required depend on bioavailability and clearance
34
Oral extended- release systems – dose calculations
Example
Calculate unit dose of drug for a sustained release formulation, to be administered at
intervals of 12 h. Pharmacokinetic properties and desired plasma levels are listed
below:
• Desired average steady state plasma level Css = 10 µg/ml = 10 mg/L
• Elimination rate constant = 0.5 h-1
• Volume of distribution = 7 L
• Oral bioavailability F = 84%
Css 10 mg/L
Sustained release unit dose = 𝜏 k 𝑒 V𝑑 = 12 h . 0.5 h−1 7 L = 500 mg
F 0.84

Using the equation above, dose / dosing frequency changes required in patients with
altered clearance (hepatic or renal impairment) can be estimated.

35
Oral extended- release systems

Drug release order

• While zero-order may be theoretically desirable, non-zero order release products may
be clinically equivalent.
• Small changes in tissue concentrations generally do not result in differences in clinical
performance.
• Zero order release from the dosage form may not always translate to uniform plasma
levels - may also be influenced by drug stability in the GIT, regional absorption
differences.

36
Extended-release design

37
Oral extended- release systems
Majority of marketed extended-release formulations are based on one of the following
Reservoir (membrane-controlled) systems – drug containing core is encased by an insoluble polymer
coat drug release
Water

Matrix systems –drug is dispersed in an excipient matrix which controls drug relrease
drug release

Water

Osmotic pumps – Osmotically- active excipients in the formulation result in water uptake through a
semipermeable membrane. Drug-containing fluid is forced out of aperture(s) in the membrane
Semipermeable membrane
Drug layer
Expanded osmotic layer
Osmotic layer 38
Reservoir (membrane-controlled) systems

39
Reservoir (membrane-controlled) systems

Drug Release mechanism

• Water from the dissolution medium enters the drug reservoir through the release-controlling film.
• The drug in the core dissolves and diffuses through the film.
o The dissolved drug may partition into the polymer phase of the film and diffuse across the
barrier and out of the tablet.
o The dissolved drug may diffuse out through channels /pores in the barrier coat.
• The film controls water entry and drug release.
• Drug-depleted shell remains and is excreted in the feces.

Risk of dose dumping in case of a defective coat (pinholes, cracks)

Relatively complex to manufacture.
40
Reservoir (membrane-controlled) systems – release kinetics
Water-insoluble polymeric material encases a core containing solid drug
Release mechanism – drug diffusion through a barrier membrane
From Fick’s first law of diffusion
dM SDK
Rate of drug transport across a barrier = = Cdonor − Creceiver
dt h

D - diffusion coefficient of the molecules undergoing transport, directly

proportional to absolute temperature and inversely related to diffusant
size and barrier medium viscosity.
S - surface area of the barrier; h – barrier thickness
K – partition coefficient of the drug (polymeric barrier: release medium)
For a reservoir-type ER system, Cdonor and Creceiver are the drug
Donor concentrations within the reservoir and in the external medium,
Receiver
respectively)
41
Reservoir (membrane-controlled) systems – release kinetics
dM S D K
= ΔC
dt h

• For a given drug and dosage unit, if the following are constant:
o S (surface area of dosage unit),
o D (diffusion co-efficient of the drug in the membrane)
o K (partition coefficient of the drug between the membrane and the dissolution medium)
o h (membrane thickness)

As long as excess solid drug remains in the tablet core, Cdonor = Cs = saturation solubility of the drug in the fluid
within the reservoir, remains constant.
If sink conditions are maintained, Creceiver << Cdonor, and Cdonor – Creceiver = ΔC ~ constant.
dM SDK
Therefore, release rate, = ΔC = constant. This results in zero-order drug release as long as a constant
dt h
concentration gradient , ΔC is maintained.

