This document discusses approaches to controlled release oral drug delivery systems, specifically osmotically controlled drug delivery systems. It begins by explaining the limitations of conventional immediate release drug formulations and how controlled release systems can overcome these. It then describes how osmotic systems utilize osmotic pressure principles to control drug release independently of physiological factors. Various types of osmotic systems are classified and described in detail, including implantable pumps, single chamber and multi chamber oral osmotic pumps. Factors influencing drug release from these systems like solubility, membrane permeability, and osmotic pressure differences are also discussed.

1. APPROACHES TO CONTROLLED
RELEASE ORAL DRUG DELIVERY
SYSTEMS
ORAL PRESSURE CONTROLLED DDS
BY-NIKHIL A. BHANDIWAD
M.PHARM 1ST YEAR
DEPARTMENT OF PHARMACEUTICS

2. Osmotically Controlled Drug Delivery
System
• Conventional oral drug delivery systems are known to provide an
immediate release of drug, in which one cannot control the release
of the drug and effective concentration at the target site. The
bioavailability of drug from these formulations may vary
significantly, depending on factors such as physico-chemical
properties of the drug, presence of excipient, various physiological
factors such as the presence or absence of food, pH of the GI tract,
GI motility, etc.
• To overcome this limitation of oral route is replaced by parenteral
route.
• This route offers the advantage of
1. reduced dose
2. targeting of site
3. avoiding GI stability
4. Hepatic by-pass of drug molecule.

3. Novel Drug Delivery System
• In recent years novel drug delivery systems have
been developed which has achieved a very big
milestone in the Pharmaceutical sector.
• Sustained and consistent blood level of drug can
be achieved within the therapeutic window.
• Enhanced bioavailability
• Reduced inter patient variability
• Customized delivery profiles
• Decreased dosing frequency
• Improved patient compliance

4. Novel Drug Delivery System
• The drug release can be modulated by different ways
but the most of novel drug delivery systems are
prepared using matrix, reservoir or osmotic principle.
• In matrix systems, the drug is embedded in a polymer
matrix and the release takes place by partitioning of
drug into the polymer matrix and the surrounding
medium.
• In contrast, reservoir systems have a drug core
surrounded by a rate controlling membrane.
• The osmotic systems utilize the principles of osmotic
pressure for the delivery of drugs in both the routes
oral as well as parenteral.

5. CLASSIFICATION OF CONTROLLED
DRUG DELIVERY SYSTEMS
• Controlled drug delivery system is classified as
follows:
1. Rate pre-programmed drug delivery systems
2. Activation-modulated drug delivery systems
3. Feedback-regulated drug delivery systems
4. Site targeting drug delivery systems

6. Types of Rate pre-programmed drug
delivery systems
1. Polymer membrane permeation-controlled
drug delivery systems
2. Polymer matrix diffusion-controlled drug
delivery systems
3. Micro reservoir partition- controlled drug
delivery systems

7. Types of Activation-modulated drug
delivery systems
• Physical means
1. Osmotic Pressure- activated drug delivery systems
2. Hydrodynamic pressure- activated drug delivery
systems
3. Vapour pressure- activated drug delivery systems
4. Mechanically activated drug delivery systems
5. Magnetically activated drug delivery systems
6. Sonophoresis –activated drug delivery systems
7. Iontophoresis-activated drug delivery systems
8. Hydration-activated drug delivery systems

8. • Chemical means
1. pH –activated drug delivery systems
2. Ion-activated drug delivery systems
3. Hydrolysis-activated drug delivery systems
• Biochemical means
1. Enzyme-activated drug delivery systems
2. Bio chemical-activated drug delivery system

9. Types of Feedback- regulated drug
delivery systems
1. Bio erosion- regulated drug delivery system
2. Bio responsive drug delivery systems
3. Self-regulating drug delivery systems
• Types of Site targeting drug delivery systems-
Osmotic drug delivery systems comes under
the category of physical means of activation
modulated drug delivery system.

10. OSMOTIC DRUG DELIVERY SYSTEMS
• Osmosis-Osmosis can be defined as the net
movement of water across a selectively
permeable membrane driven by a difference in
osmotic pressure across the membrane.
• It is driven by a difference in solute
concentrations across the membrane that allows
passage of water, but rejects most solute
molecules or ions.
• Osmotic systems utilize the principle of osmotic
pressure for the delivery of drugs.

