1. INTRODUCTION:

Controlled release system provides the major market of a newly designed dosage form value due to its advantages over conventional dosage forms of ease of administration, better patient compliance, reduce dosing frequency and less side effect.

These products provide benefits over immediate release formulation including greater effectiveness in the treatment of chronic diseases, reduced side effects and greater patient convenience due to simplified dosing schedule^[1]. Out of various controlled drug delivery systems osmotic controlled drug delivery system^[2,3] utilizes principle of osmotic pressure for controlled delivery of active ingredients. Osmotic drug delivery system can be used to improve the pharmacokinetic properties of drugs by better adjustment of the release rate with respect to conventional solid dosage forms. Osmotic pumps^[4] belong to the class of rate controlled systems providing continuous delivery and within it drugs can be stored in liquid or solid form. In ODDS the drug dose and dosing interval are optimized to maintain drug concentration within the therapeutic window. ODDS deliver the drug at predetermined zero order rate for prolonged time period. So it is used as the standard dosage forms for constant drug delivery. ODDS provide a uniform concentration of drug at the site of absorption and thus after absorption allow maintenance of plasma concentration within therapeutic range which minimizes side effects and reduces the frequency of administration. Osmotic controlled release preparation is a novel drug delivery system^[5] with drug delivery rate as characteristic and controlled with the osmotic difference between inside and outside of the semi permeable membrane. When an osmotic system contacts with water, water diffuses into the core through the micro porous membrane setting up an osmotic gradient and thereby controlling the release of drug. Drug release from osmotic system is independent of pH and other physiological parameters and possible to modulate the release characteristics by optimizing the properties of drug and system. Osmotic drug delivery technique is most interesting and widely acceptable among all other technologies. The route^[6] of administration of ODDS may be oral and parental. Oral osmotic systems are known as gastro intestinal systems and parental osmotic systems are known as implantable pumps.

2. Advantages of osmotic drug delivery system:^[6,7]

(1)The release of drugs follows zero order kinetics after an initial lag.

(2)The delivery of drug may be delayed or pulsatile.

(3)The drug release is independent of gastric P^H, drug and in hydrodynamic condition.

(4)The drug delivery provides high degree of in vitro in vivo correlation.

(5)The drug release is higher than conventional drug delivery system.

(6)The release of drug is less affected by the presence of food in gastrointestinal tract.

3. Disadvantages of osmotic drug delivery system:^[8]

(1)The method of preparation is very costly.

(2)The making of hole in semi permeable is very difficult.

(3)There is a chance of dose dumping if the coating process is not well controlled.

4. Osmosis:

Osmosisis defined as the spontaneous movement of a solvent from a solution of lower solute concentration to a solution of higher solute concentration through an ideal semi permeable membrane which is permeable only to the solvent but impermeable to solute. It is driven by a difference in solute concentrations across the membrane that allows passage of water, but rejects most solute molecules or ions. Van’t Hoff^[9] gave the equation for osmotic pressure. He obtained that osmotic pressure is proportional to concentration and temperature and the relationship is described by the following equation 1.

π = i-----RT=iCRT (1)

where π is osmotic pressure of the solution, n is the number of moles of solute(mol), i is the Van’t Hoff factor, V is volume of solution(L), C and R are the molar concentration of solute(mol/L) and molar gas constant (8314Jmol^-1K^-1) respectively and T is absolute temperature (K).The Van’t Hoff factor(i) is the number of moles of solute actually dissolved in solution per mole of added solid solute i.e. i equals to one if the solute does not dissociate(e.g nonelectrolytes) in water or becomes larger than one in case of dissociation occurs. Hence the number of solute molecules is more in ionic compounds. Considering α as the degree of dissociation and m as the number of ions, a solute can dissociate into I molecules according to the equation^[10] given below.

I=1+α(m-1) (2)

5. Mechanism of osmotic drug delivery system:

When an osmotic system is exposed to water or any body fluid, water will flow into the core due to osmotic pressure difference across the semi permeable membrane under the osmotic pressure gradient. The volume flow of water or water flux into the core reservoir is expressed^[11] in equation 3.

dv A

----- = ---- L(σd π -dp) (3)

dt h

Where dv/dt is water flux, A is area of the semi permeable membrane, h is thickness of the membrane, and dp are the are the osmotic and hydrostatic pressure difference between the inside and outside of the system, L is mechanichal permeability and σ is the reflection coefficient. The drug will be pumped out of the system through the orifice at a controlled rate is expressed in equation 4.

dm dv

----- = --- C (4)

dt dt

Where dm/dt is solute/drug delivery rate and C is the concentration of drug in dispersed fluid. Reflection coefficient is taken to consideration when there is leakage of drug through the membrane. The SPM which is perfect does not allow solute to pass through it and σ is close to unity. If the orifice is sufficiently large the hydrostatic pressure will be negligible which tends to zero. Hence the equation 3 becomes.

dv A

----- = ----L(σd π ) (3)

dt h

dv A

----- = ----Lσd π (5)

dt h

The osmotic pressure of gastrointestinal fluids is negligible as compared to that of core, hence is replaced by and Lσ is replaced by a constant K. Hence the equation becomes.

dv A

----- = ----K π (6)

dt h

Hence the pumping drug rate from the core can be expressed^[12] as:

dm A

----- = ----K π C (7)

dt h

6. Osmotic drug delivery devices:

The osmotic drug delivery devices generally classified into two broad categories such as implantable osmotic pump and oral osmotic pumps. These are explained below.

