Of all the routes investigated for systemic drug delivery via pharmaceutical products with varying dosage forms, oral drug delivery is the one that is most frequently used. Because of its affordability, patient acceptance, and simple administration, the oral route is thought to be the most natural, practical, and safe [1]. The oral route offers the largest active surface area of any drug delivery method when it comes to the administration of different medications [2].

The majority of pharmaceutical products intended for oral administration are traditional drug delivery systems or instant-release types, which are made to release the medication immediately for quick absorption [1]. Therapeutic plasma concentrations fluctuate as a result of conventional dosing patterns, which might occasionally cause noticeable adverse effects. Furthermore, a variety of circumstances can affect the rate and degree of medication absorption from standard dose forms [2]. The excipients employed, the active ingredient's physicochemical characteristics, the gastrointestinal tract's physiology and pH, the rate of stomach emptying, and GI motility are some of the variables that influence how quickly and fully a medication enters the systemic circulation after administration [3].

Uncontrolled rapid drug release can be hazardous to the stomach or the entire body. As a result, different strategies are used when creating formulations to get around the drawbacks of traditional dosage forms, such as the sustained or controlled drug delivery system. Oral, intravenous, and transdermal systems are the three primary categories of controlled-release drug delivery methods. Osmotic pressure is used by oral osmotically controlled release (CR) delivery systems to distribute active drugs in a controlled manner [2]. The release characteristics of drugs from these systems can be controlled by adjusting the qualities of both the drug and the system. The release of the drug is largely independent of pH and other physiological parameters [3].

The net movement of water due to pressure across a selectively permeable membrane is known as osmosis [3]. One of the most sophisticated drug delivery systems is the osmotic drug delivery system (ODDS), which uses osmotic pressure as a propellant to deliver medications in a regulated manner. To keep drug concentration within the therapeutic window, the drug dose and dosing interval in ODDS are optimized [4]. By maintaining plasma concentration within the therapeutic range after absorption, ODDS offers a consistent concentration of the drug at the site of absorption, minimizing adverse effects and lowering the frequency of administration [5]. An osmotic gradient is created and the release of the medication is regulated when water diffuses into the center of an osmotic system through the micro porous membrane. [4]

DEVICES OF OSMOTIC DRUG DELIVERY

The following categories can be applied to osmotic drug delivery systems based on their design and current state of use:

1. Implantable osmotic pump

An implantable osmotic pump that distributes drugs to a patient consists of an osmotic engine, a substantially toroidal compartment arranged at least partially around the osmotic engine, and a piston located within the compartment. When the pump is placed in an aqueous environment, the osmotic engine is used to propel the piston through the compartment and discharge the active substance. Implantable osmotic systems include the Rose and Nelson pump, the Higuchi Theeuwes pump, and the Higuchi Leeper pump, while implantable Mini osmotic pumps include the Alzet and Duros Mini osmotic pump [4].

2. Oral osmotic pump

An oral osmotic pump is an osmotic device that delivers an active component into the patient's mouth cavity. The osmotic device consists of a semi-permeable membrane that surrounds a compartment containing an active substance that is insoluble to very soluble in aqueous fluid. The path via the semi-permeable membrane connects the device's exterior to the compartment housing the active agent, which is then delivered from the device into the oral cavity [2]. The oral osmotic pump is categorized as single chamber osmotic pumps, such as the elementary osmotic pump (EOP), multi chamber osmotic pumps, such as the push pull osmotic pump (PPOP), and osmotic pumps with nonexpanding second chambers [4].

3. Specific types

A number of osmotic pump systems, including the liquid OROS/liquid oral osmotic system, the osmotic bursting osmotic pump (OBOP), and the controlled porosity osmotic pump (CPOP), have been developed recently. (e.g. L OROS hard cap, L OROS soft cap, delayed liquid bolus delivery system, telescopic capsule, OROS CT, sandwiched osmotic tablets (SOTS), monolithic osmotic system, osmat, multiparticulate delayed release systems (MPDRS), pulsatile delivery via expandable orifice, pulsatile delivery via a series of stops, and lipid osmotic pump.[4]

CONTROLLED POROSITY OSMOTIC TABLET

The core compartment of the controlled porosity osmotic pump tablet is filled with medication and coated in an asymmetric insoluble membrane that contains some water-soluble additives. The membrane only allows water to pass through it selectively. The aqueous environment causes water-soluble additives to dissolve and leak out of the system, causing the membrane to develop micropores that give it a sponge-like texture. The resulting microporous wall is thus permeable to both water and the medication when it is dissolved. Among the pore-formers that are used are urea, sodium chloride, and sorbitol.

