Sr or cr formulations

Presented by,
Pratiksha C Chandragirivar
M pharma 1st sem
Dept. of pharmaceutics
HSK COP Bagalkot
Facilitated by,
Dr. Anita Desai
HOD and professor
Dept. of pharmaceutics
HSK COP Bagalkot
SR/CR FORMULATIONS 1

 1. INTRODUCTION
 2. BASIC CONCEPT OF SR OR CR
FORMULATIONS
 3. ADVANTAGES
 4. DISADVANTAGES
 5. FACTORS INFLUENCING SRDF’S
 6. PHYSICAL APPROACHES

 WHAT IS DRUG DELIVERY SYSTEM?
ANS : The term “drug delivery systems” refers to the technology
utilized to present the drug to the desired body site for drug release
and absorption
HISTORY : The history of controlled release and sustained
formulations involves three time periods viz.,
1.From 1950 to 1970 was the period of sustained drug release
2.From 1970 to 1990 was involved in the determinations of the
needs of the control drug delivery
3.Post 1990 modern era of controlled release technology.

In recent years, considerable attention has been focused on the
development of new drug delivery systems. This is evidenced by
the spate of books [1-8] and review articles [9-18] published on
this subject.
There are a number of reasons for the intense interest in new
systems.
 First, recognition of the possibility of re patenting successful drugs
by applying the concepts and techniques of controlled release
drug delivery systems, coupled with the increasing expense in
bringing new drug entities to market, has encouraged the
development of new drug delivery systems.
 Second, new systems are needed to deliver the novel, genetically
engineered pharmaceuticals, i.e., peptides and proteins, to their
sites of action without incurring significant immunogenicity or
biological inactivation.
 Third, treating enzyme deficient diseases and cancer therapies
can be improved by better targeting.
 Finally, therapeutic efficacy and safety of drugs, administered by
conventional methods, can be improved by more precise spatial
and temporal placement within the body, thereby reducing both the
size and number of doses.

For the concepts of drug delivery system or dosage forms two criterias
should be kept in mind viz,.
1. First,
o It should deliver drug at a rate dictated by the needs of the body over
the period of treatment. This may necessitate delivery at a constant
rate for drugs that have a clear relationship between steady state
plasma levels and the resultant therapeutic response.
2. Second,
o It should channel the active entity solely to the site of action. This may
necessitate delivery to specific receptors, as in the case of H1 and H2
antagonists, localization to tumor cells, as required by most cancer
treatments, or to specific areas of the body as for arthritis or gout.
.

Before ,initiating a discussion of sustained release and
controlled release dosage forms ,
It is necessary to study some terminologies viz.,
 CONTROLLED RELEASE DOSAGE FORMS :
Dosage form which release drug at a constant rate and
provide plasma concentration that remains invariant with time.
 REPEAT ACTION DOASAGE FORMS :
An individual dose is released fairly soon after
administration , and second or third doses are subsequently
released at intermittent intervals.
 SUSTAINED RELEASE DOASAGE FORMS :
An initial release of drug sufficient to provide a
therapeutic dose soon after administration and then a gradual
release over a extended period.

 EXTENDED RELEASE DOSAGE FORMS :
These are the dosage forms which release the drug
slowly , so that the plasma concentration are maintained at a
therapeutic level for a prolonged period of time usually between 8-
12 hours.
 MODIFIED RELEASE DOSAGE FORMS :
According to USP these are those dosage forms whose
drug release characteristics of time course and or chosen to
accomplish therapeutic or conveniences objectives not offered by
conventional dosage forms.

WHAT IS SUSTAINED RELEASE FORMULATIONS?
SRF ‘S describes the slow release of a
drug Substance from a dosage form to maintain
therapeutic response for extended period i.e. for about
8-12 hrs. of time.
 Time depends on the dosage form viz.,
in oral form = it is in hours
in parenteral form = it is in days and months
Examples : Aspirin SR, Dextrin SR.

WHAT IS CONTROLLED RELEASE
FORMULATIONS?
These are the formulations which delivers
the drug at a predetermined rate, for locally or
systematically , for a specified period of time.
Example : GITS - Prazosin (mini press)
Morphine sulphate ( Roxonal SR)

Difference between controlled release and
sustained release formulations
Sustained release
formulations
Controlled release
formulations
1. Constitutes dosage form that
provides medication over a
extended period of time.
1 .Constitutes dosage form that
maintains constant drug levels
in blood or tissue.
2.SRF’S generally do not
follows zero order kinetic
pattern.
2.Maintains constant drug
levels in the blood in the target
tissue usually by releasing the
drug in a zero order kinetic
pattern.
3.Usually do not contain
mechanisms to promote
localization of the drug at active
site.
3. It contains methods to
promote localization of the drug
at active site.