Table 1. Implantable type of osmotic pumps

Type of osmotic pump	Composition	Mechanism of action
The Rose and Nelson pump^[13]	It consists of a drug chamber with an orifice, a salt chamber with elastic diaphragm containing excess solid salt and a water chamber is used. The drug and water chamber are separated by a rigid semi permeable membrane	The difference in osmotic pressure across the chamber moves water from the water chamber into salt chamber. The volume of salt chamber increases because of this water flow which causes the diaphragm separating salted drug chamber and pumping drug out of this device.
Higuchi Leeper pump^[14]	This system consists of a drug chamber with an orifice and a salt chamber with elastic diaphragm containing excess solid salt.	The device is activated by water imbibed from the surrounding environment when it is swallowed or implanted in the body.
Higuchi Theeuwes pump^[15]	The pump consists of an osmotic core containing the drug surrounded by semi permeable membrane with a delivery orifice	When the pump exposed to water the core imbibes water osmotically at a controlled rate determined by the membrane permeability to water and by the osmotic pressure of the core formulation. Due to pressure the flow of saturated drug solution is delivered through the delivery orifice.
Implantable miniosmotic pump
Alzet^[16]	In this the empty reservoir within the core of the pump is filled with the drug solution to be delivered. It is surrounded by salt chamber with impermeable layer between them.	The pump delivers the drug is due to the the osmotic difference between chambers. The rate of drug delivery of the pump is controlled by the water permeability of the pumps of outer membrane.
Duros miniosmotic pump^[17]	The system consists of an outer cylindrical titanium alloy reservoir. The one end of the reservoir is positioned the membrane which is permeable to water and impermeable to ions. The next to membrane is the osmotic engine and next to it is piston.	Through the exit port water from the body is slowly drawn to the semi permeable membrane into the pump by osmotic agent residing in the engine compartment which expands the osmotic agent and displaces a piston to dispense small amounts of drug formulation from the drug reservoir through orifice^[

Table 2. Oral osmotic pump

Type of osmotic pump	Composition	Mechanism of action
Single chamber osmotic pump
Elementary osmotic pump^[11,18]	Osmotic pump core contains drug and osmogents. The coating of core contains semi permeable membrane with an delivery orifice.	When the EOP system exposed with aqueous fluids it imbibes with water. The osmotic imbitions of water causes saturated solution of drug within the core which is dispensed at a controlled rate from the delivery orifice in the membrane.
Multi chamber osmotic pump
Push pull osmotic pump^[19]	The system contains two layers, one layer (upper layer) contains drug in a formulation with osmotic agent and another layer(down layer) contains polymeric osmogents with excipients and the system is coated with semi permeable membrane with a delivery orifice	When the system contacts with the aqueous environment, polymeric osmotic layer swells and pushes the drug layer and thus releasing the drug from of fine dispersion through the delivery orifice^[21].
Osmotic pump with non expanding second chamber^[20]	This type of device consists of two rigid chamber the first chamber contains a biologically inert osmotic agent and the second chamber contains the drug which is nonexpanding.	When it comes in contact with aqueous environment, water penetrates into both the chamber through the surrounding semi permeable membrane. Osmotic agent solution is formed in the first chamber then passes through the connecting hole to the drug chamber where it mixes with the drug solution before exiting through the microporous membrane that form a part of wall surrounding the chamber.
Specific types
Controlled porosity osmotic pump^[21]	The core contains drug and osmogents. The SPM of core is made up of water soluble additives	Water soluble additives dissolve when it contacts with water resulting in an situ formation of a microporous membrane. The resulting membrane is substantially permeable to both water and dissolved solutes.
Osmotic bursting osmotic pump(OBOP)^[22]	The core contains drug and osmogents. The SPM of core is without delivery orifice.	When the system placed in aqueous environment water is imbibed and hydraulic pressure is built up inside the system then wall ruptures and the contents are released.
Liquid OROS/Liquid oral osmotic system
L OROS hard cap^[23]	In L OROS hard cap system the liquid formulation is present in hard gelatin capsule which is surrounded with the barrier layer, the osmotic layer and the rate controlling membrane One delivery orifice is designed through these three layers.	When the system is exposed with the aqueous environment water penetrates across the rate controlling membrane and active the osmotic layer. The osmotic layer expands resulting the development of hydrostatic pressure inside the system and forcing the liquid formulation to be delivered from the delivery orifice.
L OROS soft cap	The liquid drug formulation is present in a soft gelatin capsule which is surrounded with the barrier layer, the osmotic layer and SPM.A delivery orifice is formed through these three layers.	When the system is in contact with the aqueous environment water is imbibed and results in the development of hydrostatic pressure inside the system forcing the liquid formulation to break through the hydrated gelatin capsule shell at the delivery orifice.
Delayed liquid bolus delivery system	This system consists of three layers a placebo delay layer, a liquid drug layer and an osmotic engine all surrounded by rate controlling SPM. The delivery orifice is drilled on the placebo layer end of the capsule shaped device.	In contact with water the osmotic engine expands, the placebo is released first delaying release of drug layer. The drug release can be delayed up to 1 to 10h depending upon the permeability of SPM and thickness of placebo layer.
Telescopic capsule^[24]	This device has two chambers, the first chamber contains the drug and an exit port and second chamber contains an osmotic engine a layer separates the two chambers.	As the system exposed fluid is imbibed the housing of the dispensing device the osmotic engine expands and exerts pressure on the slidable connected first and second wall sections.
OROS CT^[25]	The system may contain a single osmotic unit or as many as five to six push pull osmotic unit filled in a hard gelatin capsule. It consists of an enteric coat, SPM and core.	When the system is exposed it comes in contact with the gastric fluids due to enteric coating fluids from stomach does not system.As the system enters into small intestine the enteric coating dissolves and water is imbibed into the core by swelling the compartment.
Sandwiched osmotic tablets(SOTS)^[26]	The system is composed of polymeric push layer sandwiched between two drug layers with two delivery orifices	When it is placed in the aqueous environment the middle push layer containing the swelling agent swells and the drug is released from the two orifices situated on opposite sides of the tablet
Monolithic osmotic system^[27]	It consists of a simple dispersion of water soluble agent in polymer matrix	When the system comes in contact with the aqueous environmentwater imbibes causing the polymer matrix capsule surrounding the drug thus of the active liberating it to the outside environment.
Osmat^[28]	Osmat system utilizes the hydrophilic polymers to swell in matrix and gel in aqueous medium forming a semipermeable membrane in situ releases from such a matrix system containing an osmogen.	The system produces controlled drug release from swellable matrix system.
Multi particulate delayed release systems(MPDRS)^[29]	MPDRS consist of pellets consists of drug with or without osmotic agent, which are coated with a semipermiable membrane.	When the system comes in contact with the aqueous environment, water enters in the core and forms a saturated solution of soluble component. The osmotic pressure difference results in rapid expansion of the membrane and causes the formation of pores.
Pulsatile delivery based on expandable orifice^[30]	The system is in the form of capsule from which the drug is released by the capsule’s osmotic infusion of moisture from the body.	The delivery orifice of the capsule wall opens intermittently to achieve a pulsatile delivery effect. As the osmotic release proceeds pressure rises within the capsule causing the wall to expand. The orifice is small as a result of which when the elastic wall relaxes the flow of the drug through the orifice essentially stops, but when the elastic wall stretches beyond the threshold because of increase of pressure, the orifice expands sufficiently to allow the drug to be release at a required rate.
Pulsatile delivery by a series of stops^[31]	The capsule comprises of drug and absorptive osmotic agent engine that are placed in the each compartments separated by a movable partition. Pulsatile delivery is gained by a series of stop along the inner wall of capsule.	The number of stops and the longitudinal placement of the stops along the length of capsule determine the number and frequency of pulses. The design of the partition controls the pulse intensity.
Lipid osmotic pump^[32]	The core of the system consists of a water insoluble active ingredients which is lipid soluble or lipid wettable. A sufficient amount of water insoluble lipid carrier liquid is used for the pump.	The wall is microporous and is wetted by by lipid carrier. The device is prepared by fast dissolving the drug in the lipid vehicle. The osmogent is melted in the lipid and then cooled to form a lump that are broken and made into tablet. The microporous is coated at moderate flow of ambient air.
Asymmetric membrane capsule^[33]	Capsule wall made up of water insoluble semi permeable polymer	Imbibition of water through the capsule wall and dissolving soluble components within it and releasing from same wall.

