A Critical Review on Floating Drug Delivery System: Pharmacokinetics and Pharmacodynamic Aspects

Pharmaceuticals in pure crude form, which might be solid, liquid, or semi-solid, are used in drug delivery systems. They must be stable, safe, and able to get a specific amount of the medication to the right place in the body right away, reach the right concentration, and then stay there^. [1] A common disadvantage of conventional sustained release dosage forms is their inability to extend the duration in the stomach and their lack of control over drug administration, which results in fluctuations in the plasma drug concentration level. Effectively treating disease conditions, minimizing side effects, and improving patient compliance while maintaining cost-effectiveness are the ultimate goals of any medication delivery system. More than half of all drug delivery systems available on the market are oral medication delivery systems. The main reasons for choosing oral drug delivery are its low treatment costs, more patient compliance, and ease of administration. Not with standing its many benefits, a medication's frequency of administration should be raised due to its easy stomach discharge. ^[2] To overcome these challenges, pharmaceutical delivery must provide a longer duration of stomach residency. Gastro retention promotes both enhanced bioavailability and improved solubility, which is less soluble at high ambient pH 3. Many drugs that are released in the stomach have the greatest therapeutic impact because of their constant delay and controlled release. This type of drug delivery system would have comparatively fewer side effects in addition to eliminating the requirement for recurrent dosage. Controlled release drug delivery systems (CRDDS) offer a predetermined, predictable, and regulated rate of drug release.  Benefits of a controlled release drug delivery system include: elimination of side effects, reduction in frequency of dosing and drug waste, optimization of therapy, improved patient compliance, and maintenance of the optimal therapeutic drug concentration in blood with predictable and reproducible release rates for an extended period of time. Magnetic systems, swelling systems, expandable systems, raft-forming systems, bioadhesive systems, floating (low density) and non-floating (high density) systems, and superporous systems are some recent approaches for extending the gastric duration of drug delivery systems. ^[2,3]

Gastrointestinal Tract Physiology:

Stomach

The stomach serves as a mixing and storing organ. Of the 8 L of liquid in the gastro intestinal system, about 1.5 L is produced in the stomach following a meal, and between 25 and 50 ml during interdigestive periods. Numerous physiological factors, such as pH, stomach enzymes, the type and amount of gastric secretions, residence time, and the effective absorbing surface area at the site of administration, have a significant impact on the metabolism and absorption of medications. The pH of the stomach, which is influenced by several factors such as diet, disease, and the presence of gasses, fatty acids, and other fermentation products in the stomach, may have an impact on the effectiveness of medications taken orally. ^[4]  Radio telemetry has been successfully used to determine the pH of the human stomach. The average stomach pH in healthy guys is 3.6±0.4 when they are fed, while the average in subjects who are fasting is 1.1±0.15. This pH returns to its normal in around two to four hours. Age and medical problems are the second factor that influences stomach pH. About 20% of the elderly have a baseline pH value greater than 5.0 due to either decreased (hypochlorhydria) or nonexistent (achlorhydria) stomach acid production. The pH of the stomach rises in AIDS and pernicious anemia because of significant reductions in stomach acid production. Drugs like proton pump inhibitors and H2 receptor antagonists significantly lower the production of gastric acid. Five minutes to two hours is the usual range of a regular gastrointestinal time. ^[5] The stomach's three anatomical components are the fundus, body, and antrum (pylorus). The fundus and body section act as a reservoir for undigested material, whereas the antrum is the main site for mixing motions and acts as a pump for stomach emptying by pushing actions. The duodenum and stomach are separated by the pylorus. The stomach residence time is significantly influenced by the size of the pylorus. The bolus is evacuated during stomach emptying in both the fed and fasting stages. The motility pattern varies between the two states, though; it is weaker in fed mode than in fasting mode.

