Porous floating microspheres: A new dimension in controlled drug delivery


Gannu Praveen Kumar* and Jannu Anand

Department of Pharmaceutics, Talla Padmavathi College of Pharmacy, Orus, Kareemabad, Warangal, A.P, India.

*Corresponding Author E-mail: ghalo2010@gmail.com



The popularity and patient compliance of the oral drug delivery route encourages the modern forms of oral dosage forms which are more beneficiary. These include oro-dispersible tablets, controlled release tablets, effervescent and non effervescent gastro retentive floating tablets. Among these, gastro retentive tablets have prominent role in delivery of drugs with constraints such as drugs having absorption window, those absorbed locally from the upper GI tract region, and those with relatively short half-lives. But conventional dosage forms like tablets are losing their integrity due to multiple dosage regimens. Gastro retentive systems overcome these constraints and enable a delivery strategy that will function irrespective of the digestive state, clinical condition, or GI motility of the patient. In addition, longer residence time in the stomach could be advantageous in ensuring local action in the upper part of the small intestine, for example in the treatment of peptic ulcer disease and localized stomach cancers. Furthermore, improved bioavailability is expected for drugs that are absorbed readily upon release in the GI tract, primarily those absorbed from the proximal small bowel. These drugs can be delivered ideally by slow release from the stomach. Various scientific and technological attempts have been made in the development of gastroretentive dosage forms to overcome several physiological adversities, such as short gastric retention time and unpredictable gastric emptying time. Floating microspheres are the gastroretentive dosage forms are able to uniform drug release at a site for an extended period of time. The porosity has an important effect on drug release characteristics and pores may greatly increase the rate of drug expulsion and also floating property. This review highlights the classification, factors, mechanism of floating of microspheres, characterization, preparation method, development, polymers, applications, in-vitro, in vivo drug release studies and the effect of porosity on the drug release.


KEYWORDS: Floating microspheres, porous, non porous, diffusion, polymers




Among various drug delivery systems, oral route has become the most convenient route, safe and widely accepted means of administering drugs. Oral route of administration has become much popular in the pharmaceutical field because of its high acceptance by the patients. Oral controlled drug delivery design depends on the various factors such as type of delivery system, the disease being treated, the patient, duration of therapy and properties of the drug1. The main principle of oral controlled release delivery systems is to deliver the drug in a time frame that will increase bioavailability and minimize adverse effects. Development process of oral controlled drug delivery system is affected by the physicochemical properties of the drug, relevant anatomy and physiology of the stomach and dosage form characteristics.


Administration of oral controlled release dosage forms are affected by two difficulties such as short gastric retention time and unreliable gastric emptying time. One of the main challenges in retaining the drug at the absorption site is to enhance gastrointestinal retention2. Gastric emptying of pharmaceuticals is highly variable and is dependent on the dosage form and the fed/fasted state of the stomach. Normal gastric residence time usually ranges between 5 minutes to 2 hours. In case of fasted state, electrical activity events occurs in a cyclic manner in the stomach-interdigestive myoelectric cycle (or) migrating myoelectric complex. It is further divided into four phases. Phase I­­: Period with rare contractions lasting from 40 to 60 minutes. Phase II: Period of alternate contractions lasts for about 60 minutes. Phase III: Period of regular contractions for 10 to 20 minutes with maximal frequency also known as ‘house keeper’ wave. Phase IV: Period of transition between phase III and phase I3. Over the last three decades new techniques are developed and designed in a way which releases the drug in a controlled manner and at a specific site by increasing the retention time of dosage form in the stomach such as gastroretentive drug delivery systems4. Gastroretentive Drug delivery systems (GRDDS) are developed that remain in the stomach for few minutes to several hours and hence significantly increase the gastric retention of drugs. GRDDS approaches include floating systems5,6, raft forming incorporating alginate gels6, superporous hydrogels7, swelling and expanding systems8, mucoadhesive systems9,10. Floating drug delivery systems (FDDS) is one of the leading methodologies in the gastroretentive drug delivery systems. FDDS are capable of floating in the stomach over the gastric contents without affecting the gastric emptying rate for a prolonged period of time. Techniques are developed in the FDDS based on the mechanisms of buoyancy which include effervescent and non-effervescent methods11,12. Number of works have focused on single unit floating systems and experienced drawbacks like all or nothing emptying process. While the multiple unit floating systems are able to overcome the above mentioned drawback and release the drug more uniformly without disturbing the gastric emptying rate13. Microspheres are in strict sense, spherical particles with free flowing properties which consist of proteins or synthetic polymers, ideally having size less than 200µm. Microspheres have been widely used in biomedical and pharmaceutical applications. For controlled drug release purposes, these systems act as a reservoir of therapeutic agents, with spatial and temporal control of release profiles of the drug leading to desirable therapeutic outcomes14. The microparticles should have some general characteristics, such as the ability to incorporate the drug without loss of activity, tuneable release kinetics, sufficient in vivo stability for function, biocompatibility in terms of lack of toxicity and immunogenicity, degradability and potential to target specific organs and tissues. Therefore, in recent years significant effort has been put in developing drug delivery microspheres for treating various diseases15. These can be prepared by different methods such as solvent diffusion and evaporation, hot melt microencapsulation, solvent removal, spray drying and spray congealing, ionic gelation and size extrusion phase inversion. These methods have been reviewed by Jaspreet Kaur Vasir et al., 200316. Floating

