This document discusses different methods for approximating zero-order and first-order drug release from sustained release drug formulations, including encapsulated beads or granules, tablet formulations, and approaches based on modifying the drug's properties. It describes factors that influence drug release rates such as solubility, absorption rates, and enzymatic metabolism and provides examples of complexation, adsorbates, and prodrugs for achieving sustained release. In vitro drug release testing methods aim to simulate drug passage through the gastrointestinal tract and ensure batch uniformity.

1. Zero order release approximation
• A design consisting of a loading dose and
zero order release maintained dose.
• If a zero order release characteristic can
be implemented in a partial formulation,
the release process becomes independent
of the magnitude of the maintenance dose
and does not change during the effective
maintenance period

3. First order release approximation
The rate of release of drug from the maintaince portion
of the dosage form should be zero- order if the amount of
drug at the absorption site in to remain constant.
 Most currently sustained release formulation, how ever
don't release drug at constant rate and consequently do
not maintain the relative constant activity.
Observed blood level decreases over time until the next
dose is administered

4. The rate of appearance of drug at the absorption site
can be approximated be an exponential or first order
process, in which the rate of drug release is a
function of the amount of the drug remaining in the
dosage form.
• The expression that can be used to estimate the
design parameter for optimized first under release
method.
Method 1: Dm not delayed (simultaneous release of Dm & Di)
Method 2: Dm delayed when Tm=Tp
Method 3: Dm delayed release when Tm > Tp

5. • D1 = initial loading dose or immediately available portion of dose.
• Dm = Maintenance dose or slowly available portion of dosage
• Tm = Time at which release of maintenance dose.
• Kr = Specific rate of release of maintenance dose
• Tp = Peak level time
• Kr = Specific rate of release of maintenance dose
• H = Total time after administration in which the drug is effectively
absorbed

6. • Method 1: Simultaneous release of Dm and Di or Dm not
delayed
The crossing time, Ti is the time at which the blood level
profile produced by administration of separate loading and
maintain doses intersect. The closest approximation to the
ideal profile is obtained if the crossing point is made at
least equal is the desired maintenance period (h-Tp)

7. Method 2: Delayed release of Dm (Tm=Tp)
If Dm is large and Kr is made small, maintenance dose may
be released on a pseudo zero order process.
As a first approximation Kr1 may be estimated as the
reciprocal of the maintenance time . Dm is then calculated
as in method 1.

8. Method 3: Delayed release of Dm (Tm > Tp)
Increasing the delay time Tm allows the use of faster
release rates, A period equal to the time at which 99% of
the loading dose has been absorbed is selected.

10. Multiple Dosing:
Like conventional dosage form, sustained release form are
administrated as multiple dosing release, with the objective is to
maintain the required avg. drug level for the duration of therapy with
a minimal fluctuation b/w doses. If the dosing interval is made equal
to (or less than) the total anticipated drug release time (fig )
accumulation results from formulation designed with loading doses.
Significant blood level peaks may be observed with the zero-order
release model:
How ever minimal fluctuation b/w administered
Fig on next page

12. dose can be obtained if the dosing is set equal to (h+4) as shown by
curve B.
Increasing the dosing interval further while diminishing the peak
also deepens the trough in the drug level profile, defeating one of
the objective of dosage form design.
In sustained release therapy only the dosing interval is adjustable.
If two units are initially administered followed by a single unit
subsequently doses, as common in therapy with non-sustained
form, a slow fall in overall drug level accur .There are several
strategies for attaining approximation of ideal profile in the
multiple dosing of different sustained release designs based on
both cumulative and non cumulative approaches.

13. Alternatively administration of formulation designed without
loading doses can result in minimal fluctuation during the
long term therapy.
in fig Curve-c shows the result of this type of multiple
dosing regimen where a zero-order based design
consisting only slow release maintenance dose is
administrated at interval of h hours.
if absorption is consistent, profile obtained are
equivalent to those resulting from administration of drug by
constant rate infusion.

14. APPROACHES BASE ON DRUG MODIFICATION:
Two general set of method have been developed for implementation of
practical sustained release dosage form design.
Method based on the modification of the physical/or chemical properties of the
drug and method based on modification of drug release rate characteristics of
the dosage that affect bioavailability.
Design A: the physicochemical properties of a drug may be altered through
complex formation, drug adsorb ate preparation, or prodrug synthesis
possible where functional gp present .The principle advantages of this
approach to sustain release is that it is independent of the dosage form
design. Drug so modified may be formulated as the liquid suspension,
capsules or tablets. Loading doses of
Implementation of Design

15. unmodified drug may also be incorporated in formulations
that are ordinarily formulated to release both unmodified
and modified drugs without significant delay.
Mechanism:
method involved in controlling the release of drug form
complexes, adsorbates and pro-drugs. In the case of
drug complexes, the effective release rate is a function
of two processes: the rate of the dissolution of solid
complex into the biological fluids and rate of dissociation
or break down, of the complex in the solution.

