1.2. Swelling systems
These are the dosage forms, which after swallowing, swell to an extent that prevents their exit from the pylorus (Figure 3d). As a result, the dosage form retains in the stomach for a longer period of time. These systems may be named as ‘plug type systems’. Sustained and controlled drug release may be achieved by selection of polymer of proper molecular weight and swelling of the polymer retards the drug release.

On coming in contact with gastric fluid, the polymer imbibes water and swells. The extensive swelling of these polymers is due to the presence of physical/chemical cross-links in the hydrophilic polymer network. These cross-links prevent the dissolution of the polymer and hence maintain the physical integrity of the dosage form.

1.3. Expandable systems
A dosage form in the stomach will withstand gastric transit if it is bigger than the pyloric sphincter. Thus, three configurations are required: a small configuration for oral intake, an expanded gastroretentive form and a final small form enabling evacuation following drug release (Figure 3e). Thus, gastroretentivity is improved by the combination of substantial dimension with high rigidity of dosage form to withstand peristalsis and mechanical contractility of the stomach. Unfoldable and swellable systems have been investigated and recently tried to develop an effective gastroretentive drug delivery.

1.4. Ion exchange resin system
Ion exchange resin system is a system which is formulated to have gastroretentive properties. Ion exchange resin beads are loaded with bicarbonate and a negatively charged drug is bound to the resin (Figure 3f). The resultant beads were then encapsulated in a semipermeable membrane to overcome the rapid loss of carbon dioxide. Upon arrival in the acidic environment of the stomach, an exchange of chloride and bicarbonate ions takes place.

As a result of this reaction carbon dioxide was released and trapped in the membrane thereby carrying beads towards the top of gastric content and producing a floating layer of resin beads in contrast to the uncoated beads, which will sink quickly.

1.5. Raft forming system [1,10]
The raft forming system is one of the approaches which involve the formulation of effervescent floating liquid with in situ gelling properties, which has been assessed for sustaining drug delivery and targeting. Moreover, the gels formed in situ remained intact for more than 48h to facilitate sustained release of drugs. The mechanism of the raft forming system involves the formation of continuous layer called a raft. The system involves the formation of a viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells forming a continuous layer called a raft.

The layer of the gel floats on the gastric fluid because it has bulk density less than the gastric fluid, as low density is created by the formation of CO_2. So the system remains buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. The gel formed from in situ gelling, being lighter than gastric fluid, floats over the stomach contents or adheres to the gastric mucosa due to the presence of a bioadhesive nature of the polymer and prevents the reflux of gastric content into the esophagus by acting as a barrier between the stomach and the esophagus (Figure 6). Thus it produces retention of dosage form and increases gastric residence time resulting in prolonged drug delivery in gastrointestinal tract. When the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system. After release of the drug, the residual system is emptied from the stomach. This results in an increased gastro retention time and a better control of the fluctuations in plasma drug concentration.

1.5.1 The design of the raft forming system
The formulation of the raft forming system depends on the physicochemical properties of the drug molecule, the diseased condition for which treatment is required, the patient population and the marketing preference. Physico-chemical factors include molecular weight, lipophilicity and molecular charge; an anatomical and physiological factor includes membrane transport and pH of tissue fluid; formulation factors include pH, gelation temperature, viscosity, osmolarity, and spreadability.

To achieve the gastric retention of the dosage form, the dosage form must be able to satisfy the following criteria.

1. The drug should be released slowly from the system.
2. The dosage form must be able to withstand the force exerted by peristaltic waves in the stomach and the constant contractions, grinding and churning moments.
3. Should maintain specific gravity lower than gastric contents (1.004–1.01 g/cm3).
4. The dosage form must remain in the stomach for a prolonged period of time.
5. Better patient compliance.
6. Easy for administration for the patient.
7. After the release of the drug the device should be easily evacuated from the stomach.