microspheres are one of the GRDDS that have been developed based on effervescent and noneffervescent techniques17. There has been increasing interest in the use of porous material as the drug loading cores which behave as carriers, forms an integral part of various dosage forms. They are characterized by several attractive features, such as stable uniform porous structures, high surface areas, tunable pore sizes with narrow distributions, and well-defined surface properties, thus allowing them to adsorb certain kinds of drugs and release these drugs in a more reproducible and predictable manner. Porous network is important in determining both natural and practical applications such as dissolution, adsorption and diffusion of drugs. Porous carriers in formulations help to enhance the buoyancy, reduce dusting, improve flowability, influence modify release by coating or incorporation of release modifying agents18. Type and extent of interaction with water characterizes them as either hydrophobic or hydrophilic such as calcium carbonate19, calcium silicate20, polypropylene glycol21 and pluronic F12722. Floating microspheres are characterized by their micromeritic properties such as particle size, shape, pore size, tapped density, true density, flow properties like angle of repose, compressibility index buoyancy, swelling property, % yield, encapsulation efficiency and invitro release. In vitro and in vivo23 evaluation of floating microspheres has been studied by many scientists to determine the efficiency of the system. Several recent examples have been reported showing the efficiency of such systems for drugs with poor bioavailability.


2. Floating drug delivery systems

FDDS are site specific oral controlled drug delivery systems which release the drug in a controlled manner at specific site by increasing the retention time of the dosage form for local as well as systemic drug delivery5. FDDS has bulk density lower than the gastric fluids and thus float in the stomach for longer period of time to achieve sufficient bioavailability without disturbing the gastric emptying rate. This type of delivery system is suitable for drugs which have narrow absorption window in the stomach or upper small intestine24. This approach has been developed and designed for single unit and multiple unit systems. Single unit floating systems have been developed with different polymers based on effervescent and noneffervescent method. But these systems experience drawbacks with high variability of gastrointestinal transit time due to the all or nothing emptying process. Floating microspheres are multiple unit systems designed to reduce the inter subject variability in absorption, to lower the dose dumping, to improve patient compliance by decreasing dosing frequency and also to achieve better therapeutic effect of short half-life drugs3. These can also enhance bioavailability, reduce drug waste and improve solubility for drugs which are less soluble in a high pH environment5. The drug is released slowly at desired rate from the floating microspheres which results in increased gastric retention with reduced fluctuations in plasma drug concentration. Among the floating systems, multiple-unit formulations show several advantages over monolithic ones which include more predictable drug release kinetics, less chance of localized mucosal damage, insignificant impairing of performance due to failure of a few units, co-administration of units with different release profiles or containing incompatible substances, larger margin of safety against dosage form failure6.


3. Factors affecting Gastric Retention

Several approaches have been developed to retain the drug in the gastrointestinal tract for longer period of time. Gastric retention time of the dosage forms are affected by several factors17.

*         Size, shape and density of dosage forms.

*         Concomitant intake of the food, and its nature, caloric content and frequency of intake.

*         Simultaneous administration of drugs such as anticholinergic agents (eg: atropine,     propantheline), opoides (eg: codeine) and prokinetic agents (eg: metoclopromide, isapride)

*         Similarly biological factors, which effect gastric retention such as age, sex, body posture, body weight and disease state (eg: Crohn’s disease, Diabetes).