11. • Drugs release from these systems is independent
of pH and other physiological parameter.
• It is possible to modulate the release
characteristic by optimizing the properties of
drug and system.
• These systems can be used for both oral and
parenterals route of administration.
• Oral osmotic systems are known as gastro-intestinal
therapeutic systems (GITS).
• Parenteral osmotic drug delivery includes
implantable

12. Osmotic pressure
• In 1886, Vant Hoff identified an underlying proportionality between
osmotic pressure, concentration and temperature. He revealed that
osmotic pressure is proportional to concentration and temperature
and the relationship can be described by following equation-
Π = Ø c RT
Where,
Π = Osmotic Pressure
Ø = Osmotic Coefficient
c = Molar concentration
R = Gas constant
T = Absolute temperature

13. Advantages
• Easy to formulate and simple in operation.
• Improve patient compliance with reduced frequency.
• Prolonged therapeutic effect with uniform blood concentration.
• They typically give a zero order release profile after an initial lag.
• Deliveries may be delayed or pulsed if desired.
• Drug release is independent of gastric pH and hydrodynamic condition.
• The release mechanisms are not dependent on drug.
• A high degree of in-vitro and in-vivo correlation (IVIVC) is obtained in
osmotic systems.
• Higher release rates are possible with osmotic systems compared with
conventional diffusion controlled drug delivery systems.
• The release from osmotic systems is minimally affected by the presence of
food in gastrointestinal tract.
• The release rate of osmotic systems is highly predictable and can be
programmed by modulating the release control parameters.

14. Disadvantages
• Rapid development of tolerance.
• Retrieval is not possible in the case of
unexpected adverse events.
• Expensive.
• If the coating process is not well controlled
there is a risk of film defects, which results in
dose dumping.
• Size of orifice is critical.

15. CLASSIFICATION OF OSMOTIC DRUG
DELIVERY SYSTEM
 Implantable-
1. The Rose and Nelson Pump
2. Higuchi Leeper Pump
3. Higuchi Theuwes Pump
4. Implantable mini Osmotic Pump
 Oral Osmotic Pump
 Single Chamber Osmotic Pump- Elementary Osmotic Pump
 Multi Chamber Osmotic Pump- Push Pull Osmotic Pump,
Osmotic Pump with non expanding second chamber.
 Specific types- Controlled Porosity Osmotic Pump, Osmotic
bursting osmotic pump, Monolithic Osmotic System etc.

16. Implantable
Osmotic DDS
• The Rose and Nelson Pump

17. • Rose and Nelson were two Australian physiologists interested in the delivery of
drugs to the gut of sheep and cattle. Their pump was never patented.
• The pump consists of 3 chambers: a drug chamber, a salt chamber containing excess
solid salt and a water chamber.
• The drug and water chambers are separated by a rigid semi permeable membrane.
• The difference in osmotic pressure across the membrane moves water from water
chamber into salt chamber.
• The volume of salt chamber increases because of this water flow, which distends
the latex diaphragm separating the salt and drug chambers, there by pumping drug
out of the device.
• The pumping rate of Rose and Nelson pump is given by eqn-dMt/
dt=(dv/dt)C
where dMt/dt= Drug release rate
dv/dt= vol of water into salt chamber
C= Concentration of drug in drug chamber
• Alza Corporation represented the 1st series of Rose and Nelson pump.

18. Implantable Osmotic DDS
The Higuchi Leeper Pump

19. • In Higuchi Leeper Pump there is no water chamber and the device activates after
penetration of water inside from surrounding environment.
• This model is widely used for veterinary use.
• This type of pump is either swallowed or implanted in the body of animal for
delivery of antibiotic or growth hormones.
• It consists of a rigid housing and semi-permeable membrane.
• A layer of low melting waxy solid, such as microcrystalline paraffin wax is used in
place of elastic diaphragm to separate drug and osmotic chamber.
• Recent modifications accommodate pulsatile drug delivery which is achieved by
production of critical pressure at which the delivery orifice opens and drug is
released.