Figure 1: Anatomy of Stomach

The fed state's motor activity takes place in five to ten minutes after a meal is consumed and lasts as long as food is in the stomach. The duration of fed activity increases with the amount of food consumed; it usually lasts between two and six hours, but more often between three and four hours, with phasic contractions resembling Phase II of MMC. ^[6]

Gastric Motility

The force that propels the flow of dose forms throughout the GI tract is known as GI motility, and it may also influence how long the dosage forms are exposed there.

Emptying Of Dosage from The Stomach

For the dosage form to demonstrate gastric retention, it must be able to tolerate early stomach emptying. In order to accomplish this, the dose form must be able to withstand the force generated by the stomach's peristaltic waves. After its intended use, the dosage form should also be simple for the body to discard. ^[7]

II. Approaches for Gastroprotective Drug Delivery Systems

Figure 2: Strategies for Gastroprotective Drug Delivery

This technique can be used to provide medications that have an absorption window in the upper small intestine or stomach. Medications that act locally in the proximal area of the gastrointestinal system include antibiotics, which are used to eradicate Helicobacter pylori in the treatment of peptic ulcers. Since they have a lower bulk density than gastric fluids and remain afloat on the stomach contents for a longer period of time without changing the gastric emptying rate, the medication is released from the system gradually and at the desired rate. The stomach empties the delivery mechanism once the active drug has been released. ^[8] For floating medication delivery systems, the following requirements must be met:

• To act as a reservoir, the API needs to be released gradually.

• Its specific gravity should remain between 1.004 and 1.01 g/cm3, which is lower than that of the stomach's contents.

• It is necessary to create a cohesive gel barrier.

B) High Density System:

The formulation density must be more than the typical stomach content density (1.004 g/cm3) in order to use this method. To create these formulations, the medication is either coated on a heavy core or mixed with inert substances such as barium sulfate, zinc oxide, titanium oxide, and iron powder. Materials' densities can rise to 1.5–2.4 g/cm3. It was demonstrated that a density of almost 2.5 g/cm3 was required for significant GRT expansion. One disadvantage of this method is that a larger dosage form size is required to achieve the high density. ^[9]

C) Magnetic System:

This technique works on the straightforward principle that a small internal magnet is present in the dose form, and that a magnet is put on the abdomen over the stomach. With the use of an extracorporeal magnet, the duration of the dosage form's stomach residence time can be prolonged. ^[10]

F) Expandable Systems:

Drug delivery systems that are expandable are designed to have a longer GRT by expanding their volume or shape. They were initially used in animal medicine before being applied to humans. ^[11]  Expandable GRDFs are commonly used in three configurations: a small (or "collapsed") form that makes oral intake easier; an expanded form that develops in the stomach and blocks passage through the pyloric sphincter; and, finally, another small form that develops in the stomach when retention is no longer necessary after the GRDF has released its active ingredient, allowing evacuation. Expandable drug delivery systems are sometimes referred to as "plug type systems" due to their ability to narrow the pyloric sphincter. Changes in volume and shape are made possible by two processes that enable the system to expand: swelling and unfolding. The main process that causes swelling and drug release from the system is diffusion. Utilizing hydrophilic polymers like Carbopol, HPMC, and polyethylene oxide, these systems are able to extend the capacity of the system by absorbing water from the stomach contents. ^[12]

G) Super porous Hydrogel System:

Using highly swellable polymers like sodium alginate and croscarmellose sodium, superporous hydrogel systems increase the GRT by swelling up to 100 times or more and gaining sufficient mechanical strength to withstand pressure from gastric contraction. Superporous hydrogel was introduced as a different type of water-absorbent polymer system in 1998 and has gained popularity in the controlled-release formulation due to its excellent mechanical strength and elastic characteristics. However, due to the structure's low mechanical strength, swelling may be reversible, and the system may be extremely sensitive to pH changes. ^[13]

H) Mucoadhesive/Bio adhesive System:

Mucoadhesive Drug Delivery Systems are used to enhance the absorption of medications at a specific site. This technique uses mucoadhesive polymers, which stick to the stomach's epithelial surface. As such, they can prolong the duration of gastric retention. There are several ways the delivery system can adhere to the mucosal surface.