4.  Limitations of Gastric retention systems

Apart from some attractive and inviting features of floating drug delivery systems, they suffer from some disadvantages also25.

*         FDDS requires sufficient amount of gastric fluid in the gastric region for floating and release the drug controllable. It can be prevented by taking with glass full of water (200-250 ml) for every 2 hours.

*         The patient should be in straight position after administering the dosage form for floating.

*         Floating systems are administered after the meal.

*         Floating systems are not suitable for drugs which are not stable or not solubilizing in the gastric region or which gives gastric irritation.

*         Drugs like Nifedipine are not suitable for floating microsphere which is well absorbed along the entire length of GIT and undergoes extensive first pass metabolism.


5. Drug that are suitable for Gastroretention

Drugs that are used for FDDS should possess better absorption properties in the upper GIT and allow post colonic absorption is suitable for gastroretention26.

*         Drugs that act locally in the stomach. Eg: Antacids, Misoprostol, 5-flourouracil, antireflux preparations, antihelicobacter pylori agents and certain enzymes.

*         Drugs which absorb primarily in the gastrointestinal tract. Eg: Calcium supplements, Chloridiazopoxide, Cinnarizine.

*         Narrow absorption window in the gastrointestinal tract (GI tract). Eg: Riboflavin, Levodopa

*         Drugs that degrade in the colon. Eg: Ranitidine hydrochloride, Metronidazole.

*         Drugs that destruct normal colonic bacteria. Eg: Amoxicillin trihydrate.

*         Drugs which are insoluble in the intestinal fluids (acid soluble basic drugs)

Eg: Diazepam, chlordiazepoxide, chlorpheniramine, cinnarizine, diltiazem, etoprolol, prorenolol, and verapamil.


6. Techniques in developing floating microspheres

Floating drug delivery systems are classified into Non-effervescent and Effervescent systems based on the mechanism of buoyancy to achieve gastric retention to obtain sufficient bioavailability.


6.1. Multiple unit non-effervescent systems

The non-effervescent system floats in the gastric region based on the mechanism of swelling of polymer to an extent, so that it retains in the stomach. So, these are referred as “Plug type Systems” which remains at the pyloric sphincter. Polymers commonly used in the non effervescent systems are gel forming or highly swellable cellulose type hydrocolloids, polysaccharides, matrix forming material such as polycarbonate, polyacrylate, polymethacrylate, polystyrene, as well as natural polymer such as chitosan and carbopol6.




6.1.1. Beads

The term bead is defined as a spherical particle with a size varying from 50 nm to 2 mm, containing a core substance. The term bead is used synonymously with microspheres or microcapsules.


6.1.1. 1. Alginate beads

These spherical beads can be formed by dropping sodium alginate solution of calcium chloride, which forms the calcium alginate complex. Frances stops et al., 2008 developed calcium alginate beads to incorporate riboflavin as a model drug to improve bioavailability. Spherical beads can be formed by dropping sodium alginate solution into the aqueous solution of calcium chloride, causing the precipitation of calcium alginate. Buoyancy can be achieved by spherical calcium alginate beads which contains internally air cavities making them less denser than the gastric fluid. They found that, riboflavin slowly releases from the floating beads in the gastric media than the intestinal fluid27. Casein- gelatin beads

E. Bulgarelli et al., 2000 investigated oral controlled drug delivery system with casein–gelatin beads containing emulsifying properties, which causes air bubble incorporation and the formation of large holes in beads. The percentage of casein in the matrix increases the drug loading of both low and high porous matrices, although the loading of high porous matrices is lower than that of low porous matrices. Increasing casein percentage in cagel beads, the fluorescein sodium salt content also increases. The authors found that the release rate decrease from cagel beads as porosity increases, according to the increase of the casein percentage in the matrix composition28. Pectin beads