20. Implantable Osmotic DDS
The Higuchi Theuwes Pump

21. • This device consists of rigid housing made up of SPM which is strong enough to withstand
the pumping pressure developed inside the device due to permeation of water.
• The drug is loaded only prior of application of device.
• The release of drug from device can be controlled by use of salt chamber altering the
permeability characteristics of outer membrane and orifice.
• Osmotic pump of this form are available under trade name of Alzet.
• A mixture of citric acid and sodium bi-carbonate in salt chamber in presence of water
generate CO2 gas exerting a pressure on the elastic diaphragm eventually delivering the
drug from the device.

22. Implantable Osmotic DDS
Implantable mini Osmotic Pump

23. • Implantable Mini osmotic pump shown in the above figure it is composed of three
concentric layers-the drug reservoir, the osmotic sleeves and the rate controlling semi
permeable membrane. The additional component called flow moderator is inserted
into the body of the osmotic. The inner most compartment of drug reservoir which is
surrounded by an osmotic sleeve, a cylinder containing high concentration of osmotic
agent.
• The osmotic sleeve is covered by a semi permeable membrane when the system is
placed in aqueous environment water enters the sleeve through semi permeable
membrane, compresses the flexible drug reservoir and displaces the drug solution
through the flow moderator.
• These pumps are available with variety of delivery rates between 0.25 to 10ml per
hour and delivery duration between one day and four weeks.

24. Single Chamber Osmotic Pump
Elementary Oral Osmotic Pump

25. • The elementary osmotic pump is a new delivery system for drugs. It
delivers the agent by an osmotic process at a controlled rate. Control
resides in the:
A) Water permeation characteristics of a semi permeable membrane
surrounding the formulating agent
B) Osmotic properties of the formulation.
• In its simplest embodiment the system is constructed by coating an
osmotically active agent with the rate controlling semi permeable
membrane. This membrane contains an orifice of critical size through
which agent is delivered.
• The dosage form after coming into contact with aqueous fluids, imbibes
water at a rate determined by the fluid permeability of the membrane and
osmotic pressure of the core formulation.
• This osmotic imbibition’s of water result in formation of a saturated
solution of drug within the core, which is dispensed at controlled rate from
the delivery orifice in the membrane.
• Though 60 -80 percent of drug is released at a constant rate from the EOP,
a lag time of 30-60 minute is observed in most of the cases as the system
hydrates before zero order delivery from the system begins.
• These system are suitable or delivery of drugs having moderate water
solubility.

26. Multi Chamber Osmotic Pump
Push –Pull Osmotic Pump

27. • Push pull osmotic pump is a modified EOP through, which it is possible to deliver
both poorly water soluble and highly water soluble drugs at a constant rate.
• This system resembles a standard bilayer coated tablet. One layer (depict as the
upper layer) contains drug in a formulation of polymeric, osmotic agent and other
tablet excipients. This polymeric osmotic agent has the ability to form a suspension
of drug in situ.
• The other layer contains osmotic and colouring agents, polymer and tablet
excipients. These layers are formed and bonded together by tablet compression to
form a single bilayer core.
• The tablet core is then coated with semipermeable membrane. After the coating
has been applied, a small hole is drilled through the membrane by a laser or
mechanical drill on the drug layer side of the tablet.
• When the system is placed in aqueous environment water is attracted into the
tablet by an osmotic agent in both the layers.
• The osmotic attraction in the drug layer pulls water into the compartment to form
in situ a suspension of drug.
• The osmotic agent in the nondrug layer simultaneously attract water into that
compartment, causing it to expand volumetrically and the expansion of non drug
layer pushes the drug suspension out of the delivery orifice.

28. Multi Chamber Osmotic Pump
Osmotic Pump with Non Expanding Second Chamber

29. Specific types • Controlled Porosity Osmotic Pump
• The pump can be made with single or multi compartment dosage form, in either form, the delivery system
comprises a core with the drug surrounded by a membrane which has an asymmetric structure, i.e. comprises
a thin dense skin layer supported by a porous substructure.
• The membrane is formed by phase inversion process controlled by the evaporation of a mixed solvent system.
• Membrane is permeable to water but impermeable to solute and insensitive pore forming additive dispersed
throughout the wall.
• When exposed to water, low levels of water-soluble additive are leached from polymer materials that were
permeable to water yet remained insoluble.
• Then resulting sponge like structure formed the controlled porosity walls of interest and was substantially
permeable to both water and dissolved drug agents.
• Rate of drug delivery depends upon the factors are water permeability of the semi permeable membrane and
the osmotic pressure of the core formulation, thickness and total surface area of coating.
• All of these variable are under the control of the designer and do not vary under physiological condition,
leading to the robust performance.
• The rate of flow of water into the device can be represented as
dv / dt = Ak / h (Dp-DR)
Where
dv/dt = Rate of flow of water
k = Membrane permeability
A = Area of the membrane
Dp = Osmotic pressure difference
DR = Hydrostatic pressure difference
h = Thickness of the membrane