1. Wetting theory: Relates to the capability of mucoadhesive polymers to spread and establish contact with mucosal layers.
2. Diffusion theory: Involves interpretation of mucin strands with porous structure of polymer.
3. Absorption theory: Suggests that bioadhesion is influenced by Vander Waals forces and hydrogen bonding.
4. Electronic theory: In the electronic theory, attractive forces generated between the mucosal surface and mucoadhesive polymer.

Chitosan, HPMC, acrylic acid, cholestyramine, sodium alginate, sucralfate, dextrin, tragacanth, polyethylene glycol, polylactic acid, etc. are materials that have the ability to stick together. Because of the GIT's high mucus turnover, even while some of these polymers effectively produce bioadhesion, it is challenging to sustain this bioadhesion. ^[14]

III. Factors Affecting Gastric Retention: ^{[15, 16, 17]}

1.Size

It has been reported that dosage form units with a diameter more than 7.5 mm had a higher GRT than those with a diameter of 9.9 mm.

2.Shape

Comparing tetrahedron and ring-shaped devices with flexural moduli of 48 and 22.5 kg/sq in (KSI) to other designs, it has been reported that they have better GRT and 90% to 100% retention at 24 hours.

3.Density

The floating property must be less than 1.0 gm/cm3, but once the dosage form is submerged in the fluid, the formation of hydrodynamic equilibrium causes the floating propensity to usually decrease over time. Stomach retention occurs when dosage forms with a density lower than that of stomach fluid exhibit floating behavior.

4) Fed or Fasted State
The migrating myoelectric complex (MMC), which occurs every 1.5 to 2 hours, or bursts of intensive motor activity are what define GI motility during fasting. Because the MMC eliminates undigested material from the stomach, the unit's GRT should be quite short if the formulation is delivered concurrently with the MMC. But in the fed situation, MMC is delayed and GRT is noticeably longer.

5) Nature of Meal

Drug release can be prolonged and the rate of gastric emptying slowed down by indigestible polymers or fatty acid salts that change the motility pattern of the stomach to a fed state.

6) Caloric Content

A meal heavy in fat and protein might increase GRT by 4 to 10 hours.

7) Gender

Regardless of body surface area, height, or weight, men's mean ambulatory GRT (3.4± 0.6 h) is lower than that of women of the same age and race (4.6± 1.2 h).

8) Age

The GIT is significantly longer in older persons, especially those beyond 70.

9) Posture

Posture GRTs may vary across patients in supine and upright ambulatory situations.

10) Concurrent Administration of Drugs

The GRDDS is affected by opiates like codeine, prokinetic drugs like metoclopramide and cisapride, and anticholinergic drugs like atropine and propantheline.

11) Amount of Gastric fluid

The volume of liquids given has an impact on the stomachic evacuation time. When the number is large, the evacuation process proceeds more quickly. While stomachic evacuation is slowed down by colder fluids, it is accelerated by hotter ones.

12) Biological Factors

Crohn's disease and diabetes also have an impact on the GRDDS.

IV. Floating Drug Delivery System

Davis first described floating systems in 1968. These systems have sufficient buoyancy to stay in the stomach for an extended amount of time and float above its contents. The medicine is administered gradually and at the right rate as the device floats over the contents of the stomach, enhancing GRT and reducing fluctuations in plasma drug concentration.

Mechanism of FDDS

Floating drug delivery systems stay afloat in the stomach for a long time without influencing the gastric emptying rate because their bulk density is lower than that of gastric fluid. The medications are released from the system at the desired rate and slowly while the system is floating on the contents of the stomach. The dosage form requires a small amount of floating force (F) to remain buoyant on the surface of the meal. An innovative device for calculating the resulting weight to evaluate the kinetics of the floating force has been reported in the literature. The device continuously calculates the force equal to F (as a function of time) required to hold the submerged object in place. By enhancing FDDS in terms of stability and endurance of floating forces created, this device helps to mitigate the drawbacks of erratic intragastric buoyancy capacity changes. (Sharma, 2011)

F = F buoyancy – F gravity = (Df – Ds) gv

F = Total vertical force, Df = Fluid density, Ds = Object density, g = Acceleration due to gravity, v = Volume

V. Classification of FDDS

Effervescent System

A drug delivery system can float in the stomach using a floating chamber that is filled with air, vacuum, or an inert gas. Either carbonate-bicarbonate salts and organic acids (like citric and tartaric acids) mix effervescently to produce CO₂, or an organic solvent (like ether or cyclopentane) volatilizes to release gas into the floating chamber.