The of concept of sustained release formulation
can be divided into two considerations i.e.,
a. Release rate
b. Dose consideration
A. RELEASE RATE:
Here , Kr= Drug release , Ka= Drug absorption
Ke= Drug elimination.

In conventional dosage form Kr>Ka in this, the release of
drug from dosage form is not rate limiting step.
The above criteria i.e.( Kr > Ka ) in case of immediate
release, where as in non immediate ( Kr< Ka ) I.e. release is rate
limiting step.
So that effort of developing S.R.F. must be directed
primarily altering the release rate. The rate should be independent of
drug removing in the dosage from over constant time.
The release rate should follow zero order kinetics,
Kr = rate in = rate out = Ke Vd . Cd
Ke = overall elimination (first order kinetics).
Vd = total volume of distribution.
Cd = desired drug concentration.

B. DOSE CONSIDERATIONS:
To achieve the therapeutic level and
sustain for a given period of time for the dosage form generally
consists of 2 part
a. Initial (primary)dose
b. Maintenance dose
Therefore the total dose ‘W’ can be
W = Di + Dm
In a system ,the therapeutic dose
release follows zero order process for a specified period of time.
W = Di + K0 r. Td
Td = time required for sustained release from one dose.

If maintenance dose begins to release the drug during dosing t = 0
then,
W = Di + K0 r. Td - K0 r. Tp
where, Tp = time of peak drug level
However a constant drug can be obtained by suitable
combination of Di and Dm that release the drug by first order
process, then
W = Di + K0 r. Td + (Ke . Cd / Kr ) Vd .
Sustained release, sustained action, prolonged action,
controlled release , extended action , time release dosage forms
are terms used to identify drug delivery system that are designed
to achieve a prolonged therapeutic effect continuously releasing
medication over an extended period of time after administration of
single dose.

1. Reduction in dosing frequency.
2. Enhanced patient convenience and compliance due to less
frequent drug administration.
3. Reduction in adverse effects (both systematic and local) of potent
drugs in patients.
4. Reduction in health care costs.
5. Improved efficiency of treatment.
6. Reduces nursing and hospitalizing time.
7. Reduction in blood level fluctuations of the drug ,thus the better
management of disease.
8. Maximum bioavailability with minimum dose.
9. Minimizes the accumulation of drug with chronic dosing.
10. Cure or controlled condition promptly.
11. Makes use of special effects. E.g. treatment of arthritis.

1. Possibility of dose dumping due to food , physiologic or formulation
variables or grinding of oral formulations by patients and thus increased
risk of toxicity.
2. Reduced potential for dose adjustment of drugs normally administered in
varying strengths.
3. Cost of single unit dosage form is higher than that of conventional dosage
form.
4. Increase potential for first pass metabolism.
5. Requirement of additional patient education for proper medication.
6. Decreased systemic availability in comparison to immediate release
conventional dosage form , this may be due to incomplete release ,
increased first metabolism, increased instability, insufficient resident time
for complete release, site specific absorption, PH dependent solubility etc,.
7. Poor in vitro and in vivo correlation.
8. Retrieval of drug is difficult in case of toxicity, poisoning and
hypersensitivity reaction.
SR/CR FORMULATIONS
16

 There are mainly six factors influences the
performances of sr or cr formulations those are as
follows :
1. Drug properties
2. Route of drug delivery
3. Target sites
4. Acute or chronic therapy
5. The disease
6. Patients

1. Drug properties :
 The physiochemical properties of a drug , Including stability,
solubility, partitioning characteristics, charge, and protein binding
propensity, play a dominant role in the design and performance of
controlled release systems.
2. Route of drug delivery:
 The area of the body in which drugs will be applied or administered
can be restrictive on the basis of technological achievement of a
suitable controlled release mechanism or device.
 At times, the drug delivery system, in certain routes of
administration, can exert a negative influence on drug efficacy,
particularly during chronic administration, and hence other routes
of administration should be considered.
 Performance of the controlled release systems may also be
influenced by physiological constraints imposed by the particular
route, such as first-pass metabolism, GI motility, blood supply, and
sequestration of small foreign particles by the liver and spleen.