7. Basic components of osmotic pumps:

7.1. Drugs:

The drugs having short biological half life (2-6h), prolonged treatment drugs e.g. nifedipine^[34], glipizide ^[35], metoprolol^[36]etc. and highly potent drugs can be designed for osmotic drug delivery system. Solubility of drug should not be very high or very low.

7.2. Osmotic components/osmogents:

Osmotic agents maintain a concentration gradient across the membrane. They create a driving force for the uptake of water and assist in maintaining drug uniformity in the hydrated formulation. Osmogents are used in the fabrication^[37] of osmotically controlled drug delivery systems and modified devices for controlled release of relatively poorly water insoluble drugs. Osmogents generate osmotic pressure in the concentrated solution ranging from 8 atm to 500atm.

7.2.1. Classification of Osmogents:^[12]

7.2.1.1. Water-soluble salts of inorganic acids osmogents:

The examples of water soluble salts of inorganic acids osmogents are magnesium chloride or sulphate, sodium chloride, sodium sulphate, potassium chloride, sodium bicarbonate, sodium or potassium hydrogen phosphate etc.

7.2.1.2. Organic polymeric osmogents:

The examples of organic polymeric osmogents are sodium carboxy methylcellulose, hydroxyl propyl methyl cellulose, hydroxyl ethyl methylcellulose, methylcellulose, polyethylene oxide, polyvinyl pyrollidine, polyacrylamides, carbopols etc.

7.2.1.3. Carbohydrates:

The examples of carbohydrates which are used for osmogents are arabinose, ribose, xylose, glucose, fructose, galactose, mannose, sucrose, maltose, lactose, raffinose, etc.

7.2.1.4. Water-soluble amino acids:

The water soluble amino acids which are used for osmogents are glycine, leucine, alanine, méthionineds Glycine, leucine, alanine, méthionine, etc.

7.2.1.5. Water soluble salts of organic acids osmogents:

The water soluble salts of organic acids osmogents are sodium and potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate etc.

7.3. Semipermeable membrane(SPM):

Semipermeable membrane is also known as selectively permeable membrane or partially permeable membrane or differentially permeable membrane.SPM is a membrane that allows solvent and certain molecules or ions to pass through it by diffusion or specialized facilitated diffusion. ODDS contains SPM as outer layer. The membrane is impermeable to the passage of drug and other ingredients present in the compartments. The formation of SPM includes cellulosic polymers such as cellulose ethers, cellulose esters and cellulose ester-ether. The examples of material used for SPM preparations are cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate etc. The other SPM forming polymers are group consisting of acetaldehyde dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellulose dimethylamino acetate, polyamides, polyurethanes etc. The semipermeable membrane is generally 200-300µm thick to withstand the pressure within the device. The selection of material is selected whose reflection coefficient is closer to one. The ideal properties of semipermeable membrane must have sufficient wet strength, wet modulus, rigid dimensional integrity, water permeability and the reflection coefficient and leakiness of the osmotic agent should approach the limiting value of unity^[38].

7.4. Coating solvents:

Coating solvents are suitable for making polymeric solutions and that is used for manufacturing the wall of osmotic device^[39] include inert organic and inorganic solvents. They should not affect the core and other additives. The solvents used for coating solvents are methylene chloride, acetone, methanol, ethanol, Isopropylalcohol, butyl alcohol, ethyl acetate, cyclohexane, carbon tetrachloride, water etc. The mixtures of solvents such as acetone-methanol(80:20), acetone-ethanol(80:20), acetone-water(90:10), methylene chloride-methanol(79:21), methylene chloride-methanol-water(75:22:3)etc.

7.5. Emulsifying agents:

Emulsifying agents^[40] are added to wall forming material to produce an integral composition which is useful to make the wall of the device for operation. They regulate the surface energy of materials to improve their blending into the composite and maintain their integrity in the environment of use during the drug release period. The examples of emulsifying agents are polyoxyethylenated glyceryl recinoleate, polyoxyethylenated castor oil having ethylene oxide, glyceryl laureates, glycerol (sorbitan oleate, stearateorlaurate) etc.