It is categories into two types:

A. Volatile liquid/ vacuum type:

These systems use volatile liquid that evaporate in the stomach, creating vacuum that make the system float.

I) Inflatable System

A pullout system with a space filled with volatile liquids that evaporate at body temperature makes up this system. Therefore, the chamber inflates and the system floats when these systems are placed in the stomach. A bioerodible polymer filament composed of polymers such as polyvinyl alcohol and polyethylene makes up the inflated chamber. The polymer slowly degrades and releases the drug when the inflated chamber floats in the gastrointestinal fluid. After some time, the inflated section collapses because the polymer dissolves.

ii) Intragastric floating system:

It has a vacuum-filled chamber with a microporous section that acts as a drug reservoir.

iii) Intragastric-osmotically controlled system:

Osmotic control can be achieved with a biodegradable capsule that combines an osmotic pressure-controlled drug delivery device with inflated floating support congestion. ^[19]

B. Gas generating system

The low density FDDS is based on the CO2 that is released after oral administration when it comes into touch with stomach contents. CO2 is released when the materials react with the stomach's acidic contents and get trapped in the gel-based hydrocolloid within the stomach. It makes the dosage form rise and keeps it buoyant. The end effect is a float on the chime since it reduces the specific gravity of the dosage form.

The following are the sub type of gas generating system:

I) Floating Capsules

In these dosage forms, medications are encapsulated in hydrophilic polymers such ethyl cellulose and Eudragit RS-100, as well as effervescent agents like calcium carbonate and sodium bicarbonate.

Ii) Floating Pills

Many types of oral floating dosage forms have been developed using an effervescent ingredient in the inner layer and a hydrophilic polymer in the outer layer. The effervescent agent releases CO2 when it comes into contact with the stomach content, which causes the system to float, while the hydrophilic polymer's outer layer swells and subsequently sinks when it comes into contact with the gastric fluid.

Iii) Floating System with Ion Exchange Resins

These floating systems' main objective is to increase the GRT of dosage forms by using ion exchange resin. They consist of drug resin complex beads covered with hydrophilic polymers and loaded with bicarbonate ions. It creates CO2 gas when it comes into touch with stomach contents, which causes the beads to float. ^[20]

Non-Effervescent System

Gel-forming (or swellable) cellulose hydrocolloids made of polysaccharides and matrix-forming polymers like polycarbonate, polymethacrylate, and polystyrene make up non-effluent floating drug delivery systems.  When taken orally, the gel-forming hydrocolloids that are combined with the medication swell when they come into touch with stomach contents.  The air retained by the expanding polymer gives the dosage form buoyancy, and this method maintains the drug's bulk density barrier and shape.

i) Colloidal Gel Barrier Systems

This approach prolongs the time that the drug is retained in the stomach and increases the amount of drug that reaches its absorption site in solution form. In order to keep the medication afloat in the stomach contents, it basically comprises gel-forming hydrocolloids. Such a system contains one or more matrix-forming polymers, such as polycarbophil, polystyrene, and polyacrylate, as well as gel-forming cellulose hydrocolloids, such as hydroxypropyl methylcellulose, and polysaccharides. Upon encountering the gastrointestinal fluid, the system's hydrocolloid hydrates, forming a colloid gel barrier that shields the surrounding. ^[21]

ii) Microporous Compartment System

In this technique, a microporous compartment having pores on both the top and bottom sides enclose a drug reservoir. To prevent the undissolved medicine from coming into contact with the stomach surface, the outer wall of the drug reservoir compartment is completely sealed. The floating chamber, which is made of trapped air, allows the delivery system to float above the stomach's gastrointestinal contents. Drugs cannot exist because of the volume of gastric fluid that enters through the aperture, which also continually transports the dissolved medication down the intestine for absorption.