Beneficial materials are those that can form 5–95% pores with pore diameters between 10 and 100?m.
Numerous investigations have been carried out to examine the mechanism of drug release in situations where solubility ranges from moderate to high. Additionally, various solubility modulators are being examined. The solubility of the drug in the tablet core, the coating thickness, the amount of leachable pore-forming agent(s), and the osmotic pressure difference across the membrane all affect how quickly drugs escape from a controlled porosity osmotic pump [2]. The medication release rate from this system is dependent on the coating surface area, osmotic pressure, drug solubility, and thickness of the soluble component. On the other hand, neither pH nor physiological circumstances affect this system [3].

ADVANTAGES [1, 4]

1. Following an initial lag, the release of medication from controlled porosity osmotic pump tablets occurs according to zero order kinetics.
2. There could be a pulsatile or delayed medication delivery.
3. The drug release is unaffected by the body's physiological state, the drug, the pH of the stomach, and hydrodynamic conditions.
4. Osmotic systems have a very predictable release rate that can be adjusted by varying the release control parameters.
5. A high degree of in vitro in vivo correlation is provided by the drug administration method.
6. Compared to traditional drug administration methods, the drug release is higher.
7. The medication has no effect on the releasing mechanisms.
8. The presence of food in the gastrointestinal tract has less of an impact on medication release.
9. The drug delivery rate from CPOP is programmable and consistent.
10. Since the holes are produced in situ, laser drilling is not necessary.
11. Scaling up manufacturing is a pretty simple process.
12. Because the medication is administered via the complete surface as opposed to a single delivery opening, stomach discomfort issues are decreased.
13. It works well with medications that are water soluble, somewhat soluble, and insoluble in water.

   DISADVANTAGES [1, 4]

1. The preparatory process is highly expensive.
2. If unanticipated negative effects occur, retrieval therapy cannot be controlled.
3. Because of the release of the drug's saturated solution, it may irritate the skin or create ulcers.
4. If the coating process is not well managed, there may be an opportunity for dose dumping.
5. The amount of food consumed and the gastric motility affect the system's residence time in the body.
6. The emergence of drug tolerance is a possibility.

MECHANISM OF DRUG RELEASE

The water soluble additives dissolve and create a microporous structure in the coated membrane when the controlled porosity osmotic pump tablets are in an aqueous environment. The micropores that form in SPM have the potential to be continuous with microporous lamina, connected by winding routes with both regular and irregular geometries [6].

Additives for pore formation with concentrations between 5% and 95% result in pores with sizes between 10A? and 100 lm. Drugs that are water soluble, partially water soluble, and water insoluble can all be treated using this method. When the semi-permeable membrane comes into contact with water, it becomes the shape of a sponge. Water permeates semi-permeable membranes, creating a medication solution that is discharged via the pores. The kind and concentration of osmogent determine the rate of water entry, and the size and quantity of pores as well as the hydrostatic pressure generated by the incoming water determine the release of drugs [7].

Different osmotic pump principles for drug delivery systems employ water as a solvent. For actuation, the solvent flow is delivered by each pump across the semi-permeable membrane. The drug utilized as an osmotic agent dissolves when solvent flows through the membrane into the osmotic device, dislodging the saturated drug solution through outlets. Equation (1) expresses the volume flow of solvent into the core reservoir.

dvdt=AhL(?d?-dp)

dmdt=dvdtC

Where, C is the drug's concentration in the distributed fluid and dm/dt is the solute/drug delivery rate.
The reflection coefficient is taken into account when there is medication leakage via the membrane. When the SPM is perfect, no solute can travel through it, and ? is almost equal to unity. A large enough aperture will result in very little hydrostatic pressure, which eventually approaches nil. Thus, Eq. (1) becomes

dvdt=AhL?d?