7.6. Flux regulating agents:

Flux regulating or flux enhancing agent or flux decreasing agents are used in wall forming materials to regulate the fluid permeability of flux through wall. This agent can be used to increase or decrease the liquid flux^[41].The flux regulating agents may be hydrophilic substances and hydrophobic substances. The hydrophilic substances such as polyethylene glycols(300 to 6000Da),polyhydric alcohols, polyalkylene glycols increase the flux whereas hydrophobic substances such as phthalates substituted with alkyl or alkoxy(diethyl phthalateordimethoxyethylphthalate) decrease the flux.

7.7. Wicking agents:

Wicking agent^[42] has the ability to draw water into the porous network of delivery device. The wicking agent may be swellable or non swellable in nature. They have the ability to undergo physisorption with water. Physisorption is the form of absorption in which the solvent molecules can loosely adhere to surfaces of the wicking agent via vanderwaal’s interactions between the surface of the wicking agent and the absorbed molecule. The wicking agent function is to carry water to the surfaces inside the core of the device and creating channels or a network of increased surface area. The examples of wicking agents are colloidal silicon dioxide, kaolin, titanium dioxide, alumina, niacinamide, polyvinyl pyrrolidone, bentonite, sodium lauryl sulphate etc.

7.8. Plasticizers:

Plasticizer is used to lower the temperature in phase transition of the wall and also increase the workability, flexibility and permeability of the fluids. The ranges of plasticizer or mixture of plastizer between 0.01parts to 50 parts which is incorporated to 100parts of wall forming materials. Suitable solvents are used having high degree of solvent power for materials and compatible with the materials over both the processing and the temperature ranges to remain in the plasticized wall impart flexibility to the material^[43].Plasticizers can change a hard and brittle polymer into a softer, more pliable material and possibly make it more resistant to mechanical stress. The examples of plasticizers are phthalates(dibenzyl, dihexyl, butyl, octyl), triacetin, epoxidized tallate, triisoctyl trimellitate, alkyl adipates, citrates, acetates, propionates, glycolates, myristates, benzoates, halogenated phenyls etc.

7.9. Pore forming agents:

These agents are generally used in the pumps developed for poorly water soluble drug and in the development of controlled porosity and multiparticulate osmotic pumps. The pore forming agents^[44] form microporous structure in the membrane due to its leaching during the operation of the system usually used for poorly water soluble drugs. The pores may be formed in the wall before operation of the system by gas formation by volatilization of components or by chemical reactions in polymer solution which creates pores in the wall. The pore formers may be inorganic and organic in nature. The examples of pore forming are alkaline metal salts such as sodium chloride, sodium bromide, potassium chloride, potassium sulphate, potassium phosphate etc., alkaline earth metals such as calcium chloride, calcium nitrate etc., carbohydratessuchassucrose, glucose. fructose, mannose, lactose, sobitol, mannitol, diols, polyols etc.

7.10. Barrier layer formers:

The function of barrier former^[45] is to restrict water entry into certain parts of the delivery system and to separate the drug layer from the osmotic layer. The examples of barrier layer formers are high density polyethylene, wax, rubber etc.

7.11. Polymers:

Polymers are incorporated in the formulation development of osmotic systems for making drug containing matrix core. The highly water soluble compounds can be added in hydrophobic matrices and moderately water soluble compounds can be coentrapped in hydrophilic matrices to obtain more controlled release. The mixtures of both hydrophilic and hydrophobic polymers have been used in the development of osmotic system of water soluble drugs^[1]. Swellable polymers are used for the pumps containing moderately water soluble drugs because they increase the hydrostatic pressure inside the pump due to their swelling nature. Non swellable polymers are used in case of highly water soluble drugs. The hydrophilic polymers such as hydroxyl ethyl cellulose, carboxy methyl cellulose, hydroxyl propyl methyl cellulose, poly vinyl pyrrolidone can be used for osmotic systems. The hydrophobic polymers such as ethyl cellulose and wax materials can be used for this purpose.

8. Key parameters for designing of osmotic drug delivery systems:

8.1. Drug delivery orifice size:

Osmotic drug delivery systems contain at least one delivery orifice in the SPM for drug release. The size of delivery orifice is optimized in order to control the drug release from the osmotic systems. To achieve an optimal zero order delivery profile the cross sectional area of the orifice must be smaller than a maximum size to minimum drug delivery by diffusion through orifice. The area is large above minimum size to minimize the hydrostatic pressure build up in the system. Some methods to create a delivery orifice in osmotic tablet coating are use of mechanical drill, laser drilling, use of modified punches, system with passageway formed in situ and use of pore former substances in the coating.

8.1.1. Laser drilling:

In laser drilling process the top view of the portion of the apparatus used to drill hole in the osmotic tablets and the tablets in which holes are to be formed are charged in the hopper. The tablets drop by gravity into the slots of the rotating feed wheel and are carried at a predetermined velocity to the passageway^[46] forming station. At the passageway forming station each tablet is tracked by an optical tracking system. If the speed of the moving tablet increases the hole may become elliptical because of movement of tablets during the laser firing time. To eliminate this problem tracking velocity is synchronized with the velocity at which the tablets are moving.

8.1.2. Systems with passageway formed in situ:

The delivery passageway of oral osmotic systems is explained in US patent no.5736,159. The system consists of a tablet core of the drug along with water swellable polymers and osmotic agents which is surrounded by rate controlling membrane. When there is contact with the aqueous environment water is imbibed osmotically^[47] at a controlled rate and water swellable polymer expands as the osmotic agents dissolves and increases the osmotic pressure inside the tablet.

5.1.3. Use of modified punches:

In modified punches the dosage form is pierced^[48] using a piercing device that is biased in a sheathed position and unsheathed upon application of compression force. The coating powder to be compressed is charged to the die mold and an unpierced tablet core is placed upon it. Additional quantity of coating powder is added to the die mold subsequent to which both compression and piercing are done simultaneously.