iii) Floating Microspheres / Microballoons

Hollow microspheres, often known as micro balloons, are believed to be the most efficient buoyant mechanism. It consists of the hollow centre of the microsphere. Their exterior polymer shelf contains a hollow microsphere that contains a medication. This microsphere was made using novel Solvent diffusion method for emulsion. ^[22]

Iv) Alginate Beads/Floating Beads

Multi-unit floating dosage forms have been made using calcium alginate spherical beads, which have a diameter of roughly 2.5 mm. One way to make them is to combine calcium chloride aqueous solution with sodium alginate solution, which produces calcium alginate to precipitate. After that, the beads are separated, freeze-dried for 24 hours at 400 °C, then snap-frozen in liquid nitrogen to create a porous system. The constructed system would maintain a floating force for more than 12 hours, and these floating beads offer a longer residence length of more than 5.5 hours. ^[23]

V) Layered Tablets

Layered tablets are growing in popularity because to their excellent stability, cost, and ease of preparation.

a. Single-layered floating tablet:

These tablets were developed by mixing gas-generating agents with drugs inside a matrix tablet. In the stomach, these formulations stay buoyant and increase GRT because their bulk density is lower than that of gastric fluid.

B. Double-Layered Floating Tablet:

It is made up of two formulations that are layered one on top of the other and have two different release patterns.

Raft Forming System

When a gel-forming solution such as sodium alginate solution with carbonates or bicarbonates comes into contact with gastric fluid, it swells and produces a viscous, cohesive gel that contains trapped CO₂ bubbles. This gel creates a raft layer on top of gastric fluids, allowing the drug to enter the stomach slowly. Antacids, such as calcium carbonate or aluminium hydroxide, are present in these kinds of formulations to lower stomach acidity. ^[24]

Figure 3: Raft Forming System

The rationale for drug selection becomes significant for this drug delivery strategy. The selection criteria for floating systems encompass a broad spectrum of medication physicochemical properties. The biopharmaceutical system (BCS) is an important consideration when choosing a medication. In BCS classification, drug permeability and solubility are crucial elements. For FDDS, medications must be highly soluble in the stomach to increase bioavailability. The preferred medication should have a dissociation constant higher than 2.5 since an acidic medicine can be absorbed in the stomach and remain unionized at gastric pH. In order to promote quick absorption through lipoidal membranes, a medicine must have a partition constant larger than one in order to be considered lipophilic. A shorter half-life is optimal for the medication (2–6). ^[25]

VII. Pharmacokinetics and Pharmacodynamic of FDDS ^[26,27]

 Pharmacodynamic Aspect

5. Minimize adverse activity at colon:

The amount of drug that reaches the colon is reduced when the drug is kept in the gastro-retentive dose form in the stomach. As a result, the drug's undesirable impacts in the colon could be avoided. Because beta-lactam antibiotics are only absorbed from the small intestine and their presence in the colon causes the growth of bacteria, this pharmacodynamic feature provides the rationale for floating formulation.

5. Reduce counter activity of the body:

The pharmacological reaction that affects the body's normal physiological functions frequently causes a rebound effect that reduces the effectiveness of the medication. It has been demonstrated that a gradual release of the medication into the body lessens this counteractivity, increasing the efficacy of the medication.

5. Improved selectivity in receptor activation:

Additionally, reducing fluctuations in drug concentration allows for some selectivity in the pharmacological effect produced by medicines that activate different types of receptors at varying quantities.

5. Reduce fluctuation of drug concentration:

When the drug is continuously administered using a floating system, blood drug concentrations fluctuate within a smaller range than with immediate-release dose forms. For medications with a narrow therapeutic index in particular, this helps reduce variations in pharmacological effects and avoid concentration-dependent side effects linked to peak concentrations.