1.5.2 Drugs used for the raft forming system
Raft forming systems have received much attention for the delivery of antacids and drug delivery for gastrointestinal infections and disorders. The raft forming system is the potential approach for heart burn and esophagitis. This system is suitable for acid soluble drugs that are poorly soluble or unstable in intestinal fluids. Various drugs that can be used for the raft forming system are summarized in Table 1 with their category.

Thus the criteria of the drug to be considered for the selection of the drug for gastro retention are as follows:

1. Drugs that are locally active in the stomach.
2. Drugs that have narrow absorption window in the gastrointestinal tract.
3. Drug that are absorbed from the stomach and upper part of the gastrointestinal tract.
4. Drugs that are unstable in the intestinal or colonic environment.
5. Drugs that disturb normal colonic microbes.
6. Drugs that degrade in the colon.
7. Drugs that exhibit low solubility at high pH values (or are poorly soluble at alkaline pH).

1.5.3 The criteria of the drug that are not suitable for gastric retention are;

1. Drugs that have very limited acid solubility.
2. Drugs that suffer instability in the gastric environment.
3. Drugs intended for selective release in the colon.

1.5.4 Polymer used for formulation
Various polymers are employed in floating drug delivery systems so as to target the delivery of the drug to a specific region in the gastrointestinal tract i.e. stomach. Various natural and synthetic polymers are used in the formulation of the raft forming drug delivery system.

Natural polymer such as alginic acid, guar gum, gellan gum, xyloglucan, pectin, chitosan etc. and synthetic polymer such as poly (DL lactic acid), poly (DL-lactide-co-glycolide) and poly-caprolactone, HPMC etc. are used for formulation development of the raft forming drug delivery system.

A polymer used for in situ gels should have the following characteristics

1. It should be biocompatible.
2. It should have pseudo plastic behavior.
3. The polymer should be capable of increasing the viscosity with increasing the shear rate.

Advantages of floating raft forming gastroretentive drug delivery system:

1. Raft forming system forms a low density viscous layer on gastric contents and hence provides more effective surface area than a tablet.
2. These lead to more drug release and improve bioavailability.
3. Floating obtained faster than the other floating dosage form.
4. Improve patient compliance by making a once a day therapy.
5. Improve therapeutic efficacy.
6. Easy to administer to a patient.

Limitation of floating raft forming gastroretentive drug delivery system:

1. These systems are formulated in the form of solution which is more susceptible to stability problems. These are due to chemical degradation (oxidation, hydrolysis, etc.) or microbial degradation.
2. The formulation must be stored properly because if the formulation is not stored properly it may cause stability problem. This is due to change in the pH of the system on prolonged storage or on storing inappropriate temperature conditions.
3. Exposure of certain polymer to radiations (e.g. UV, Visible, electromagnetic, etc.) induces the formation of gel within the package.

2. Non-Effervescent Floating Dosage Forms [11]: Non-effervescent floating dosage forms use a gel forming or swellable cellulose type of hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a simple approach of thoroughly mixing the drug and the gel-forming hydrocolloid. After oral administration this dosage form swells in contact with gastric fluids and attains a bulk density of GIT. The air entrapped within the swollen matrix imparts buoyancy to the dosage form. The so formed swollen gel-like structure acts as a reservoir and allows sustained release of drug through the gelatinous mass.

2.1. Single layer floating tablets: They are formulated by uniform mixing of a drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid and maintains specific gravity less than one. They are formulated by blending of a drug with low-density enteric materials such as cellulose acetate phthalate and hydroxyl propyl methyl cellulose.

2.2. Bi-layer floating tablets: A bi-layer tablet contains two layers. One is an immediate release layer which releases loading dose from the system while the other is a sustained release layer which releases dose by absorbing gastric fluid, forming an impermeable colloidal gel barrier on its surface, and maintains a specific gravity less than unity and thereby remains buoyant in the stomach.