8.1.4. Use of pore formers:

Incorporation of water soluble additives in the membrane wall is widely used for the development of CPOP system. These water soluble additives dissolve on coming in contact with water leaving behind pores in the membrane through which drug release takes place. These pore formers or leachable materials produce one or more passageways with different geometrical shapes^[49]. The pores may be formed in the wall prior to the operation of the system by gas formation within curing polymer solutions, resulting voids and pores in the final form of the membrane.

8.2. Solubility:

The kinetics of osmotic drug release depends on the solubility of the drug in the core of osmotic devices. Considering osmotic device core contains pure drug, the fraction of drug released from the core follows zero order kinetics. The release of drug from the device is expressed as the following equation.

F_(Z)=1-S/ϼ

where F_(Z)is the fraction of drug released by zero order kinetics, S is the drug’s solubility(g/cm³) and ϼ is the density(g/cm³) of the osmotic system. The drugs having solubility of <0.05(g/cm³) release the drug above 95% in the form of zero order kinetics. Some approaches are designed to deliver drugs having extremes of solubility are given below.

8.2.1. Use of wicking agents:

The wicking agents^[50] in osmotic formulations were added for poorly water soluble drugs. The agent is dispersed entirely the composition that increases the contact surface area of drug with the contact of aqueous fluids. g. colloidal silicon dioxide, sodium lauryl sulfate, etc. Hence the drug is released predominantly in a soluble form through the delivery orifice in the membrane.

8.2.2. Resin modulation approach:

Ion-exchange resin approaches are commonly used to modify the solubility of drugs. Citric acid and adipic acids were used to maintain a low core p^H to assure that both the drug and resin carry positive charge. Pentaerythritol was used as osmotic agent and the release of diltiazem hydrochloride^[51] was in a controlled manner up to an extended period and follows p^H independent zero order release.

8.2.3. Use of swellable polymers:

Swellable polymers were used for osmotic delivery of drugs having poor aqueous solubility of drugs. The formulation design consists of a compartment containing the drug, swelling agent^[52] and osmogents encapsulated with a rate controlling membrane. The examples of swelling agents are vinyl acetate copolymer, vinylpyrrolidone and polyethylene oxide.

8.2.4. Use of effervescent mixtures:

The effervescent mixture can be used to deliver poorly water soluble drugs in the form of osmotic delivery system. When this type system is administered then the effervescent mixture^[53] containing the drug delivered under pressure through the delivery orifice in the membrane. Mixture of citric acid and sodium bicarbonate were used as effervescent couple for the delivery of aspirin. The formulation swells aqueous fluids across the membrane causing the couple to generate an effervescent solution that dispenses the drug in a suspension form.

8.2.5. Use of cyclodextrin derivatives:

The cyclodextrin-drug complex^[54] is used as an approach for delivery of poorly water soluble drugs from osmotic systems. In CPOP type of osmotic system testosterone solubility is increased by using cyclodextrin complex. The solubility of testosterone at 37⁰C is 0.039mg/ml, and improved to 76.5mg/ml through complexation with sulfobutyl ether ᵝ cyclodextrin sodium salt,(SBE)_7mᵝ -CD.

8.2.6. Use of alternative salt form:

Change in salt form of drug may change solubility, as was reported for oxprenololand metoprolol. It was found that hydrochloride salt of oxprenolol was too soluble in water (70%w/v) making it difficult to maintain extended^[55] zero order delivery from osmotic dosage form. Hence it is replaced by less soluble succinate salt. In case metoprolol fumarate salt form is used instead of tartrate salt. The salt form was found to have optimum solubility and extended release upto 24h.

8.2.7. Use of encapsulated excipients:

The encapsulated excipients mainly used in capsule device coated with asymmetric membranes to deliver drugs having poor water solubility. The poorly water soluble drug glipizide was improved by addition of encapsulated excipients(p^H controlling) within capsule device. Solubility modifier excipient used in form of mini-tablet coated with rate controlling membrane to prolong its availability within the core. Thus the solubility of glipizide was improved and giving prolong release from device^[56].

8.2.8. Use of crystal habit modifiers:

If the drug has more than one crystal form having different aqueous solubility, it is beneficial to include a crystal modifying agent^[57].To slightly soluble drug carbamazepine by addition of crystal modifying agents (hydroxyl ethyl cellulose and hydroxyl methyl cellulose) and other excipients provides zero order drug release in the form of osmotic system.

8.2.9. Co-compression of drug with excipients:

Incorporation of excipients modulate the solubility^[58] of drug within the core and control the release of the drug in osmotic systems. Different excipients can be used to modulate the solubility of drugs with different mechanisms like saturation solubility, pH dependent solubility. McClelland et.al explained in CPOP of highly water soluble drug diltiazem hydrochloride(solubility more than 590mg/ml at 37⁰C).The majority of drug fraction was released at first order rather than the zero order rate due to high water solubility. The solubility of diltiazem hydrochloride was reduced to 155mg/ml by addition of sodium chloride(at 1M concentration) into the core tablet formulation. The modification gave more than 75% of the drug to be released by zero order kinetics over a 14-16h period.

8.2.10. Use of lyotropic crystals:

The lyotropic liquid crystals is used to assist osmotic delivery of poorly water soluble drugs. The lyotropic liquid crystals^[59] are non polymeric compounds molecular weight ranging from 200-1500D.It is also known amphipathic compounds. It forms mesophases and swell in presence of water. The examples of liquid lyotropic crystals are phosphatidyl choline (lecithin), phosphatidylethanolamine, phosphatidylserine, phosphatidyl glycerol etc. Alcolec lecithin and mixture of soyabean phospholipids was used for osmotic delivery of two insoluble drugs such as glipizide and prazosin and giving extended drug release up to 24h.

8.3. Osmotic pressure:

It is essential to keep constant osmotic pressure by maintaining a saturated solute solution to achieve zero order release rate. The osmotic pressure generated by the saturated drug solution is not sufficient to achieve the required driving force. Hence osmotic agents are added to generate osmotic pressure inside the device.