 Pharmacokinetics Aspects

5. Absorption window:

The drug's classification as an agent with a narrow absorption window is confirmed by a number of experimental methods that are currently available to evaluate the molecule's absorption properties. These techniques aid in elucidating the permeability in various gastrointestinal (GI) tract segments and determining the mechanism of intestinal absorption. When absorption happens through limited-capacity active transporters, prolonged exposure to the drug may improve the transport activity's efficacy in comparison to an uncontrolled release mode of administration.

5. Enhanced Bioavailability:

Following confirmation that the compound has a small absorption window, it is critical to assess if continued administration of the molecule to the appropriate site could increase bioavailability. It has been noted, for example, that some bisphosphonates, including alendronate, can be absorbed straight from the stomach. Nevertheless, the degree of this absorption pathway is still restricted, even in rats that have had prolonged stomach retention of the bisphosphonate due to experimental or surgical methods. On the other hand, compared to conventional CR polymeric formulations, the bioavailability of controlled release floating systems for levodopa and riboflavin is noticeably higher. It is deduced that the overall absorption rate is simultaneously influenced by a number of processes associated with medication absorption and transit through the gastrointestinal system. To ascertain the drug's release profile from the dosage form that will improve bioavailability, in vivo investigations are therefore essential.

5. Enhance first pass biotransformation:

Comparable to the enhanced efficacy of capacity-limited active transporters, continuous administration of the drug to metabolic enzymes (specifically cytochrome CYP3A4) instead of a single bolus dose may result in a significant increase in the pre-systemic metabolism of the compound under test.

5. Reduce frequency of dosing:

A prolonged and steady release from a controlled release floating system may result in flip-flop pharmacokinetics for medications with a comparatively short biological half-life, enabling a reduction in the frequency of dose. This feature encourages improved patient adherence, which improves treatment results.

5. Target therapy for local aliments in upper GIT:

Long-term delivery of the medication to the stomach using floating devices may be advantageous for local treatments in the small intestine and stomach.

VIII. Drug Candidate Suitable and Unsuitable for FDDS ^[28,29,30]

5. Direct Compression Method ^[31]

One of the simplest and most widely used methods is this one.

Step 1: Measure all of the ingredients, including the active pharmaceutical ingredient (API), binders, gas-forming agents, and polymers.

Step 2: Combine the active drug with gas-forming agents (like sodium bicarbonate) and floating polymers (like HPMC).

Step 3: Add the lubricants, diluents, and binder (PVP).

Step 4: Utilize a blender or mixer to ensure an even distribution of the components.

Step 5: Employ a tablet press to compress the mixture into tablet form.

Step 6: If desired, coat the tablet to control the release of the medication.

5. Dry Granulation Method ^[32]

This process involves slugging to create granules, especially for components that are sensitive to moisture or cannot tolerate high temperatures during the drying process.

5. Effervescent Method

This type of floating tablet relies on the production of gas, such as CO₂. Method:

Step 1: Weigh and mix the medication with effervescent agents (like citric acid and sodium bicarbonate) and floating polymers (like HPMC).

Step 2: Blend thoroughly to ensure uniform distribution.

Step 3: Use a tablet press to form the mixture into tablets.

Step 4: The tablet floats by producing CO2 when it interacts with gastric fluids.

5. Ionotropic Gelation Method ^[33]

The gelation of the natural polysaccharide sodium alginate, which is the main polymer, is achieved using calcium ions (counter-ions) that carry an opposite charge to form instant micro-particles.

5. Wet granulation method ^[34]

This method includes preparing granules before the tablet compression process. Method:

Step 1: Measure the polymers, gas-forming agents, and the active drug.

Step 2: In the blender, thoroughly mix the dry components.

Step 3: Add granulating agents, usually water or an organic solvent, to form a wet substance.

Step 4: Form granules by passing the moist mixture through a sieve.

Step 5: Dry the granules using a fluidized bed dryer or an oven.