Enas M et al., 2009 compare the two types of beads (calcium alginate and calcium pectinate beads) to enhance the floating, encapsulation efficiency and invitro drug release which is prepared by the emulsion–gelation method. Famotidine showed an initial burst effect within the first 10 min due to the presence of surface deposited drug along with rapid water infiltration creating aqueous channels to permeate out. Those polymers offer a flexible, easily controllable and consistent process for achieving the homogeneity and uniformity of famotidine-loaded beads formation. Inclusion of mineral oil droplets confers buoyancy for at least 6 h. Their results demonstrated the superiority of alginate matrices over pectinate matrices to sustain the drug release29. In another work Badve SS et al., developed hollow/porous calcium pectinate beads for floating-pulsatile release of diclofenac sodium intended for chronopharmacotherapy. The floating beads obtained is porous (34% porosity), hollow with bulk density<1 and Ft50% of 14-24 h. They suggested the use of hollow calcium pectinate microparticles as promising floating-pulsatile drug delivery system for site- and time-specific release of drugs acting as per chronotherapy of diseases30. Guar gum beads

Reddy T et al., 2002 developed gastric resistant microbeads of metal ion cross-linked carboxymethyl guar gum for oral drug delivery. The solution of sodium salt of carboxymethyl guar gum, containing Bovine serum albumin as a model drug, is added, as droplets, to different multivalent metal ion solutions, they get cross-linked to form insoluble microbeads. Trivalent metal ions like Al+++ and Fe+++ is found to be superior to divalent metal ions like Ba+ +, Ca++, Cu++ and Cd++. The optimum concentrations around which these ions provide maximum drug retention have been found to be much lower for trivalent ions. Beads cross-linked with them released the protein over a longer duration in enzyme free simulated intestinal fluid, than those cross-linked with divalent ions. Mg++, Sr++, Co++ and Zn++ failed to form isolable beads31.


6.1.2. Hollow Microspheres

Microspheres are hollow, thin walled spheres of polymer manufactured with a mean particle size of around 11 and 18 microns. Hollow microspheres are also termed as microballoons having a diameter ranging from 10-300 micrometers. Hollow microspheres have a unique microstructure, characterized by a hollow center surrounded by a porous or nonporous shell. One of the most efficient methods of gastroretentive drug delivery system is floating microsphere which belongs to non-effervescent system. As shown in Fig 1.0, hollow microspheres are developed by common method i.e. solvent evaporation method. The polymer is dissolved in an organic solvent and the drug is either dissolved or dispersed in the polymer solution. The solution containing the drug is emulsified into the aqueous phase to form oil in water emulsion. After the formation of emulsion, the organic solvent is evaporated either by increasing the temperature under the pressure or continuous stirring. The solvent removal leads to polymer precipitation at the oil-water interface of the droplets, forming the cavity and thus making them hollow to impart the floating properties. These ideally have the size less than the 200µm.  Microspheres thus formed are characteristically free flowing powders which can be made up of synthetic polymers or proteins16.


Fig 1.0 Formation of hollow microspheres 16,32


Hollow microspheres are low density systems which can float on gastric contents for prolonged period of time.  It releases the drug slowly at a desired rate with minimizing the fluctuations in plasma level and enhances the bioavailability6. Pandey manisha et al., 2010 developed the floating microspheres using the HPMC and ethylcellulose by loading famotidine in their outer polymer shells prepared by a novel emulsion solvent evaporation method. The dimethylformamide: dichloromethane solution of the drug and polymer is poured into the agitated aqueous solution of polysorbate 80 which is thermally controlled at 400c. The gas phase generated in dispersed polymer droplet by the evaporation of dichloromethane forms internal cavity in microspheres. The microspheres exhibiting prolonged drug release and remain buoyant over the gastric contents of acidic dissolution media for 12 hours33. Ling Zhao et al., 2010 investigated hollow microspheres which is prepared from the polymer blends of polyvinyl pyrrolidone and ethylcellulose containing the water insoluble drug as nifedipine. Hollow microspheres is prepared by using solvent diffusion evaporation method with the various ratios of polymer which is co dissolved in ethanol/ether solution. By increasing the ratio of polymer blends shows the increasing of drug release rate. Nifedipine hollow microspheres are suitable for floating-type controlled release delivery systems for the oral administration34. N.J. Joseph et al., 2002 developed the polycarbonate hollow microspheres containing piroxicam as drug by using solvent evaporation technique. Their results showed that porous nature of the microspheres floating in the simulated fluids. Many large pores and cavities can be formed by the rapid evaporation of dichloromethane35. Y.S. Tanwar et al., 2007 developed the Verapamil hydrochloride floating microspheres for improving the drug bioavailability by prolonging the gastric residence time. Cellulose acetate, acrycoat S100 and eudragit S 100 microspheres is prepared by using the solvent evaporation method. Encapsulation efficiency is high with the cellulose acetate microspheres and in vivo evaluation is carried out in dogs by incorporating the barium sulphate with the dosage forms36.