16. In general dissolution step may be described
following expression:
Rate Dissolution: Ks(solubility) (surface area)
Where Ks is the dissolution rate constant, a
function of the hydrodynamic state as well as
factor influencing the diffusion process (e.g.
viscosity)

17. Technicalities: the formulator has the option of altering
surface area through particle size control/ and solubility
of the drug complex through selection of the complexing
agent.
while both processes are dependent on the pH
and composition of the gastric and intestinal fluids, the
dissociating step is critically so, since its rate may be pH
dependent, may be determined by the ionic composition
of the fluid and may be affected by the natural digestive
processes including enzymatic and bile salt action.
The formulator should select the appropriate
complex for preparation with the knowledge of the
specific in vivo processes involved in the control of drug
release from the complex. E.g. tannate complex of
bases are hydrolyzed in both acidic and basic media.

18. the dissociation of the complex being more rapid at
the gastric pH. Drug release from cationic ion-
exchange resin complexes depends on Na ion
concen in GI fluids and although a stearate salt of a
weak base resists the action of gastric fluid, natural
digestive processes in the intestine act to dissociate
the complex.
If the rate of dissolution is greater than the
rate of dissociation, then the dissolution of the
complex is rate determining.
P. size of the complex should be adjusted to
establish the most appropriate rate of release with
sufficient excess solid phase, zero order release may
also be approximated.

19. Design B: Drug absorbate represent a special
case of complex formation, in which product is
essentially insoluble, drug availability in
determined only by the rate of dissociation
and there for, acess of the adsorbent surface
to water as well as the effective surface area
of adsorbate.
prodrug are therapeutically in active drug
derivatives that regenerate the parent drug by
enzymatic or non enzymatic hydrolysis.

20. Fig shown the scheme that identifies the
potential process for achieving sustained
action.
Dissolution Dissocation Absorption
D.C (Solid). D.C (Solution) D
(Drug absorbate) Desorption Absorption
A.D. D
(Solid)
Pro drug
Dissolution Absorption metabolism Excretion
P.D (Solid). P.D (Solution) P.D P.D
Plasma

21. Factors:
the solubility, specific absorption rate, and / or
elimination rate constant of an effective prodrug should
be significantly lower then that of the parent compound.
Approaches based on dosage form modification.
Most per oral sustained release product have been
formulated as encapsulation or tablet.
Formulation based on modification of physicochemical
properties of these dosage form can be classed into
three product type.
1- Encapsulated slow release beads (or granules)
2- Tabletted mixed or slow release granulation
3- Slow release (core) tablet.

22. • One layer or the other coat of the tablet is
prepared from a potentially rapid disintegration
granulation leaving the less quickly
disintegrating layer or core which contains the
maintenance dose.
System prepared as tabletted mixed released
granulation, may or may not be designed to
disintegrate quickly, simulating the administration of
an encapsulated form in the latter case.
Advantages encapsulated s. released dosage form
have two specific advantages over core tablet dosing
1- Undisintegrated tablet may remain in the stomach for
extended period of time, excessively delaying
absorption of the maintenance dose.

23. Disintegration of the capsule shell in the
gastric fluid release particle that can pass
unimpeded through the pyloric valve.
2- there is statistical assurance of drug
release with encapsulated form , since
release of drug by a significant fraction of
the granule is highly probable, if a core
tablet fail to release drug, all of the
maintaince dose is lost.

24. Product evaluation and testing
In vitro measurement of drug availability:
it is not possible to simulate in a single in vitro
test system the range of variables that affect
drug release during the passage of sustained
release medication through GIT.
Properly designed in vitro test for drug
release serve two important functions.
1- Data from such test are required as guide to
formulation during the development stage prior
to clinical test

25. 2- in vitro testing is necessary to ensure batch to
batch uniformity in the production of a proven
dosage form.
Methods: different method are usually required by
these two distinctly different testing solution .
Ideal characteristics of Method: method used to
measure drug release profile should have the
following characterstics.
1- The analytical technique should be automated
so that the complete drug release profile can be
directly recorded.

26. 2- Allowance should be made for changing
the release media from simulated gastric
to simulated intestinal fluid at reliable
programmed time interval to establish the
effect of the retention dosage form in
gastric fluid as well as to approximate
more closely the pH shift, that the dosage
form is likely to encounter in vivo.
3- The hydrodynamic state in the
dissolution vessel should be controllable
and capable of variation.