Table 3: Osmotic agents with their osmotic pressure^[60,61]

S. No.	Osmogents	Osmotic pressure(atm)
1.	Adipic acid	8
2.	Fumaric acid	10
3.	Lactose	23
4.	Mannitol	38
5.	Potassium sulphate	39
6.	Tartaric acid	67
7.	Citric acid	69
8.	Dextrose	82
9.	Sorbitol	84
10.	Xylitol	104
11.	Potassium phosphate	105
12.	Melanic acid	117
13.	Sucrose	150
14.	Lactose-dextrose	225
15.	Potassium chloride	245
16.	Lactose-sucrose	250
17.	Fructose	355
18.	Mannitol-fructose	415
19.	Sucrose-fructose	430
20.	Dextrose-fructose	450
21.	Lactose-fructose	500
22.	Mannitol-dextrose	225
23.	Dextrose-sucrose	190
24.	Mannitol-sucrose	170
25.	Mannitol-lactose	130
26.	Sodium phosphate monobasicH₂O	28
27.	Sodium phosphate dibasic anhydride	29
28.	Sodium phosphate dibasic7H₂O	31
29.	Sodium phosphate dibasic12H₂O	31
30.	Sodium phosphate tribasic12 H₂O	36
31.	Sodium chloride	356

8.4. Semipermeable membrane:

The SPM is permeable to water and not to ions. Hence the release rate is independent of the pH of the environment. The SPM should stable both the outer environment and inner environment of the device.

9. Patents on osmotic drug delivery system:

Table.4: Patents on osmotic drug delivery system

Sl. No	Patent No.	Title	Publication date	Inventors	Ref. No.
1.	US4256108	Microporous semipermeable laminated osmotic system	Mar.17,1981.	Felix Theeuwes	62
2.	US4285987	Osmotic system for dispensing drugs	Aug.25,1981	Atul.D.Ayer,F.Theeuwes	63
3.	EP0169105	Controlled porosity osmotic pump	Jan.22,1986	Gaylen M.Zentner,Gerald S.Rork,Kenneth J.Himmnelstein	64
4.	US5672167	Controlled release osmotic pump	Sept.30,1997	Amulya L.Athayde,Rolf A.Faste,C.Russell Horres Jr,Thomas P.Low	65
5.	WO1994001093	Controlled porosity osmotic enalpril pump	Jan.20,1994	John L.Haslam,Gerald S.Rork	66
6.	EP0309051	Controlled porosity osmotic pump	Mar.11,1992	John L.Haslam,Gerald S.Rork	67
7.	CA1320885	Controlled porosity osmotic pump	Aug.3,1993	John L.Haslam,Gerald S.Rork	68
8.	WO2001032149	Osmotic controlled release drug delivery device	May 10,2001	Laura A Debusi,Stephen B Ruddy,David E Storey	69
9.	US8109923	Osmotic pump with remotely controlled pressure generation	Feb.7,2012	LE Hood,MY Ishikawa,EKY Jung,R Langer,T Clarence,TLL Wood,VYH Wood	70
10.	US4946686	Solubility modulated drug delivery system	Aug.7,1990	Gregory A. Mccelland,Gaylen M.Zentner	71
11.	US3977404	Osmotic device having microporous reservoir	Aug.31,1976	F.Theeuwes	72

10. Marketed products

Table 5: Some marketed products of osmotic drug delivery systems^[61,73]

S. No.	Product name	Active pharmaceutical ingredients	Design of osmotic pump	Developer/Marketer
1.	Acutrim	Phenylpropanolamine	EOP	Alza/Heritage
2.	AlpressLP	Prazosin	PPOP	Alza/Pfizer
3.	CarduraXL	Doxazosin	PPOP	Alza/Pfizer
4.	CoveraHS	Verapamil	PPOPwithtimedelay	Alza/GD Searle
5.	DitropanXL	Oxybutinin chloride	PPOP	Alza/UCB Pharma
6.	Dynacire CR	Isradipine	PPOP	Alza/Novartis
7.	Efidac24	Pseudoephiderine	EOP	Alza/Novartis
8.	Glucotrol XL	Glipizide	PPOP	Alza/Pfizer
9.	MinipressXL	Prazosin	PPOP	Alza/Pfizer
10.	ProcadiaXL	Nifedipine	PPOP	Alza/Pfizer
11.	Sudefed24h	Pseudoephidrine	PPOP	Alza/WarnerLambert
12.	Teczam	EnalprilandDiltiazem	EOP	Merck/Aventis
13.	Tiamate	Diltiazem	PPOP	Merck/Aventis
14.	Volmax	Albuterol	PPOP	Alza/Muro

11. CONCLUSION:

Osmotic drug delivery systems utilize the principle of osmosis for drug delivery system. The drug delivery from osmotic system is independent of the physiological factors of gastrointestinal tract. By optimizing various formulation factors such as solubility, osmotic pressure of core components, size of delivery orifice and nature of rate controlling membrane the drug delivery can be controlled. The release of drug follows zero order kinetics and more safer than conventional dosage forms.

12. ACKNOWLEDGEMENTS:

The authors would like to acknowledge the contributions of University College of Technology, Faculty of Pharmacy, Department of pharmaceutics, Osmania University, Hyderabad, Telangana, India for providing necessary facilities to carry out the review work. This study was part of a Ph.D thesis under Osmania University, Hyderabad.

13. REFERENCES:

1. Parmar NS, Vyas SK, Vaya N. Osmotic Pump A Novel Drug Delivery System. In: Jain NK, Editors. Advances in controlled and novel drug delivery systems. New Delhi: CBS Publishers and distributors;2004,p.18-37.

2. Li X and Jasti BR. Osmotic controlled drug delivery systems, In: Designof controlled release of drug delivery systems, McGraw Hill, 2006; p.203-229.

3. Verma RK, Garg S. Current status of drug delivery technologies and future directions. Pharma Technol On line(http://www.pharmaportal.com) 2001;25:1-14.

4. Malaterre V, Ogorka J, Loggia N, Gunny R. Oral osmotically driven systems:30 years of development and clinical use Eur. J. Pharm. Biopharm. 2009;73:311-323.