2.3. Hydrodynamically balanced systems: Seth and Tossounian were the first to designate these hydrodynamically balanced systems (Figure 7). These are single-unit dosage forms, containing one or more gelforming hydrophilic polymers. Hydroxypropyl methylcellulose (HPMC) is the most common used excipient, although hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose (NaCMC), agar, carrageenan or alginic acid is also used. The polymer ismixedwith a drug and usually administered in a gelatin capsule.

The capsule rapidly dissolves in the gastric fluid, and hydration and swelling of the surface polymers produce a floating mass.

2.4. Microballoons/hollow microspheres: Microballoons/hollow microspheres loaded with drugs in their other polymer were prepared by simple solvent evaporation or solvent diffusion methods to prolong the gastric retention time (GRT) of the dosage form. Commonly used polymers to develop these systems are polycarbonate, cellulose acetate, calcium alginate, Eudragit S, agar, low methoxylated pectin etc. Buoyancy and drug release from dosage form are dependent on quantity of polymers, the plasticizer polymer ratio and the solvent used for formulation

There are several commercial products available based on the research activity of floating drug delivery [2,12] (Table 2).

II. Evaluation of floating drug delivery systems: Various parameters that need to be evaluated in gastro-retentive formulations include floating duration, dissolution profiles, specific gravity, content uniformity, hardness, and friability in case of solid dosage forms. In the case of multi particulate drug delivery systems, differential scanning calorimetry (DSC), particle size analysis, flow properties, surface morphology, mechanical properties and X-ray diffraction studies are also performed. Hardness, and friability in case of solid dosage forms. In the case of multi particulate drug delivery systems, differential scanning calorimetry (DSC), particle size analysis, flow properties, surface morphology, mechanical properties and X-ray diffraction studies are also performed [13,14].

For Single Unit Dosage Forms (ex: tablets)
Floating lag time [15]: In this the time taken by the tablet to emerge onto the surface of dissolution medium and is expressed in seconds or minutes.

In-vitro drug release and duration of floating: This is determined by using USP II apparatus (paddle) stirring at a speed of 50 or 100 rpm at 37°C in simulated gastric fluid (pH 1.2 without pepsin). Aliquots of the samples are collected and analyzed for the drug content. The time (h) for which the tablets remain buoyant on the surface of the dissolution medium is the duration of floating and is visually observed.

In vivo evaluation for gastro-retention [1,16]: This is carried out by means of X-ray or Gamma scintigraphic monitoring of the dosage form transition in the GIT. Tablets hardness, weight variation, etc are also evaluated.

Gastroscopy: Gastroscopy is peroral endoscopy used with fiber optics or video systems. Gastroscopy is used to inspect visually the effect of dosage form for prolongation in stomach.

Magnetic marker monitoring: In this technique, dosage form is magnetically marked with incorporating iron powder inside the dosage form. Image of the dosage form can be taken by very sensitive bio-magnetic measurement equipment. Advantage of this method is that it is radiation less and thus not too much hazardous

For Multiple Unit Dosage Forms [17] (ex: microspheres): From In vitro release, floating duration and in vivo gastro-retention tests, multiple unit dosage forms are also evaluated for

Morphological and dimensional analysis: It is done with the help scanning electron microscopy (SEM). Optical microscope can also be used for measuring size.

% yield of microspheres: the yield of microspheres was calculated from the formula: Weight of microspheres obtained ×100/total weight of drug and polymer.

Entrapment efficiency: By a suitable method the drug is extracted, analyzed and calculated from: Practical amount of drug present ×100/Theoretical drug content.

In vitro floating ability (Buoyancy %): A known quantity of microspheres are spread over the surface of a USP (Type II) dissolution apparatus filled with 900 ml of 0.1 N HCl containing 0.002% v/v Tween 80 and agitated for 12 hours at 100 rpm. when 12 hours are completed, the floating and settled layers are separated, dried in a desiccator and weighed.

The buoyancy is calculated from the following formula
Buoyancy (%) = Wf/(Wf + Ws) × 100
Wf- Weights of floating and Ws- Settled microsphere.