Since osmotic pressure in gastrointestinal fluids is much lower than in core, d? is used in place of ?, and a constant K is used in place of L ?. As a result, the equation becomes

dvdt=AhK?

Thus, the drug pumping rate from the core can be represented as follows:

dmdt=AhK?C

This basic formula works for controlled porosity osmotic pump tablets as well as all osmotically driven pumps [4].

IMPORTANT COMPONENTS OF CONTROLLED POROSITY OSMOTIC PUMP TABLETS

Drug

Only this system can be used to design a medication that is naturally water soluble. Drugs with a brief biological half-life (two to six hours), long-acting medications (glipizide, nifedipine, etc.), and extremely powerful medications can be developed for this system [4].

Osmogent

An crucial component of osmotic formulations are osmogenes. They keep the membrane's osmotic gradient intact. Osmogenes dissolve in biological fluid that has entered the osmotic pump through a semipermeable membrane. This causes an increase in osmotic pressure inside the pump and forces medication out of the pump through a delivery orifice. They also help to keep the medicine consistent in the hydrated formulation and provide a driving force for the uptake of water. An osmogene could be a medication that dissolves in water. The choice is made in accordance with the drug's solubility as well as the quantity and pace at which the drug will be released from the pump. Drugs that have minimal solubility will exhibit zero order release, albeit slowly. Osmotic agent is added to the formulation in order to improve the release rate [1].

       
           
       
Table no: 1 Osmotic agents with their osmotic pressure [1-4, 13].

Other names for semi-permeable membranes are differentially permeable, partially permeable, and selectively permeable [4]. Solvent and certain chemicals or ions can move through SPM membranes through diffusion or specialized assisted diffusion. SPM is present in CPOP as the outer layer. The medication and other components contained in the compartments cannot travel through the membrane [8].The membrane needs to be stable in the device's internal and external conditions [9]. The membrane is biocompatible with the other chemicals in the formulation and is inert, maintaining its dimensional integrity to provide a steady osmotic pressure during drug administration [8]. The other group of polymers that create SPMs includes polyamides, polyurethanes, cellulose acetate ethyl carbamate, cellulose   acetate, and acetaldehyde dimethyl cellulose acetate. For the semi-permeable membrane to resist the pressure inside the device, it is typically 200–300 lm thick.

Ideal properties of Semi- permeable membrane [9]

1. The material's wet modulus and wet strength must be adequate.
2. The semi-permeable membrane needs to maintain strict dimensional integrity while the device is in operation.
3. To keep the water flux rate within the intended range, the membrane needs to have enough water permeability.
4. The osmotic agent's reflection coefficient and leakiness should become closer to the limiting value of unity.

Coating Solvents

The majority of cellulose acetate is utilized in the creation of different CPOP tablets. Cellulosic polymers such cellulose ethers, cellulose esters, and cellulose ester-ether are involved in the synthesis of SPM. The polymeric solutions that are used to create the osmotic device wall can be made with coating solvents. Both inorganic and organic inert solvents are a part of it. Carbon tetrachloride, water, cyclohexane, methylene chloride, acetone, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethyl acetate, etc. Are among the solvents used for coating solvents [10]. Acetone-methanol (80:20), acetone-ethanol (80:20), acetone-water (90:10), methylene chloride-methanol (79:21), methylene chloride-methanol-water (75:22:3), and other solvent combinations are among them [11].

Emulsifying agents

These work especially well when combined with wall-forming materials. They create an integral composite that is helpful in activating the device's wall. They function by controlling the surface energy of constituents to enhance their assimilation into the composite and preserve their integrity in the drug release milieu. Utilizing self-emulsifying agents, certain patented innovations enable the distribution of liquids from osmotic delivery systems. Typical surfactants have been utilized for this purpose, including polyoxyethylenated glyceryl ricinolate, polyoxyethylenated castor oil with ethylene oxide, glyceryl laureates, and glycerol (sorbiton oleate, stearate, or laurate) [4,8].

