Sustained release formulations

1. Sustained Release Formulations
M.Phil. Pharmaceutics

2. What is an ideal drug delivery system?
• it should deliver drug at a rate according to the needs
of the body over the period of the treatment.
• It should direct the active ingredient solely to the site
of action.
• This is achieved by development of new various
modified drug release dosage forms, like-
• Control release dosage forms
• Repeat action dosage forms.
• Sustained release dosage forms
• Extended release dosage forms etc

3. Some important definitions are
• CONTROLLED RELEASE DOSAGE FORMS:
• Dosage forms release drug at a constant rate and provide plasma concentration that
remains invariant with time.
• REPEAT ACTION DOSAGE FORMS.
• an individual dose is released fairly soon after administration , and second or third
doses are subsequently released at intermittent intervals.
• SUSTAINED RELEASE DOSAGE FORMS.
• an initial release of drug sufficient to provide a therapeutic dose soon after
administration , and then a gradual release over an extended period.
• EXTENDED RELEASE DOSAGE FORMS.
• These release drug slowly , so that 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 location are choosen to accomplish therapeutic or
conveniences objectives not offered by conventional dosage forms.

4. Sustained release dosage
forms (SRDF’S)

5. Introduction
• Sustained release ,sustained action, prolonged
action ,extended action, time release depot ,
repository dosage forms are the terms used to
indicate a drug delivery systems that are
designed to have a prolonged therapeutic
effect by continuously releasing medication
over an extended period of time after
administration of single dose.

6. ADVANTAGES OF SRDF OVER OTHER CONVENTIONAL DOSAGE
FORMS
• Decreased local and systemic side effects
reduced gastrointestinal irritation.
• Reduction in dosing frequency.
• Improved patient compliance and reduced
patient care time.
• Reduced fluctuations in circulating drug levels
• Reduced cost.

7. DISADVANTAGES OF SRDF
• Unpredictable or poor in-vitro and in-vivo
correlation.
• Dose dumping.
• Reduced potential for dosage adjustment.
• Poor systemic availability in general

8. CANDIDATES FOR SRDF
• In general the drugs best suited for SRDF having
following characteristics
• Have neither very short (less than 2 hours) Nor very
Long Half life (more than 8 hours)
• with Desirable absorption and solubility characteristics
• Are administered in relatively small doses
• Possess a high therapeutic index
• Are used in the treatment of chronic rather than
acute conditions.

9. Techniques used in SRDF
• There are two type of methods used for
development of SRDF
1. based on drug modification
2. based on dosage form modification

10. DRUG MODIFICATION
It can be done by either
a. Complex formation.
• Cationic exchange resins
• Tacid complexes
• Alginic acid complexes
b. Drug adsorbate formation.
• It is the special case of complex formation in which the drug is
essentially insoluble.
• e.g. clays like bentonite
c. Pro- drug formation.
• Pro-drugs are therapeutically inactive that regenerate the parent drug on
metabolism .
• For pro-drug Kd and Ke must be less than its parent drug.

11. DOSAGE FORM MODIFICATION
A. Embedded matrix principle.
• In which drug is embedded in a matrix of a retardant material
and compressed into tablets. The retardant materials may be
• Skeleton matrix forming e.g. PVC
• Water insoluble but potentially erodible e.g.
1.stearyle alcohol
2.carnuba wax
• Polymers forming hydrophilic matrices e.g. methyl cellulose
sodium car boxy methyl cellulose.

12. B. Barrier principle
• A layer of retardant material is imposed
between the drug and elution medium ( the
formulation may be in the form of granules or
tablets.
• Coating used are
I. Solid hydroxylated lipid ( hydrogenated
castor oil / glyceryl hydroxyl stearate) mixed
with modified cellulose.
II. Formalized gelatin

13. c. Osmotic principle
• The drug is covered with a semi permeable
membrane that allows the water to move
inside thus building up an osmotic pressure
and forcing the drug to exude out of tiny hole
made by laser.

14. MECHANISM OF RELEASE OF DOSAGE
FROM SRDF
1. Dissolution controlled system
• Easy to design
• Formulated by slowing dissolution rate of drug
in GIT through incorporating it into an
insoluble polymer and coating with diff.
material of varying thickness.
• Rate limiting step in such DDS is diffusion of
drug across boundary layer.

15. Contd.
The rate of dissolution is given by following
equation
dm/dt = ADS/h
Where
S= aq. Solubility of drug
A=surface area of tablet
D=Diffusivity of drug
h= thickness of boundary layer

16. continued
• Dissolution control can be achieved in following ways:-
• Slow dissolution of drug
• Drug with inherently slow dissolution rate.
• Drugs that transforms into a slow dissolving form.
• Slow dissolution rate of reservoir membrane & matrix
• Embedment in slowly dissolving, degrading erodible
matrix.
• Encapsulation or coating with slowly dissolving
degrading erodible substances.