3. Target sites:
 In order to minimize unwanted side effects, it is desirable to
maximize the fraction of applied dose reaching the target organ or
tissue. This can be partially achieved by local administration or by
the use of carriers.
 However, the absorptive surfaces of most routes are impermeable
to macromolecules or other targeted delivery systems, thereby
necessitating either intravascular or intra arterial administration.
4. Acute or chronic therapy:
 Consideration of whether one expects to achieve cure or control of
a condition and the expected length of drug therapy are important
factors in designing controlled release systems.
 Attempts to generate a one year contraceptive implant presents
significantly different problems in design than does an antibiotic for
acute infection.
 Moreover, long term toxicity of rate-controlled drug delivery
systems is usually different from that of conventional dosage
forms.

5.The disease:
 Pathological changes during the course of a disease can play a
significant role in the design of a suitable drug delivery system.
Example:
In attempting to design an ocular controlled-release product for an
external inflammation, the time course of changes in protein
content in ocular fluids and in the integrity of the ocular barriers
would have to taken into consideration.
 Sometimes, one can take advantage of the unique manifestations
of the disease state.
Example:
The higher plasminogen activator levels in some tumor cells can
lead to preferential bioconversion of peptidyl prodrugs in these
cells. Similarly, the higher tyrosinase level in melanoma cells has
been demonstrated to allow targeting to and preferential
bioconversion of 2, 4-dihydroxphenylalanine in them.

6.The patient:
 Whether the patient is ambulatory or bedridden, young or old,
obese or gaunt, etc., can influence the design of a controlled
release product.
 An implant or intramuscular injection of a drug to a bedridden
patient with little muscle movement may perform in a manner
significantly different from that of an ambulatory patient.
 Some of these factors represent individual patient variation and
cannot be controlled by the research scientist while others must be
considered.
Example: single unit controlled release products are particularly
prone to intra- and inter-subject variation because of variabilities in
individual GI motility.

PHYSICO
CHEMICA
L
APPROAC
HE
AQUEOUS
SOLUBILITY
AND PKA
PARTITION
COEEFFICIENT
AND
MOLECULAR
SIZE
DRUG
STABILITY
PROTEIN
BINDING

A. Aqueous Solubility
 As we know that for the better absorption the drug must be in
solution form, compounds with very low aqueous solubility results
in oral bioavailability problems because of limited gastrointestinal
transit time of the un dissolved drug particles and limited solubility
at the absorption site.
 A drug with good aqueous solubility , especially if Ph independent ,
serves as a good candidates.
 Drug to be absorbed first must dissolve in aqueous phase
surrounding the site of administration and then partition into
absorbing membrane.

 For many compounds, the site of maximum absorption will
also be the area in which the drug is least soluble.
Example:
Tetracycline dissolves to a greater extent in the stomach than in
the intestine, although it is best absorbed in the intestine.
Such drugs may be poor candidate for sustained/controlled release
systems,
 unless the system is capable of retaining the drug in the stomach
and gradually releasing it to the small intestine
or
 unless the solubility is made higher and independent of the
external environment by encapsulating the drug with an acid (if the
drug is a weak base) or a base (if the drug is a weak acid) in a
membrane system.

 Examples of other drugs which are limited in absorption by their
dissolution rate are digoxin , warfarin , griseofulvin , and salicylamide
.
 Although the action of a drug can be prolonged by making it less
soluble, this may occur at the expense of inconsistent and incomplete
bioavailability.
 The choice of mechanism for oral sustained/controlled release
systems is limited by aqueous solubility of the drug.
 If the mechanism is of dissolution, it must give some extent of
dissolution rate.
 The dissolution rate must be clearly depicted by the equation called
“Noyes Whitney equation”
dc/dt = Kd A Cs
where, dc/dt = Dissolution rate
Kd = Dissolution rate constant
A = Total surface area of a drug
Cs = aqueous saturation solubility

 Diffusional systems will be poor choices for slightly soluble drugs
because the driving force for diffusion, the concentration in
aqueous solution, will be low.
 Prevention: In contrast, such drugs may be effectively
incorporated in matrix systems.
 On the positive side for dissolution concept for the sr
formulations, the slow dissolution rate of compounds can be
utilized to achieve sustained/controlled drug release by
incorporation in a matrix system. On the negative side,
dissolution-limited bioavailability may occur.