6.2. Multiple unit effervescent systems

Floating system can also be achieved by the effervescent technique which includes use of gas generating system and volatile liquid/vacuum system. These systems are to be floated in the gastric region  by utilizing the gas generating systems such as carbonates (calcium carbonate, sodium bicarbonate) and organic acids (citric acid, tartaric acid). Gas generating systems generate carbondioxide and help to float over the gastric contents due to buoyancy. Volatile liquid containing system is an alternate method of effervescent system which generates the gas that evaporates at body temperature3.


6.2.1. Gas generating systems

These gas generating systems utilize the effervescent technique such as carbonates and organic acids to achieve the gastric retention of the microspheres. An effervescent reaction occurs between carbonate/bicarbonate salts and citric/tartaric acid to generate carbondioxide when they come in contact with the gastric fluid. The gas generating systems gets entrapped in the jellified hydrocolloid layer of the systems leads to an upward movement of the dosage form and maintains it in a floating condition2. The design of multiple unit gas generating system is shown in Fig 2.0. The system consists of drug-containing core pellet coated with the effervescent layer and gas entrapped polymeric membrane13.


Fig 2.0 Gas Generating System13


6.2.2. Types of Gas generating systems Sodium bicarbonate based gas generating system

Sodium bicarbonate is an effervescent gas generating system which acts as raising agent by releasing carbon dioxide at required temperatures. It reacts with other components to release carbon dioxide which gives buoyancy to the dosage form. These buoyant systems utilize matrices prepared with swellable polymers like methocel, polysaccharides like chitosan, effervescent components like sodium bicarbonate, citric acid and tartaric acid. The optimal stochiometric ratio of citric acid and sodium bicarbonate for gas generation reported is 0.76:16. Other approaches and materials that have been reported are highly swellable hydrocolloids and light mineral oils, a mixture of sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating minicapsules with a core of sodium bicarbonate, lactose and polyvinyl pyrrolidone coated with hydroxypropyl methylcellulose32. In recent study, Bibaswan Mishra et al., 2009 described a gastroretentive floating controlled drug delivery system containing torsemide in the form of microsphere which is prepared by ionic gelation technique and evaluated for its processing parameters. Formulations containing retardant material such as sodium alginate and HPMC K15, foam forming agent sodium bicarbonate prepared which is loaded with torsemide. Solid, discrete and reproducible free flowing microspheres is obtained which remain buoyant over a period of 8hrs in the release medium and the amount of sodium bicarbonate have been found to be significant. It is found that the torsemide floating microspheres can be successfully prepared with high entrapment efficiency and prolonged released behavior with a substantial floating ability37. In another study Sahoo S.K et al., 2007 prepared ciprofloxacin hydrochloride floating microspheres with an aim of increasing the gastric residence time containing sodium bicarbonate which is used as the gas forming agent. The enhanced buoyancy and controlled release properties of microspheres made them an excellent candidate for developing floating drug dosage form38.


(i) Alginate beads

In this study Bajpai et al., 2007 focused on the development of floating barium alginate beads to prolong the gastric residence time and increase drug bioavailability. These beads have been prepared by different ratios of sodium alginate and sodium bicarbonate as porogen. Their reports show that 1.5% content of (porogen) NaHCO3 remains buoyant for more than 9 h and release all the entrapped (model drug) vitamin B2 for nearly 8-9 hours in the simulated gastric fluid (SGF, pH 1.2) at 37°C39.


(ii) Dextran beads

S.K. Bajpai et al., 2007 prepared calcium alginate and dextran beads and using the sodium bicarbonate as porogen to enhance the floating of beads in simulated gastric fluid with increasing concentration. Various micromeritic properties are determined with different compositions. The authors found that release of calcium from the beads is observed to follow diffusion-controlled Higuchi kinetics40.