5. Madhavi BB, Nath AR, Banji D. Ramalingam R, Madhu MN and Kumar DS. Osmotic drug delivery system :a review. Pharmakine 2009;2:5-14.

6. Kaushal AM and Garg S: An update on osmotic drug delivery patents. Pharm. Tech.,2003, 27, 38-44

7. Verma RK, Arora S, Garg S. Osmotic pumps in drug delivery Critical Review in Therapeutic Drug Carrier Systems 2004;21(6):477-520.

8. Singh K, Walia MK, Agarwal G, Harikumar SL. Osmotic pump drug delivery system: a novel approach Journal of Drug Delivery and Therapeutics 2013;3(5):156-162.

9. Grattoni A, Merlo M, Ferrari M. Osmotic pressure beyond concentration restrictions J. Phys. Chem. B 2007;111:11770-11775.

10. Herrlich S, Spieth S, Messner S, Zengerle. Osmotic micropumps for drug delivery. Advanced Drug Delivery Reviews.2012;64:1617-1627.

11. Theeuwes F. Elementary osmotic pump J.Pharm.Sci.1975;64:1987-1991.

12. Verma RK, Krishna DM and Garg S. Formulation aspects in the development of osmotically controlled oral drug delivery systems. J Control Release 2002;79:7-27.

13. Rose S, Nelson J.A Continuous long term injector Aust.J.Exp.Biol.Med.Sci.1955;33:415-421.

14. Higuchi T and Leeper HM. Improved osmotic dispenser employing magnesium sulfate and magnesium chloride.US Patent3760804 ;1973.

15. Theeuwes F, Higuchi T, Inventors; Alza corporation, Palo Alto, CA, Assignee. Osmotic dispensing device for releasing beneficial agent.US Patent;1974,3845770.

16. ALZET Osmotic pumps http://www.alzet.com/research_applications.

17. Wright JC, Johnoson RM and Yum SI. Duros Osmotic Pharmaceutical Systems for Parenteral and Site Directed Therapy. Drug. Deliv. Technol 2003;3:3-11

18. Prajapati HM, Prajapati ST, Patel CN.A review on recent innovation in osmotically controlled drug delivery system. Int. J of Pharma. Research and Bioscience 2012;1(3):158-194.

19. Mishra B, Makesh BK and Sankar C.Oral push pull osmotic pumps of pentazocine hydrochloride development and evaluation. Ind. J Pharm Sci.,2006;68(1):85-87.

20. Srenivasa B, Kumar NR, Murthy KVR. Development and in vitro evaluation of osmotically controlled oral drug delivery system. Easstern Pharmacist 2001;22.

21. Zentner GM, Rork GS, Himmelstein KJ. The controlled porosity osmotic pump. J Control Release 1985;1(4):269-282.

22. Padma priya S, Ravichandram V, Suba V.A review on osmotic drug delivery system. Int. J of Research in Pharmaceutical and Biomedical Sciences 2013;4(3):810-821.

23. Dong L ,Wong P and Espinal S. loros hardcap: A new osmotic delivery system for controlled release of liquid formulations: In :Proceedings of the International Symposium on controlled release of biomedical materials, San Dieego;2001.

24. Sareen R, Jain N and Kumar D. An insight to osmotic drug delivery. Curr Drug Deliv. 2012;9(3):285-96.

25. Theewes F, Wong PSL, Burkoth TL, Fox DA and Bicek PR. Colonic drug absorption and metabolism. Marcel Decker, New York;1993,pp137-158.

26. Lee HB, Liu L, Ku J, Khang G, Lee B and Rhee JM. Nifedipine controlled delivery sandwiched osmotic tablet system ,J Control Release 2000;68:145-156.

27. Liu L and Wang X. Solubility modulated monolithic osmotic pump tablet for atenolol delivery. Eur J Pharm Biopharm 2008;68(2):298-302.

28. Thakor RS, Majmudar FD, Patel JK and Rajput GC. Osmotic drug delivery systems current scenario. Journal of Pharmacy Research 2010;34:771-775.

29. Schultz P, Kleinebudde P.A new multiparticulate delayed release system Part I Dissolution properties and release mechanism. J Control Release 1997;47:181-189.

30. Ramdan MA, Tawashi R. The effect of hydrodynamic conditions and delivery orifice size on the rate of drug release from elementary osmotic pump system. Drug Dev Ind Pharm 1987;13(2):235-248.

31. Arora S, Ali J, Ahuja A, Baboota S and Qureshi J. Pulsatile drug delivery systems an approach for controlled drug delivery. Ind. J.Pharm.Sci.2006;68(3):295-300.

32. Godbillion JH, Gerardin A, Richard J, Leroy D, Moppert J. Osmotically controlled delivery of metoprolol in man in vivo performance of oros system with different duration of drug release.Br.J.Clin.Pharma.1985;19:69S-76S.

33. Kumar L, Shivani, Kumar A, Parashar D, Bhadra S. Asymmetric membrane capsule(AMC):an useful osmotic drug delivery system Int J. Pharm Pharm Sci.2012;4(2):54-59.

34. Swanson DR, Barclay BR, Wong PSL et.al. Nifedipine gastrointestinal therapeutic system.Am.J.Med.1987;83(6B):3-9.

35. Thombre AG, DeNoto AR, Gibbes DG. Delivery of glipizide from asymmetric membrane capsules using encapsulated excipients. J. Cont. Rel. 1999;60:333-341.

36. Bauer K, Kaik G, Kaik B. Osmotic release oral drug delivery system of metoprolol in hypertensive asthmatic patients, Pharmacodynamic effects on beta 2-adrenergic receptors. Hypertension 1994;24:339-346.

37. Vyas SP, Khar RK. Controlled drug delivery:concept and advances. Vallabh prakashan,NewDelhi;2001,477-501.

38. Khavare NB, Dasankoppa SF, Najundaswamy NG.A review on key parameters and components in designing of osmotic controlled oral drug delivery systems. Indian J of Novel Drug Delivery 2010;2(4):122-131.

39. Jerzewski Rand Chien Y. Osmotic drug delivery, In:Treatise on controlled drug delivery:Fundamentals, optimization, Application. Marcel Dekker;1992,225-253.