Flux regulating agents

The wall-forming materials are mixed with agents that control, enhance, or decrease flow. It helps control the flux's fluid permeability through the wall. The liquid flux can be adjusted in advance by choosing this particular agent. They also make the lamina more porous and flexible. In contrast to hydrophobic materials like phthalates substituted with an alkyl or alkoxy (e.g., diethyl phthalate or dimethoxy ethyl phthalate), hydrophilic substances like polyethethylene glycols (300 to 6000 Da), polyhydric alcohols, polyalkylene glycols, and the like tend to improve the flux. For this aim, materials that are essentially water-impermeable, such as insoluble oxides or salts, can also be employed [12, 13].

Wicking agents

Water can be drawn into the delivery device's porous network by the wicking agent. It is possible for the wicking agent to be swellable or nonswellable. It is capable of going via physisorption with water. Vanderwaal interactions between the wicking agent's surface and the absorbed molecule allow solvent molecules to cling loosely to their surfaces during physisorption, a type of absorption. The purpose of the wicking agent51 is to transport water to the surfaces inside the device's core and form a network or channels with a greater surface area. Wicking agents include sodium lauryl sulphate, bentonite, colloidal silicon dioxide, kaolin, titanium dioxide, alumina, niacinamide, and polyvinyl pyrrolidone [14].

Plasticizers

Plasticizers improve the workability, flexibility, and permeability of the fluids while lowering the temperature of the wall's second order phase transition or elastic modulus. Typically, one hundred parts of wall-forming materials are mixed with 0.001 to 50 parts of a plasticizer or mixture of plasticizers. High solvent power, compatibility with the materials throughout the processing and temperature range, permanence—as evidenced by the materials' strong tendency to stay in the plasticized wall—flexibility, and nontoxicity are all characteristics of suitable solvents. Dibenzyl, dihexyl, or butyl octyl phthalates, triacetin, epoxidized tallate, or tri-isoctyl trimellitate, alkyl adipates, citrates, acetates, propionates, glycolates, myristates, benzoates, and halogenated phenyls are examples of exemplary plasticizers. These plasticizers aid in modulating and achieving the necessary release rate in the design of osmotic controlled release systems [15].

Pore forming agents

When the system operates, the pore-forming chemicals leach into the membrane, creating a microporous structure that is typically utilized for medications that are poorly soluble in water. Prior to the system operating, the pores in the wall might be created by chemical reactions in the polymer solution or by gas production caused by the volatilization of components [4]. Both organic and inorganic materials can be used as pore formers. Alkaline metal salts (sodium chloride, sodium bromide, potassium chloride, potassium sulphate, potassium phosphate, etc.), alkaline earth metals (calcium chloride, calcium nitrate, etc.), and carbohydrates (sucrose, glucose, fructose, mannose, lactose, sorbitol, mannitol, diols, polyols, etc.) are examples of substances that can form pores [15].

Barrier layer formers

Various materials are employed as barrier layers to keep water out of specific areas of the delivery system and to keep the drug layer and osmotic layer apart. Hydrophilic polymers make up the water-permeable covering of a multilayered reservoir. On the other hand, latex compounds like polymethacrylates are used to create layers that are impenetrable to water. Moreover, a barrier layer made mostly of fluid-impermeable substances, such as high-density polyethylene, wax, rubber, and the like, can be positioned between the drug layer and the osmotic composition [13].

       
           
       
Table no2: Criteria and specifications of controlled porosity osmotic pump [4]

Fourier transform infrared spectroscopy (FTIR)

By examining the notable variations in the form and location of the absorbance bands, the Fourier Transform Infrared (FTIR) approach can be used to highlight the implications of the various functional groups of drugs and excipients. Using this procedure, individual samples and the drug and excipient mixture were completely crushed and mixed with potassium bromide (1:100) for three to five minutes in a mortar. Then, the discs were compacted into discs by applying five tons of pressure for five minutes in a hydraulic press. The pellet was placed in the sample holder and the FTIR spectrophotometer was used to scan it from 4000 to 400 cm1. Then, all sample characteristics and combination characteristics peaks were found. Then, pure medication and excipients were compared to the peaks of the improved formulation. It was deemed compatible if there was no interaction between the drug's peak and the optimized formulation's excipients [16].