(iii) Pectin beads

Sriamornsak Pornsak et al., 2007 investigated pectin as a carrier for an intragastric floating drug delivery by a means of calcium pectinate gel (CaPG) beads. Incorporation of sodium bicarbonate into pectin solution resulted in porous structured beads. Acidity of gelation medium increased the pores in the structure of beads containing calcium carbonate due to carbon dioxide generated from reaction of carbonate salts with acid. It is obvious that the highly porous freeze-dried beads showed a good floating ability with fast drug release. The drug release could be prolonged by using pectin with lower degree of methylesterification, 10% calcium carbonate, acidified gelation medium, and high drug loading41. Calcium carbonate based gas generating systems

(i) Alginate beads

In a recent research report, Baljit singh et al., 2010 developed the floating alginate beads with the natural gum as sterculia gum, pantoprazole as a model drug and calcium chloride as cross linking agent. These beads have been evaluated for the effect of different swelling media on percentage swelling of sterculia–Ca2+–alginate beads and floating sterculia–Ca2+–alginate beads after 24h at 37o C and it floats for 1440 min and release the drug in controlled manner42. Shishu et al., 2007 developed the multiple-unit-type oral floating dosage form (FDF) of 5-fluorouracil (5-FU) to prolong gastric residence time, target stomach cancer, and increase drug bioavailability which is prepared by dispersing 5-FU together with calcium carbonate into a mixture of sodium alginate and HPMC solution and then dripping the dispersion into an acidified solution of calcium chloride. The beads containing higher amounts of calcium carbonate demonstrated instantaneous, complete, and excellent floating ability over a period of 24 hours. The authors performed invivo tests in mice and found that multiple-bead FDF reduce the tumor incidence in mice by 74%, while the conventional tablet dosage form reduced this incidence by only 25% 43.


(ii) Gellan beads

Rajinikanth PS et al., 2007 prepared gellan based floating beads of acetohydroxamic acid (AHA) by ionotropic gelation method to achieve controlled and sustained drug release for treatment of Helicobacter pylori infection. These beads are evaluated for various parameters such as diameter, surface morphology and encapsulation efficiency. The concentrations of gellan, chitosan, calcium carbonate and the drug influenced the in vitro drug release characteristics of beads. Chitosan coating increased encapsulation efficiency of the beads and reduced the initial burst release of the drug from the beads. Kinetic treatment of the drug release data revealed a matrix diffusion mechanism. Their reports show that, an oral dosage form of floating gellan beads containing AHA may form a useful stomach site specific drug delivery system for the treatment of H. pylori infection44.


7. Role of polymers in floating microspheres

For more than two decades, considerable use of polymeric materials to deliver therapeutic agents has attracted attention of various investigators throughout the scientific community. Polymer chemists, chemical engineers along with pharmaceutical scientists are highly engaged in bringing out the design and development of various controlled drug delivery systems. The idea of controlled release from polymers dates back to the 1960s through the employment of silicone rubber. Degradable microspheres can be employed for sustained drug release at desirable doses. Polymers are generally employed in floating drug delivery systems so as to target the delivery of drug to a specific region in the gastrointestinal tract i.e. stomach.  Both synthetic and natural polymers have been studied extensively in the design of drug delivery systems. Biocompatibility can be achieved by the use of natural polymers such as cellulose, chitin, and chitosan or by the employment of polymers made from naturally occurring monomers such as lactic and glycolic acids. Drug delivery systems targeted to stomach which is based on the utilization of various natural polymers offer superiority over other systems. Moreover, these polymers are safe, nontoxic, and capable of chemical modification and gel forming nature. Polymers derived from synthetic monomers also show excellent delivery properties. Biodegradable polymers (those derived from plant sources) are usually in the form of starch or cellulose. Animal sources include collagen and gelatin, while marine sources include chitin which is processed into chitosan. Microbial biopolymer is able to produce polylactic acid (PLA) and polyhydroxy alkanoates (PHA). As shown in table 1 synthetic and natural polymer is further classified into biodegradable and non-biodegradable polymers1, 14.


8. Floating microspheres using noneffervescent  technique

Floating microspheres consist of many synthetic polymers or natural polymers such as gel formers, polysaccharide which hydrate to form a colloidal gel barrier and controls the intimate contact of fluid directly with the drug and consequently controlled release. The air trapped by the swollen polymer lowers the density and gives buoyancy to the microsphere as shown in Fig 3.023. Hollow microspheres of acrylic resins, eudragit, polyethylene oxide, cellulose acetate; polystyrene floatable shells; polycarbonate floating balloons and gelucire floating granules are the recent developments3.