40. Verma RK, Mishra B, Garg S. Osmotically controlled oral drug delivery. Drug Dev Ind Pharm 2000;26:695-708.

41. Patel H, Patel U, Kadikar H, Bhimani B, Daslaniya D, Patel G. Areview on osmotic drug delivery system. Int. Res J of Pharm 2012;3(4):89-94.

42. Mahalaxmi R, Phanidhar, Sastri, Ravikumar, Atin Kalra, Pritam Kanagale and Narkhede. Enhancement of Dissolution of Glipizide from controlled porosity osmotic pump using wicking agents and a solubilizing agent. Int. J. Pharm Tech Res.2009;1(3):705-711.

43. Guo J. An investigation into formation of plasticizer channels in plasticized polymer films. Drug Dev.Ind.Pharm.1994;20:1883-1893.

44. Kelbert M, Bechard SR. Evaluation of cellulose latex as coating material for controlled release products. Drug Dev. Ind Pharm 1992;18:519-538.

45. Dong LC, Espinal S, Wong PSL. Inventors Alza corporation Mountain View CA Assignee. Dosage form comprising liquid formulation .US Patent 6174547.Jan16;2001.

46. Theeuwes F, Saunders RJ, Mefford WS. Process for forming outlet passageways in pills using a laser US Patent 4088864,May 9,1978.

47. Chen C, Lee D, Xie J. Controlled release formulation for water insoluble drugs in which a passageway is formed in situ.US patent 5736159 April 7,1998.

48. Ayer AD, Balkie HH. Method and apparatus for forming a hole in a drug dispensing device.US Patent 5071607 Dec10,1991.

49. Haslam JL. Rork GS. Controlled porosity osmotic pump.US4880631 Patent Nov 14,1989.

50. Rudine EM, Burnside BA, Flanner HH, Wassink SE, Couch RA, Pinkett JE. drug delivery system US patent 6,110,498 Aug.29,2000.

51. Zentner GM, McClelland, Sutton SC. Controlled porosity solubility and resin modulated osmotic drug delivery systems for release of diltiazem hydrochloride J Control. Release 1991;16:237-244.

52. Khanna SC. Therapeutic system for sparingly soluble active ingredients US patent 4,992,278,Feb.12.1991.

53. Theewes F. Osmotic dispenser with gas generating means.US patent 4,036,228 July 19,1977.

54. Okimoto K, Miyake M, Ohnishi N, Rajewski RA, Stella VJ, Irie T, Uekama K. Design and evaluation of an osmotic pump tablet for prednisolone a poorly water soluble drug using (SBE)-_7m- ᵝ-CD.Pharm.Res.1998;15:1562-1568.

55. Theeuwes F, Swanson DR, Guittard G, Ayer A, Khanna S. Osmotic delivery systems for the beta-adrenoceptor antagonists metoprolol and oxprenolol :design and evaluation of systems for once-daily administration Br. J. Clin. Pharmacol. 1985;19:69S-76S.

56. Thombre AG, DeNoto AR, Gibbs DC. Delivery of glipizide from asymmetric membrane capsules using encapsulated excipients J. Control. Release. 1999;60:333-341.

57. Koparkar AD, Shah SB. Oral osmotic system for slightly soluble active agents US patent 5,284,662,Feb.8,1994

58. McClelland, Sutton SC, Engle K, Zentner GM. The solubility modulated osmotic pump In vitro/in vivo release of diltiazem hydrochloride Pharm.Res.1991;8:88-92.

59. Curatolo WJ. Dispensing devices powered by lyotropic liquid crystals US patent 5,108,756 April28,1992.

60. Ghosh Tanmoy, Ghosh Amitav. Drug delivery through osmotic systems an overview. J. of Applied Pharmaceutical science 2011;01(2):38-49.

61. Keraliya AR, Patel C, Patel P, Keraliya V, Soni GT, Patel CR and Patel MM. Osmotic drug delivery system as a part of modified release dosage form. Int. Scholarly Research Network 2012;2012:1-9.

62. Theeuwes F. Microporous semipermeable laminated osmotic system, Alza corporation.1981;US Patent no4256108

63. Ayer AD, Theeuwes F. Osmotic system for dispensing drugs, Alza corporation.1981;US Patent no4285987.

64. Zentner GM, Rork GS, Himmnelstein KJ. Controlled porosity osmotic pump, Merck and Co.1986; EP Patent no. 0169105.

65. Athayde AL, Faste RA, Horres Jr. CR, Low TP. Controlled release osmotic pump, Recordati corporation, US Patent no.5672167.

66. Haslam JL, Rork GS. Controlled porosity osmotic enalpril pump, Merck and Co.Inc.1994;WO Patent no.1994001093.

67. Haslam JL, Rork GS. Controlled porosity osmotic pump, Merck and Co.Inc.1992;EP Patent no.0309051.

68. Haslam JL, Rork GS. Controlled porosity osmotic pump, Merck and Co.Inc.1991;CA Patent no.1320885.

69. Debusi LA, Ruddy SB, Storey DE. Osmotic controlled release drug delivery device, Merck and Co.Inc.2001;WO Patent no.2001032149.

70. Hood LE, Ishikawa MY, Jung EKY, Langer R, Clarence T, Wood TLL, Wood VYH. Osmotic pump with remotely controlled pressure generation The Invention Science Fund Lic.2012,US Patent no.8109923.

71. Mccelland GA, Zentner GM. Solubility modulated drug delivery system Merck and Co.Inc.1990;US Patent no.4946686.

72. Theeuwes F. Osmotic device having micro porous reservoir, Alza corporation 1976;US Patent no.3977404.

73. Patel NK, Mehta TA.A review on oral osmotically driven systems Int. J Pharm Pharm Sci2013; 5(3):1005-1013.

Received on 04.11.2017 Modified on 10.12.2017

Res. J. Pharm. Dosage Form. & Tech. 2017; 9(4): 147-157.

DOI: 10.5958/0975-4377.2017.00024.6