17. Types of dissolution Controlled System
1. Matrix dissolution Controlled System
• it consists of a drug mixed with a polymer such
as bees wax or carnuba wax and from which the
drug is then released slowly depending upon the
porosity of the tablets.
2. Reservoir dissolution Controlled System
• In this type the drug is coated with polymer
material such as Cellulose and PEG and the
release of drug depends upon solubility and
thickness of coating.

18. MECHANISM OF RELEASE OF DOSAGE
FROM SRDF
2. Diffusion Controlled System:
• In this system the rate controlling step is diffusion of the drug
across the physical barrier.
• This system always follows first order kinetics
• This DDS can be prepared either by encapsulating the drug in
polymer or dispersing the drug in the matrix
The rate of diffusion is given by following equation
dm/dt = ADK ▲C/ l
Where
K= Partition co-efficient of drug between drug core and membrane
A= surface area of tablet
D= Diffusion co efficient
l= Diffusion path length
▲C= Concentration differnce across membrane

19. Types of diffusion Controlled System
• Porous matrix controlled system
• Rate controlling element is water swellable material
e.g. xanthan gums ,guar gum , high viscosity grades of
HPMC,HPC, alginates
• Porous membrane controlled system
• Rate controlling element is non-swellable water
insoluble polymer
• e.g. ethylcellulose, PMA. Drug release controlled
through micropores.

20. Methods Using ION Exchange
• Resins are water insoluble compounds having
both anionic and cationioc groupps
• Complex is formed upon prolong exposure of
ionic solution of drug with ionic resins
• Drug is slowly released when this complex
comes incontact with the gastric acid.
• E.g Nicorette is nictione in complex with
COOH group of resin.

21. Methods using Osmotic pressure
• In this design a semipermeable membrane is
placed in a tablet around the drug which
allows the inward movement of water and
pumping out drug at a zero order rate through
a small hole. E.. Procardia XL (Nifedipine)
• There are two types of this design
• Type A has drug in a osmotic core
• Type B has drug in flexible bad with
surrounding osmotic core.

22. pH independent Formulation
• Different buffers such as salts if amino acids
like citric acid,phthalic acid and phosphoric
acid are used in formulation to maintain a Ph
thus not affecting drug release.
• Formed by mixing the drug with buffering
agent/s and the granulating with suitable
excipients ad then coating with GIT juices
resistant polymer.

23. Factors Governing the Design of SRDF
• Physico-Chemical Properties
1. Molecular Size and Diffusivity
2. Aqueous Solubility
3. pKa - Ionization Constant
4. Partition Coefficient
5. Stability

24. Molecular Size and Diffusivity
•
• The ability of a drug to diffuse through a polymer is called
diffusion coefficient of that drug and depends upon the
molecular size
• In most polymers it is possible to relate log D to some function
of molecular size as,
• Log D = - Sv log v + Kv = - SM log M + Km
• where,
• V – Molecular volume.
• M – Molecular weight.
• Sv, Sm, Kv & Km are constants.
• The value of D is related to the size and shape of the cavities,
as well as the drugs.
• The drugs with high molecular weight show very slow kinetics.

25. Aqueous Solubility
• A drug with good aqueous solubility, serves as a good candidate
for SRDF.
• Drug to be absorbed it first must dissolve in the aqueous phase
surrounding the site of administration and then partition into
absorbing membrane.
• The dissolution if drug is greatly affected by the aqueous
solubility and the relation is clear by following relation
• dc/dt = KDA.cs
Where
• dc/dt is dissolution rate
• A is total surface area of drug
• C is aq. Saturation solubility of drug
thus the intial rate is directly propotional to the solubility of
drug

26. pKa - Ionization Constant
• Pka is the measure of strength of an acid or a
base and determines the presence of a charge
on a molecule at any given pH.
• Since all the drugs are either weak acids or
weak bases thus the presence or absence of
charge on a molecule is very important for its
ability to cross the membrane and hence
determines its dissolution.

27. Conti.
• Weakly acidic drug exist as unionized form in
the stomach absorption is favored by acidic
medium.
• Weakly basic drug exists as ionized form in the
stomach hence absorption of this type is poor
in this medium.

28. Partition Coefficient
• Between the time a drug is administered and is
eliminated from the body, it must diffuse through a
variety of biological membranes.
• As the membranes are lipid in nature Oil/Water
partition coefficient plays a major role in evaluating the
drug penetration
• K=Co/Cs
• Drugs with extremely high partition coefficient are very
oil soluble and penetrates in to various membranes very
easily an stay there for longer times
• Drugs with low partition co-efficient have low
bioavailability

29. Stability
• Solid state undergoes degradation at much slower
rate than in the suspension or solution etc..
• Drugs stable in stomach gets released in stomach
and which are unstable gets released in intestine.
• Drugs with stability problems in any particular
area of G.I.T are less suitable for the formulation.
• Drugs may be protected from enzymatic
degradation by incorporation in to a polymeric
matrix.

30. EXAMPLES OF PHARMACEUTICAL
TECHNOLOGYS USED IN SRDF
• Oral Drug delivery systems
• These SRDF systens mostly involve diffusion or
dissolution or both to facilitate slow release of
drug in GIT.