Drug-excipient (DE) interactions: FTIR is used for this type evaluation. The DE interaction is indicated by new peak appearance or disappearance of original drug or excipient peak. From the mentioned evaluation parameters, the effect of ageing on granules is also evaluated with the help of Differential Scanning Calorimeter or Hot stage polarizing microscopy.

III. Characterization Parameters
Size and shape evaluation [18]: Determining solubility rate of the drugs and its bioavailability the particle size and shape plays a major role. The size of particle of the formulation was determined by using Sieve analysis, Photo analysis, Air elutriation analysis, Optical microscope, Sedimentation techniques, Electro resistance counting methods (Coulter counter), Laser diffraction methods, ultrasound attenuation spectroscopy, etc.

Floating Properties: Effect of formulation variables on the floating properties of gastric floating drug delivery system was determined by using continuous floating monitoring system and statistical experimental design.

Surface Topography 1: The surface topography and structures were determined using scanning electron microscope (SEM) operated with an 10 KV acceleration voltage, Atomic force microscopy (AFM), Contact angle meter, Contact profiliometer.

Determination of Moisture Content: Karl fisher titration was used for determination of moisture content of the prepared formulations. The other methods used are Thermo gravimetric methods, Vacuum drying, Air oven method, Freeze drying, and Moisture Meters.

Sol–gel transition and gelling time [1,19]: Raft forming system is an effervescent liquid which involves the formation of viscous cohesive gel in contact with gastric fluids. The sol–gel transition temperature may be defined as the temperature at which the phase transition of sol meniscus is first noted when kept in a sample tube at a specific temperature and then heated at a specified rate. Gel formation is indicated by a lack of movement of meniscus on tilting the tube.

Gel strength 1: This is used to determine gelling property of prepared formulation. This parameter can be evaluated using a rheometer. In this test a specified amount of gel is prepared in a beaker, from the sol form. Gel containing beaker is raised at a certain rate, then pushing a probe of rheometer slowly through the gel. The changes in the load on the probe can be measured as a function of depth of immersion of the probe below the gel surface

Viscosity and rheology 1: This is an important parameter to be evaluated for the raft forming system. The viscosity and rheological properties of the polymeric formulations, either in solution or in gel made with artificial tissue fluid (depending upon the route of administrations) were determined with a different viscometer. The viscosity can be determined with Brookfield viscometer or some other type of viscometers such as Ostwald's viscometer.

Various commercial formulations of the raft forming system 1 are tabulated in Table 3.

Drug absorption in the gastrointestinal tract is a highly variable procedure and prolonging gastric retention of the dosage form extends the time for drug absorption. FDDS promises to be a potential approach for gastric retention. The gastroretentive drug delivery system is a burgeoning field in which most of the researchers are developing various technological approaches in order to produce the desired gastric retention. Various gastric retention approaches are studied such as floating drug delivery systems, high density system, mucoadhesive system, expandable system, swelling system and ion exchange system each having their own advantages and disadvantages.

Among the various approaches the raft forming system has emerged as an efficient means of enhancing the bioavailability and controlling the delivery of many drugs. It provides stomach specific drug release for longer duration which remains buoyant on the gastric surface. As the system remains in the stomach for longer duration, local action of the drug is increased due to prolonged contact time with the gastric mucosa. Thus leads to less frequent dosing and improved efficiency of treatment. Raft forming system is not only helpful for sustained drug delivery but also convenient for pediatric and geriatric patients. This system is helpful as an alternative of oral solid dosage form with the advantages of liquid dosage form. Sustained and prolonged release of the drug, good stability and bioavailability characteristics make the raft forming system very suitable candidate for gastric retention of the drug. Thus the raft forming system promises to be the potential approach for gastric retention drug delivery system. Due to unpredictability of human GIT development of efficient GRDFs is a real challenge to pharmaceutical technology as the drug delivery system must remain for a sufficient time in the stomach which is not compatible with normal physiology.