Fig 3.0 Floating mechanism based on noneffervescent technique23


9. Floating microspheres using effervescent technique

This system consists of sustained release pills as seeds surrounded by double layers. The outer layer consists of swellable polymer and inner layer is effervescent layer. When the system is immersed in the solution at 370c, it sinks at once in the solution and formed swollen pills, like balloons with a density much lower than the 1 gm/ml as shown in Fig 4.0. The reaction occurs due to the gas generating by neutralization in the effervescent layers with the diffusion of water through the outer swellable membranes layers. Microspheres containing the gas generating systems like sodium bicarbonate and calcium carbonate are used to float the particles in the stomach for several hours5.


Fig 4.0 Floating mechanism based on effervescent technique22


Stages of floating mechanism: (A) penetration of water (B) generation of gas and floating (C) dissolution of the drug       (a) conventional sustained release pill (b) efferevescent layer (c) swellable layer (d) expanded swellable membrane layer.


10. Preparation of Noneffervescent/effervescent floating microspheres

Floating microspheres are prepared by using any of the following methods such as solvent evaporation, insitu polymerization, coacervation phase separation, spray drying and spray congealing. Required amount of the polymer and drug is dissolved in suitable organic solvent to form uniform dispersion which is then passed into the dispersing medium through the syringe needle under stirring. Droplets are formed with continuous stirring and solvent diffuses out of the droplets leading to crystallization at the surface which undergoes solidification. The microsphere preparation is shown in Fig 5.045.


Fig 5.0 Emulsion solvent diffusion method18


10.1. Encapsulation efficiency

Increasing or controlling the encapsulation efficiency is desirable, since it can prevent the loss of precious medication and can help to extend the duration of treatment. The drug content of the encapsulated microspheres can be described by two quantities as shown in Equation (1).


On the other hand, the loading capacity is defined by the following Equation (2)

DEE- drug encapsulation efficiency,  LD - loading capacity; Sw - weight of the sphere.

Issues of relevance concerning encapsulation efficiency include sphere formation temperature and the nature of the polymer14. Jia Yu et al., 2007 has provided a significative study on biodegradable microspheres which correlated encapsulation efficiency to sphere preparation temperature. The authors found that the highest encapsulation efficiency occurred at the lowest and highest formation temperatures tested (about 90% at 10 0c and 400c, and about 75% at 250c). Different mechanisms governed the encapsulation process at different temperatures46.


10.2. Control of microsphere size

Microsphere size can be affected by the polymer concentration in the second emulsion, temperature, viscosity, the stirring rate in the second emulsion step, and the amount of emulsifier employed.

Considering the effect of polymer concentration, it has often been reported that increasing the concentration of polymer in the second emulsion increases sphere size14.  Jia Yu et al., 2007 showed that sphere size is also a temperature dependent which is evaluated by laser diffraction technique. Lower and higher temperatures produce larger spheres whereas intermediate produces smaller spheres. At higher temperatures due to the higher rate of solvent evaporation larger spheres are formed which results in higher solvent flow pressure moving more material from the sphere center outward. At lower temperatures, the solutions with higher viscosity resulted in the formation of larger sphere size and also studied the variation of sphere size for the same formulation with respect to the different stirring speeds. High stirring speeds produce smaller microspheres due to the smaller emulsion droplets produced by a higher stirring speed which provides more energy to disperse the oil droplets in water46.


10.3. Porosity

The role of a pore is to act as passage between the external and the internal surfaces of a solid, allowing material, to pass into, through or out of the solid. It represents the physical picture of porous solid and various types of pores that may occur in a solid. It is probable that pores are irregular in shape and may also be interconnected. An open pore is one which is connected to the external surface of a solid and allows the passage of an adsorbate through the solid in contrast to the closed pore that is a void within the solid which is not connected to the external surface and hence is isolated. Third type of pore is the transport pore that connect different parts of the external surface of the solid to the inner micro porosity and finally the blind pores that are connected to the transport pores but do not lead to any other pore or surface. Porosity is the collective term for these pores and their distribution in the structure of the solid. Based on the pore size, the porosity is classified as microporosity, mesoporosity and macroporosity as given in table 2.047.