31. Osmotic Bursting Osmotic Pump
• This system is similar to an EOP expect delivery
orifice is absent and size may be smaller.
• When it is placed in an aqueous environment, water
is imbibed and hydraulic pressure is built up inside
until the wall rupture and the content are released to
the environment.
• Varying the thickness as well as the area the
semipermeable membrane can control release of
drug. This system is useful to provide pulsated
release.

32. Specific types
Monolithic Osmotic System

33. • It constitutes a simple dispersion of water-soluble agent in polymer
matrix.
• When the system comes in contact in with the aqueous environment,
water imbibition’s by the active agents takes place rupturing the
polymer matrix capsule surrounding the drug., thus liberating it to the
outside environment. Initially this process occurs at the outer
environment of the polymeric matrix, but gradually proceeds towards
the interior of the matrix in a serial fashion.
• However this system fails if more then 20 –30 volumes per litre of the
active agents is incorporated in to the device as above this level,
significant contribution from the simple leaching of the substance take
place.

34. Factors affecting drug release rate
• Solubility
1. APIs for osmotic delivery should have water
solubility in the desired range to get optimized drug
release.
2. However, by modulating the solubility of these
drugs within the core, effective release patterns
may be obtained for drugs which might otherwise
appear to be poor candidate for osmotic DDS.

35. Factors affecting drug release rate
• Solubility –modifying approaches
1. Use of swellable polymers: vinyl acetate copolymer, polyethylene oxide have uniform
swelling rate which causes drug release at constant rate.
2. Use of wicking agents: These agents may enhance the surface area of drug with the
incoming aqueous fluids. e.g. colloidal silicon dioxide, sodium lauryl sulfate, etc.
Ensotrol® technology uses the same principle to deliver drugs via osmotic mechanism.
3. Use of effervescent mixtures: Mixture of citric acid and sodium bicarbonate which
creates pressures in the osmotic system and ultimately controls the release rate.
4. Use of cyclodextrin derivatives: They are known to increase solubilityof poorly soluble
drugs. The same phenomenon can also be used for the osmotic systems.
5. Use of alternative salt form: Change in salt form of may change solubility.
6. Use of encapsulated excipients: Solubility modifier excipient used in form of mini-tablet
coated with rate controlling membrane.
7. Resin Modulation approach: Ion-exchange resin methods are commonly used to modify
the solubility of APIs. Some of the resins used in osmotic system are Poly (4-vinyl
pyridine), Pentaerythritol, citric and adipic acids.
8. Use of crystal habit modifiers: Different crystal form of the drug may have different
solubility, so the excipient which may change crystal habit of the drug can be used to
modulate solubility.

36. Factors affecting drug release rate
• Osmotic Pressure
The next release-controlling factor that must be
optimized is the osmotic pressure gradient between
inside the compartment and the external
environment.
The simplest and most predictable way to achieve a
constant osmotic pressure is to maintain a saturated
solution of osmotic agent in the compartment.
The following table shows osmotic pressure of
commonly used solutes in CR formulations-

37. Compound Osmotic Pressure
Lactose-Fructose 500
Mannitol-Fructose 415
Sodium-Chloride 356
Potassium Sulphate 39
Sodium Phosphate
tribasic.12H2O
36
Sodium Phosphate
dibasic anhydrous
29

38. Factors affecting drug release rate
• Size of Delivery Orifice
• To achieve an optimal zero order delivery profile, the cross sectional
area of the orifice must be smaller than a maximum size to
minimize drug deliver by diffusion through the orifice.
• Furthermore, the area must be sufficiently large, above a minimum
size to minimize hydrostatic pressure build up in the system.
• The typical orifice size in osmotic pumps ranges from 600μ to 1
mm.
• Methods to create a delivery orifice in the osmotic tablet coating
are:
 Mechanical drill
 Laser drill
 Indentation
 Use of leachable substances in the permeable
membrane