Step 6: After mixing with lubricants, compress the granules into tablets

5. Hot Melt Extrusion method ^[35]

This technique is beneficial for enhancing the solubility of drugs that are poorly soluble in water.

Method:

Step 1: Combine the medication with plasticizers and polymers (like HPMC).

Step 2: Heat the mixture to melt the medication and polymers together.

Step 3: Pass the molten mixture through an extruder to obtain a uniform bulk.

Step 4: Once cooled, cut the extrudate into the desired size.

X. Components of FDDS ^[36,37,38]

The following components are utilized in the formulation of FDDS

 Hydrocolloids - Hydrocolloids are slightly modified synthetic cellulose derivatives that can be anionic or non-ionic, such as acacia, pectin, agar, gelatine, and bentonite.

Polymers - Various polymers, including HPMC K100M, HPMC K15M, HPMC K4M, polyethylene glycol, polycarbonate, sodium alginate, PVA, PVP, Eudragit, Carbopol, methyl methacrylate, and acrylic polymers, are commonly use in the development of floating drug delivery systems.

Effervescent agent - Sodium bicarbonate, citric acid, tartaric acid, nitroglycerin, and di-sodium glycine carbonate are utilized as effervescent agents in the formulation of effervescent-based floating systems.

Inert fatty substances - Fatty substances that possess a specific gravity of less than one can minimize the hydrophilic characteristics and thus enhance buoyancy. Examples include beeswax, fatty acids, long-chain alcohols, and mineral oil.  

Release rate modifier - The formulation’s release rate can be altered by incorporating excipients such as lactose and mannitol.

Release rate retardants - These substances reduce solubility, thereby slowing the release rate of the medicinal compounds. Examples include dicalcium phosphate, talc, and magnesium stearate.

Buoyancy increasing agent - Components like ethyl cellulose, which have a low bulk density of less than one, can be utilized to enhance the buoyancy of the formulation, potentially making up 80% of the total weight.

Low-density material - These materials may be employed, if needed, to reduce the formulation's weight to facilitate flotation, such as polypropylene foam powder.

Miscellaneous - Adjuvants such as preservatives, stabilizers, lubricants, and binders can be included in the formulation based on specific requirements.

XI. Evaluation of FDDS

1. Drug-excipients interaction

Fourier Transform Infrared Spectroscopy (FTIR) can be used to investigate drug-excipient interactions. A DE interaction is indicated by the appearance of new peaks or the disappearance of recognizable peaks from the medication or excipient. Additionally, techniques like Hot Stage Polarizing Microscopy and Differential Scanning Calorimetry can be used to evaluate the impacts of aging. ^[39]

2. Precompression Parameters:

Bulk density

A predetermined amount of powder is poured into a graduated cylinder to calculate the bulk density. The bulk volume of this blend is then measured, allowing for the calculation of bulk density using the formula:

Bulk density=Total mass of powder/Bulk volume of powder

Tapped Density

According to standard processes, a measuring cylinder with a known mass of the blend is tapped for a predefined amount of time and from a predetermined height. The tapping procedure is repeated after recording the cylinder's initial volume.

The tapped density can be calculated using the formula:

Tapped density = Total mass of powder / Tapped volume of powder

Hausner's Ratio

This ratio is derived by dividing the tapped density by the bulk density, using the formula:

Hausner's Ratio = Tapped density / Bulk density

Compressibility Index

The flow characteristics of the powder can be assessed by comparing the bulk density (ρo) and tapped density (ρt) and observing the rate at which packing occurs. The compressibility index is determined using the following formula:

Compressibility index (%) = (ρt - ρo) / ρt × 100

Where, ρo represents bulk density in g/ml and ρt indicates tapped density in g/ml.