PKA (dissociation constant):
 The aqueous solubility of weak acids and weak bases
is governed by the pKa value of the compound and pH
of the medium.
 weakly acidic drug exist as unionized form in the
stomach absorption is favored by acidic medium.
 For weak acid,
St = So (1+ Ka [H]) = So (1+10 pH - pKa)
where , St = Total solubility Of the weak acid
So = Solubility of the unionized form
Ka = Acid dissociation constant
H = Hydrogen ion concentration

 For weak bases,
Weakly basic drugs exists as ionized form in the
stomach hence absorption of this type is poor in this
medium.
St = So + (1+[H]Ka) = So (1+ 10 pKa - pH)
Where,
St =Total solubility of both conjugate and free base
form of weak base.
So = Solubility of the free base

B. PARTITION CO-EEFICIENT AND
MOLECULAR SIZE
 Partition coefficient and molecular size influence not only the
permeation of a drug across biological membranes, but also diffusion
across or through a rate-controlling membrane or matrix.
 Following administration, the drug must traverse a variety of
membranes to gain access to the target area. Drugs with extremely
high partition coefficient (i.e., very oil-soluble) readily penetrate the
membranes but are unable to proceed further, while drugs with
excessive aqueous solubility i.e., low oil/water partition coefficients
cannot penetrate the membranes.
 A balance in the partition coefficient is needed to give an optimum
flux for permeation through the biological and rate controlling
membranes.
 Hansen and Dunn as well as Fujita et al. have shown that, for many
body tissues, such as the gastrointestinal tract, skin, and blood-
aqueous barrier of the eye, the optimum n- octanol/water partition
coefficient at which maximum flux occurs is approximately 1000.

 The ability of a drug to diffuse through membranes, its so called
diffusivity, is related to its molecular size by the following
equation:
Log D = -Sv log V + kv = -Sm log M + Km
Where,
D = Diffusivity
M = molecular weight
V = molecular volume, and
Sv, sM, kv, and Km are constants in a particular
medium.
 In general, the denser the medium, the smaller the diffusivity. For
drugs of intermediate molecular weight (150-400), diffusivities
through flexible polymers are typically of the order of 10"^-8 cm2
sec-1.

C. DRUG STABILITY :
 The stability of a drug in the environment to which it is exposed is
another physicochemical factor to be considered in the design of
sustained/controlled release systems.
 Drugs that are unstable in the stomach can be placed in a slowly
soluble form or have their release delayed until they reach the small
intestine.
 However, such a strategy would be detrimental for drugs that either
are unstable in the small intestine or undergo extensive gut-wall
metabolism, as evidenced by decreased bioavailability when these
drugs are administered from a sustained release dosage form.
 To achieve better bioavailability and controlled release of drugs that
are unstable in the small intestine, a different route of administration
should be chosen.
 Controlled release of nitroglycerin is a good example.
 On the positive side, the presence of metabolizing enzymes at the site
of administration or along the pathway to the target area can
sometimes be utilized in controlled drug delivery

D . Protein Binding
 It is well known that many drugs bind to plasma proteins with a
concomitant influence on the duration of drug action.
 Since blood proteins are for the most part re circulated and not
eliminated, drug protein binding can serve as a depot for drug
producing a prolonged release profile, especially if a high degree
of drug-binding occurs.

 Levine has shown that quaternary ammonium compounds bind
to mucin in the GI tract.
i.e., Drugs bound to mucin may increase absorption, if the bound
drug act as a depot. However, if degradation and/or washing of
the drug further down the GI tract occurs, binding of drug to
mucin may result in a reduction of free drug available for
absorption. The issue of drug and vehicle interaction with the
mucin layer and its influence on extent and duration of drug
absorption has been reviewed.
 Main forces for binding proteins are Vander Waal forces ,
Hydrogen bonding, electrostatic forces.
 Charged compounds has greater tendency to bind proteins than
uncharged one.

REFERENCES
1. Robinson, J. R., Lee V. H. L, Controlled Drug
Delivery Systems, Marcel Dekker,Inc., New
York, 1992.
2. Biopharmaceutics and pharmacokinetics a
treatise by D.M. BRAHMANKAR, SUNIL.B.
JAISWAL.
3. WWW.GOOGLE.COM

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