Zero-order release proceeds till there is undissolved solid drug inside the tablet core. Once all solid drug is depleted, ΔC
decreases and terminal release follows first-order kinetics. 42
 Reservoir (membrane-controlled) systems
• Release rate can be varied by
• Altering barrier thickness (h). Coating thickness on tablets pellets can be modified
• Changing polymer (altering membrane permeability)
• Including water soluble pore formers in the barrier coat to alter drug permeability
o When exposed to the dissolution medium, the pore formers will dissolve and generate
pores.
o Drug diffusion will occur through aqueous channels created by the pore-formers

dM S D K
= ΔC
dt h

43
Reservoir (membrane-controlled) systems
Insoluble Polymers used in coat formulation – (i) Polyvinyl acetate, (ii) ethylcellulose,
(iii) Ammonio Methacrylate Copolymer (Eudragit® RS, Eudragit ® RL)

Types of reservoir dosage forms –

1. Monolithic coated tablet
2. Coated beads – filled into capsules
3. Coated minitablets filled into capsules

44
Inert insoluble (hydrophobic) matrix systems

45
Inert matrix – release mechanism
Solid drug is dispersed uniformly in an insoluble polymer matrix
Polymers such as polyvinyl acetate, ethylcellulose, or lipids / waxes such as
carnauba wax, glyceryl dibehenate, hydrogenated castor oil, are matrix formers.

Dissolution Medium

1. Ingress of dissolution medium into the surface pores of the insoluble matrix tablet
causes dissolution of drug, and other soluble components.
2. This creates channels which allow further medium access into the matrix.
3. Drug and soluble excipients continue to dissolve in the medium and diffuse out
through the channels.
4. The drug-depleted zone moves inwards leaving outer porous matrix regions through
which drug diffusion out of the dosage form continues.
46
Inert insoluble matrix – release kinetics
Drug release is described by the Higuchi mathematical model originally
used to describe the release of a drug from a thin ointment film.

Assumptions in deriving the Higuchi equation

1. The amount of drug in the matrix far exceeds its solubility in the matrix
2. A perfect sink condition is maintained in the external medium
3. Drug particles are much smaller than the average diffusion distance
4. Diffusion co-efficient remains constant
5. No interaction occurs between the drug and the matrix
6. A pseudo steady-state is maintained during drug release

Dissolution
47
Medium
Inert insoluble matrix – release kinetics

D ε Cs
Higuchi model 𝑀t = . 2A − ε Cs t
𝜏

Mt - mass of drug released from unit surface area of the matrix at time t,
A - initial quantity of drug per unit volume of the matrix,
D - diffusion coefficient of the drug
Cs - saturation solubility of drug in the medium,.
ε - total porosity of the matrix after all the drug and soluble components have been released
τ - tortuosity of the matrix channels (a measure of the bends and turns in the matrix channels).

Drug release rate decreases with time

Drug release is proportional to the square root of time
48
Drug release from inert insoluble matrix
D ε Cs
𝑀t = . 2A − ε Cs t
𝜏
Modifying drug release
• An increase in the initial concentration of the drug will also increase release
rates
• Selection of matrix components
• An increase in the porosity of the matrix increases the rate and extent of
water influx, facilitating faster drug dissolution and release.
• An increase in tortuosity, decreases release rate by increasing diffusion path
lengths.
• Inclusion of soluble excipients that dissolve in the medium and diffuse out
of the system will increase porosity, decrease tortuosity, and thereby
increase release rates. 49
Hydrophilic Matrix systems

50
Hydrophilic Matrix systems (swellable matrices)
Solid drug is dispersed uniformly in a hydrophilic polymer matrix.

These matrices utilize high molecular weight hydrophilic polymers such as Hypromellose,
polyethylene oxide, carboxymethylcellulose sodium, xanthan gum.

• Easier to produce than reservoir systems.

• Risk of dose dumping is relatively low.
• Drug loading is generally lower than in reservoir systems.

Preparation of Matrix Systems

• Powder mixing and direct compression of tablets.
• Dry- or wet- granulation of powder mixtures (granules can be compressed or filled into capsule
shells)
• Spray congealing or melt granulation to obtain matrix granules (for wax matrices)
51
Hydrophilic Matrix systems – release mechanism

1. On exposure to the dissolution medium, polymers

absorb water, swell, and form a viscous gel layer,
which controls drug release.

2. Polymer hydration and gel formation proceed

towards the tablet core.

3. The drug dispersed in the matrix dissolves and is

released by diffusion through the swollen
polymer and the water-filled pores in the gel.

52
Hydrophilic Matrix systems – release mechanism

4. Simultaneously, the outer layers of the

swollen matrix continue to hydrate, the
polymer chains disentangle and erode
off the surface.
5. Drug release is by a combination of
dissolution, diffusion, and erosion
mechanisms
6. Especially for highly water-soluble
drugs, rapid dissolution from the tablet
surface layers occurs before the gel
layer is formed, causing an initial ‘burst-
release’ effect.