Relation between compressibility and index property

Angle of Repose

The angle of repose measures the frictional forces present in a loose powder or granules. It represents the steepest angle achievable between the surface of a mound of powder or granules and the horizontal axis. The granules were allowed to flow through a funnel affixed to a stand at a specific height (h). The angle of repose is then computed by measuring the height and radius of the resulting heap of granules:

tan ? = h / r 

? = tan?¹ (h / r)

where ? is the angle of repose, h is the height of the pile, and r is the radius of the pile ^[40]

Relationship between angle of repose and powder flow

Post-Compression Parameters:

 Hardness

 Different testers, including the Monsanto tester, Strong-Cobb tester, Pfizer tester, Erweka tester, and Schleuniger tester, are used to measure tablet hardness. These tests are crucial to ensure that tablets can endure the stresses and pressures during manufacturing, packaging, transport, and handling by patients.

Friability Test

 The friability of tablets is assessed using a Roche Friabilator, expressed as a percentage (%). Initially, ten tablets are weighed (Winitial) and placed into the friabilator. The apparatus operates at 25 rpm for 4 minutes or until it reaches 100 revolutions. The percentage friability is calculated as follows:

Friability (%) = [(Initial tablet weight - Final tablet weight) / Initial tablet weight] × 100.

A friability percentage of less than 1% is deemed acceptable. ^[41]

Tablet Dimensions

Thickness and diameter are measured using a calibrated Vernier Caliper. Three tablets from each formulation are selected randomly and measured for thickness individually.

Weight Variation

 Pharmacopeia-approved official methods for estimating weight variation are numerous. To calculate the average weight and weight variation, the weight of 20 tablets is typically recorded for each individual. USP states that the weight variation limit is 130–324 mg ± 7.5% and greater than 324 mg ± 5%.

Percent deviation = (Individual weight – Average weight / Average weight) ×100

Buoyancy Lag Time / Floating Lag Time

The time needed for gastroprotective formulations to rise to the surface of the dissolution medium is known as buoyancy lag time, and it is measured using a USP dissolution apparatus that contains 900 mL of 0.1 N HCl solution kept at 37°C. The amount of time it takes for various dosage forms to float is observed.

Total Floating Time

This parameter assesses the buoyancy of the dosage form. A dissolution apparatus specific to the dosage form type is utilized, with 900 mL of dissolution medium maintained at 37°C. The floating time or duration is identified through visual observation. ^[42]

Specific Gravity/Density

Specific gravity measurements are crucial for both low-density and high-density Gastroretentive Drug Delivery Systems (GRDDS). Specific gravity is assessed by employing the displacement method.

Swelling Index

Each tablet was weighed separately, placed in beaker with 100ml of 0.1 N HCL, and then incubated at 37⁰C. The tablets were taken out at regular intervals till 8-12 hours, and any extra surface liquid was carefully wiped off using tissue paper. These were weighed for weight gain on the analytical balance after any remaining water was drained by blotting with tissue paper.  The following formula uses for calculating swelling index (SI):

Swelling Index= (weight of tablet at time – weight of tablet before immersion)/ (weight of tablet before immersion) × 100 ^[43]

In-vitro Dissolution Studies

Dissolution rates of floating tablets are assessed using the USP dissolving testing device II (Paddle type). The dissolution test is conducted at 37°C with 900 mL of 0.1N HCl. Every hour for 12 hours, a 5 mL sample of the solution is collected from the dissolving apparatus, replacing it with fresh dissolution media. The absorbance of the solutions is measured after filtering through Whatman's filter paper.

X-Ray/gamma Scintigraphy

 X-ray/gamma scintigraphy is a widely used technique for assessing parameters in floating dosage forms. It assists in identifying the location of the dosage form within the gastrointestinal tract (GIT) and can be utilized to predict and correlate gastric emptying times along with the transit of the dosage form through the GIT. By incorporating a radio-opaque substance into a solid dosage form, it can be made visible by X-rays. Likewise, adding a γ-emitting radio-nuclide in a formulation allows for indirect external observation through a γ-camera or scintiscanner. In γ-scintigraphic methods, the γ-rays emitted from the radio-nuclide are directed onto a camera, facilitating monitoring of the dosage form's position in the GI tract. ^[44]

XII. Advantages and Disadvantage of FDDS [45,46]