39. Basic Components of Osmotic Systems
• Drug-
• It should have a short biological half-life and which is used for prolonged
treatment are ideal candidate for osmotic systems.
• Examples- Diltiazem HCl, Carbamazepine, Metoprolol, Oxprenolol, Nifedipine,
Glipizide etc.
• Osmotic Agent-
 Osmotic components usually are ionic compounds consisting of either
inorganic salts or hydrophilic polymers.
 Different type of osmogents can be used for such systems are catergorized as
 water-soluble salts of inorganic acids like MgCl2, MgSO4, NaCl
 water-soluble salts of organic acids like sodium and potassium acetate,
magnesium succinate, sodium benzoate sodium citrate, sodium ascorbate.
 Carbohydrates like mannose sucrose, maltose lactose
 Water soluble amino acids
 Organic polymeric osmogents

40. Basic Components of Osmotic Systems
• Semipermeable Membrane-
• An important part of the osmotic drug delivery system is the SPM housing.
• Therefore, the polymeric membrane selection is key to osmotic delivery
formulation.
• The membrane must possess certain performance criteria such as:
 Sufficient wet strength and water permeability
 Should be biocompatible
 Rigid and non-swelling
 Should be sufficient thick to withstand the pressure within the device.
• Any polymer that is permeable to water but impermeable to solute can be
used as a coating material in osmotic devices. e.g. Cellulose esters like
cellulose acetate, cellulose acetate butyrate, cellulose triacetate and ethyl
cellulose and Eudragits.

41. Basic Components of Osmotic Systems
• Plasticizers-
• Different types and amount of plasticizers used in coating membrane also
have a significant importance in the formulation of osmotic systems.
• They can change viscoelastic behavior of polymers and these changes may
affect the permeability of the polymeric films.
• Some of the plasticizers used are as below:
 Polyethylene glycols
 Ethylene glycol monoacetate; and diacetate- for low permeability
 Tri ethyl citrate
 Diethyl tartarate or Diacetin- for more permeable films

42. EVALUATION OF OSMOTIC TABLET:
• Evaluation of Powder
 Weight of Powder
 Bulk density
 Tapped density
 Carr’s index
 Angle of repose
• Evaluation of Osmotic
tablet
 Hardness
 Thickness
 Friability
 Weight uniformity
 Drug content
 In vitro Dissolution study
• Effect of Osmotic
Pressure
• Effect of PH on drug
release
• Stability study

43. MARKETED PRODUCTS
• Elementary Osmotic Pump
Brand Name API
Efidac24 Chlorpheniramine
Acutrim Phenylpropanolamine
Sudafed24 Pseudoephedrine
Volmax Albuterol
MinipressXL Prazocine
• Push-Pull Osmotic Systems
Brand Name API
Procardia Nifedipine
Covera HS Verapamil HCl
Invega Paliperidone

44. MARKETED PRODUCTS
• Implantable Osmotic Systems
Brand Name API
Viadur Leuprolide acetate
Chronogesic Sufentanil

45. Conculsions
The therapeutic value of a pharmaceutical product
depends on own parts; the rate profile of drug
absorption and the pharmacodynamics of the
drugs. Osmotic system technology has been
extended to allow rate controlled constant drug
delivery over a wide range of drugs. Delivery rates
can be designed to the limits imposed by GI transit
time and absorption capacity. The development of
once daily formulations successfully can be
acquired by osmotic systems for short half-life
drugs.

46. References
• International Journal of Research in Pharmaceutical and
Biomedical Sciences ‘A Review on Osmotic Drug Delivery
System’ by Padma Priya, Ravichandran V and Suba V ; Vol. 4
(3) Jul– Sep 2013, Pg No 810-821.
• INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND
CHEMISTRY ‘OSMOTIC PUMP DRUG DELIVERY- A NOVEL
APPROACH’ by Deepak Singla, SL. Hari Kumar and Nirmala;
Volume 2(2)-2012, Pg No 661-670.
• INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ‘A
REVIEW ON OSMOTIC DRUG DELIVERY SYSTEM’ by Harnish
Patel, Upendra Patel, Hiren Kadikar, Bhavin Bhimani, Dhiren
Daslaniya & Ghanshyam Patel; Volume 3(4)-2012 , Pg No 88-
94.

47. THANK YOU