53
Hydrophilic Matrix systems
Modifying drug release
Formulation factors influence polymer hydration, gel viscosity and gel erosion
rates and thereby affect drug release.
• higher viscosity-grade polymer, higher polymer concentrations, and
polymer blends that yield stronger gels, result in higher gel viscosity.

• Higher gel viscosity decreases rates of diffusional transport (slower water

ingress and slower rates of drug diffusion)

• Higher gel viscosity decreases rates of matrix erosion.

• Lower viscosity-grade polymers, lower polymer levels and water-soluble

excipients, result in weaker gels and faster drug release.
54
Hydrophilic Matrix systems – drug release kinetics
Factors such as dimensions, diffusion paths, viscosity are constantly changing during the release
process.
A mechanistic equation cannot be used to describe the release of drug.
𝑛
𝑓𝑟 = k 𝑡
fr – fraction released at time t
k - is a system-dependent kinetic constant.
log 𝑓𝑟 = log k + n log t
Exponent n provides information on the mechanism of release.

Depending on the geometry of the dosage form:

n close to 0.5 - release that is predominantly by diffusion (release proportional to t½).
n close to 1 - release is predominantly due to polymer swelling and erosion, values of are
obtained (zero-order release).
n between 0.5 to 1.0 is seen when both release mechanisms are involved. 55
Osmotic pump drug delivery systems
Osmotic pump drug delivery system – release mechanism
Elementary osmotic pump
Osmotic pumps rely on water entry into an
osmotically active tablet core through a
semipermeable coat.

The semipermeable coat allows water entry into the

core but is impermeable to solutes.

The resulting volume changes inside the core causes

drug transport out of the tablet through predrilled
apertures in the coat

(Alternatively, pore-formers may be included in the

coat to generate pathways for drug transport)
Push-pull type osmotic pump (product design)
Bilayer tablet core
• Layer 2- Push layer - osmotically active,
expandable, pushing layer, containing an
osmogen (such as sodium chloride) to maintain
osmotic pressure, and a swellable polymer (such
as polyethylene oxide).

• Layer 1 –Drug layer - The other layer contains

the drug, along with other excipients including
an osmogen.

• Coat - The tablet is coated with a semipermeable

membrane (3) (e.g., cellulose acetate) with an
aperture drilled on the side of the drug layer (4)
Push-pull type osmotic pump – release mechanism
Drug release mechanism
• When exposed to GI fluids, water uptake occurs by osmosis into both layers through the
coat.
• The drug layer is converted to a homogeneous drug suspension, while the push layer
expands to pump the drug suspension out through the orifice.
• Unlike diffusion-controlled systems, drug dissolution is not a prerequisite for release from
osmotic pump - advantage for poorly water-soluble drugs.
Push-pull type osmotic pump – release kinetics
The rate of water imbibition into the tablet (dV/dt) through membrane can be
expressed as follows.
Δπ - Osmotic pressure gradient across the membrane
dV S k k - Permeability of membrane to water
= Δπ h - membrane thickness,
dt h S - membrane surface area

When semipermeable coating is rigid:

• volume inside the coat stays constant
• rate at which drug suspension is pumped out is equal to the rate of total volume change
caused by water imbibition

• Surface area, coat thickness and water permeability (S, h, and k) are constant for given
osmotic tablet.
• As long as solution concentration of the osmogen is maintained inside the core, the
osmotic pressure gradient, Δπ, is constant.
• Under these conditions, water influx rate, dV/dt, stays constant.
Push-pull type osmotic pump
The rate of drug release (dM/dt) through the orifice.
dM dV CD, susp is the concentration of the drug in the suspension
= 𝐶D, susp pumped out.
dt dt

For a constant water influx rate, therefore there is a constant rate of drug pumped out of
the tablet.
Zero-order release rates can therefore be achieved independent of (i) drug properties,
(ii) medium pH, (iii) ionic strength of the medium, and other physiological variables.
An example of a push-pull type osmotic tablet is Procardia XL®, an oral controlled release formulation for
nifedipine.