Differential scanning calorimetry (DSC)

By employing differential scanning calorimetry, the drug's compatibility with the excipients employed in the formulation development process was evaluated. Drug and specific excipient physical mixes in a 1:1 ratio were prepared and subjected to DSC analysis. In a DSC pan, individual samples and a physical combination of the medication and excipients were weighed to a maximum of 5 mg. The sample pan was scanned in the 50–300 ?C temperature range after being crimped for efficient heat conduction. A 20 ?C min heating rate was employed, and the thermogram that was produced was examined for signs of interaction. Subsequently, the thermograms were contrasted between optimal formulation and pure samples [17].

EVALUATION OF OSMOTIC PUMP TABLETS

1. Precompression parameters of osmotic pump tablets

Angle of repose (?)

The heap's creation technique has a significant impact on the angle of repose test. Measurements of heap shapes can be used to determine the angle of repose. It is possible to measure the angle of repose using the traditional approach. The following formula is used to determine the powder heap's diameter and angle of repose.

tan?=2h/d

 ?=tan-1(2h/d)

Where, d is the circular support's diameter in centimeters, h is the heap's height in centimeters, and ? is the angle of repose [18].

       
           
       
Table 3: Angle of repose and its observations

Bulk density (e_b)

Pouring the granules into a graduated cylinder allows one to calculate the bulk density. The granules' mass (m) and bulk volume (Vb) are calculated. The following formula [19] is used to determine the bulk density.

Bulk density (e_b) = Mass of granules (m)/ Bulk volume of granules (V_b)

Tapped density (e_t)

For a predetermined amount of time, the measuring cylinder holding a known mass of granule blend is tapped 1000 times. Measurements are made of the mass of the granules (m) and the minimum volume occupied in the cylinder (Vt). The following formula is used to calculate the tapped density [20].

Tapped density (e_t) = Mass of granules (m)/Tapped volume of granules (V_b)

Compressibility index (Carr’s index)

The flow property properties of the granules generated by Carr are determined by the compressibility index. The potential powder arch and stability can be directly determined by looking at the % compressibility of the granules. The formula [4] can be used to compute the Carr's index.% Compressibility= (Tapped density – Bulk density) / (Tapped density) X 100

       
           
       
Table 4 : Relationship between powder flowability and % compressibility range.

Hausner’s ratio The granule flow characteristics are determined using Hausner's ratio. The ratio can be computed by dividing the bulk density by the tapped density ratio. As can be shown in Table [17].

       
           
       
Table 5: Hausner’s ratio and its flow types.

2. Post compression parameters of osmotic pump tablets

Thickness

A vernier caliper is used to measure the thickness of individual tablets, providing an accurate measurement of thickness. It gives details on how the thickness of osmotic pump pills varies. Typically, mm is used as the measurement unit for thickness. Every tablet has a maximum thickness deviation of ±5% [21].

Hardness

The Monsanto hardness tester may be used to measure tablet hardness, which is expressed in kg/cm2 [22].

Friability

A Roche friabilator was used to test the friability of tablets. After being first weighed (W0) as a group, ten pills were added to the chamber. The tablets experienced the combined impacts of shock and vibration since the plastic chamber containing them dropped them at a distance of six inches with each revolution and abrasion during the 100 revolutions of the friabilator. After that, the pills are weighed again and dusted (W).The following formula was used to determine the percentage of friability.

%Friability=F=(1-WoW)×100

 Where, W0 and W are the tablets' pre-test and post-test weights, respectively. The proportion of friability must exceed 0.5% to 1% [23].

Weight variation

To perform the weight variation test, each of the twenty tablets is weighed separately, the average weight is determined, and the weights of each tablet are compared to the average. After calculating the % weight deviation, the results were compared to the USP requirements. If no tablet deviates from the percentage restriction by more than twice and if no tablet differs by more than twice the age limit, then the tablets pass the USP test. Table 6 displays it [24].

Weight variation of nth tablet= (|w-wn|)w×100%

Where, the tablet weights are w1, w2, w3.... wn ...., w20, and the average tablet weight is w

       
           
       
Table:6 USP: specifications for weight variation of tablets.

Disintegration test