Concerta XL is an example of a trilayer osmotic system of methylphenidate with two drug containing layers
with different compositions (different drug release rates) and a bottom push layer.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a88218c-5b18-4220-8f56-526de1a276cd
Factors affecting feasibility of
ER product development

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Factors affecting feasibility of ER product development
Drug Solubility
dMsolid DS
Noyes Whitney Equation: − = (C − Cbulk )
dt ℎ s
Poorly soluble drugs (especially with a high dose) may not be ideal candidates for oral ER
products. A A significant portion of the unreleased dose may enter the colon where drug
absorption may be reduced and variable.

The absorption of poorly soluble drugs may be inherently prolonged (without any release
controlling design) due to slow dissolution
• release rate will decrease with time (as surface area decreases)
• may be difficult to control and will vary with particle size distribution and surface
characteristics

For drugs with very high solubility – it may be challenging to decrease dissolution / release rates
and slow down absorption. Less soluble derivatives of the drug may be employed.

Drugs exhibiting extremes in aqueous solubility therefore may not be suitable candidates for ER
product development.
Factors affecting feasibility of ER product development
Ionization (pKa)
Ka H+
ST = S0 1+ + for weak acids, ST = S0 1+ , for weak bases
H Ka

Solubility will be influenced by pH.

Release mechanism relying on drug dissolution will be affected by medium pH in the

GIT.

Drug absorption rate will also be affected by ionization extent – uncharged drug is
preferentially absorbed.

Ionization in the physiological pH range - additional considerations for effective design

of ER systems.
Factors affecting feasibility of ER product development
Molecular size and diffusivity
Larger molecules – lower diffusion coefficient values, slower diffusion rates

Release rates that rely on molecular diffusion through polymer matrices and barrier films will be slow

Other release mechanisms may be more suitable – matrix erosion, osmotic pumping etc.

Stability
Drugs susceptible to enzymatic, microbial or chemical degradation, may not be ideal candidates

Drugs degraded by colonic microflora may not be suitable for extended release and absorption beyond
7-8 h

Drugs susceptible to degradation in stomach may need protection during early transit
Factors affecting feasibility of ER product development
Permeability /absorption
Drugs with low permeability (BCS class III and IV) – absorption is limited and may exhibit regional
variability.

Decreasing release rates has no impact on pharmacokinetics or detrimental impact on extent of

absorption. These molecules ay not be good candidates for extended release

Protein binding
Protein binding interactions - Van der waal forces, hydrogen bonding, electrostatic attraction

Extensive binding of drug to plasma proteins – longer half life

High protein binding results in a biological depot effect (reservoir in the vascular space) – extended-
release systems may not be needed.
Factors affecting feasibility of ER product development
Metabolism
Drugs which undergo extensive intestinal or hepatic first pass may not be ideal candidates

For drugs with saturable first-pass metabolism (hepatic or gut)

• If drug bioavailability from immediate release dosage form is higher due to saturation of
metabolism, ER dosage form me exhibit reduced bioavailability
• If drug bioavailability is within the linear range for the IR and ER doses, no impact on bioavailability
is expected

Elimination Half-life
• Low half-life is often the reason for requiring ER systems
• Very low half-lives may necessitate higher release rates and higher doses
• Other variables such as dose, minimum effective concentrations, and volume of distribution will
also dictate feasibility of ER systems
EVALUATION OF EXTENDED-RELEASE PRODUCTS

In-vitro drug release testing

o Drug release testing in USP Type 1/ Type 2 apparatus (paddle, basket)
o USP Type 3 – Reciprocating cylinder apparatus - enables the product to be
subjected to different dissolution media and agitation speeds in a single run.
o USP apparatus 4 – Flow through cell - Advantages- Sink conditions, change of
media, agitation due to laminar flow.
o Evaluation of risk of dose dumping due to concomitant consumption of alcoholic
beverages may need assessment.

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EVALUATION OF EXTENDED-RELEASE PRODUCTS

In-vivo testing <USP 1088>

1. Oral solutions, or well-characterized immediate-release drug products can be used
as reference products for comparison
2. A single-dose crossover study for each strength of a modified-release dosage form
is required.
3. A multiple-dose, steady-state study using the highest strength of a modified-
release dosage form.
4. Potential for food effects including robustness of the dosage form (including dose
dumping) from extended-release dosage forms should be assessed.

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