Table 1.0: List of biodegradable and non-biodegradable polymers used for effervescent and noneffervescent floating microspheres

Synthetic polymers

Natural polymers





Chemically modified carbohydrates

Lactides and glycolides and their copolymers




DEAE cellulose

Polyalkyl cyano acrylates






Glycidyl methacrylates





Epoxy polymers






Table 2.0: Classification of porous materials/carriers for drug delivery

Types of Pores

Pore Dimensions

Pore Formation


Width less than 2 nm

Formed as a result of imperfect stacking of constituent molecules.


Width between 2 and 50 nm

Result of major defects in the structure.


Width greater than 50 nm

Formed as a result of Major lattice structure defects such as racks, fissures and etching channels.




10.3.1. Pore forming agents

Pharmaceutically exploited porous adsorbents include ethylene vinyl acetate (macroporous) alumina, silica (mesoporous), clay and zeolites, activated carbon, porous silicon dioxide, propylene foam powder, porous calcium silicate (microporous), magnesium aluminometa silicate, porous ceramics, calcium carbonate, iron oxides, bauxite, zirconium oxide, titanium dioxide (nanoporous)  and other mixed oxides. The porosity has an important effect on drug release characteristics. A larger number of pores may greatly increase the rate of drug expulsion47. Sunil k et al., 2006 developed the orlistat floating microspheres with different ratios of calcium silicate (CS) which is a porous carrier. CS, which has a characteristically porous structure with many pores and a large pore volume, has a sustained-release property. It has floating ability due to the air trapped within its pores when covered with a polymer due to the presence of porous carrier in microsphere formulation increase the drug release and floating ability20. In another study HK Kim et al., 2006 introduced a novel and simple approach suggested for obtaining a sustained rhGH (recombinant human growth hormone) release formulation, which is based on a pore-closing process of preformed porous microspheres. rhGH as a drug which is pre-loaded into porous microspheres by a solution dipping method and their pores closed by treating with water-miscible solvents that partially dissolve PLGA (Poly(D,L-lactic-co-glycolic acid)) copolymer. Porous biodegradable PLGA microspheres with interconnected pores are developed by using Pluronic copolymer as a porogen22.


Fig 6.0. Schematic illustration for rhGH sustained delivery system based on switching porous to nonporous PLGA microspheres by treating with ethanol vapor22.

10.3.2. Control of sphere porosity

Porosity has an important effect on drug release characteristics. A large number of pores may greatly increase the rate of drug release. HK Kim et al., 2006 developed the biodegradable microspheres by incorporating human growth hormone containing open and closed pores for sustained release. The preformed porous microsphere is dipped in rhGH (recombinant human growth hormone) solution and then freeze dried. The rhGH-loaded porous microspheres have been treated with ethanol vapor in a fluidized condition, producing rhGH-loaded biodegradable microspheres. By the pore closing process in a non-aqueous condition as shown in Fig 6.0, the amount of rhGH loading amount and efficiency have been greatly improved22.


11. Drug release mechanism from Porous floating microspheres

The drug release from microspheres can be of different types such as burst mechanism, pore diffusion mechanism, erosion or combination of them.


11.1. Burst mechanism

Microspheres with core of drug may release drug by osmotically driven burst effect. The burst release mechanism is a result of influx of water through the coat, into the core causing increase in intra matrix pressure. This increased pressure results in rupturing of the wall of microspheres and hence release of drug. Y. Cuppok et al., 2011 studied the drug release mechanism form blends of Kollicoat SR: Eudragit NE polymers. The resulting release rate decreased with increasing Eudragit NE content, due to the lower mobility of the drug in these films. Also, the release rate decreased with increasing coating level, due to the increasing length of the diffusion pathways to be overcome. In order to verify these theoretical predictions, metoprolol succinate layered sugar core is coated with 10 and 20% Kollicoat SR: Eudragit NE 90:10, 70:30 and 50:50 and drug release have been measured in demineralized water at 37 0c. The authors found that the experimentally measured drug release rate is much higher in all cases than theoretically predicted. Thus, crack formation is highly likely in these systems. The hydrostatic pressure build up within the pellets upon water penetration into the systems rapidly breaks the film coatings, resulting in additional drug release through water-filled channels (via diffusion and/or convection). This is true for all the investigated Kollicoat SR: Eudragit NE blends and coating levels in the case of sugar starter cores. Furthermore, metoprolol succinate layered microcrystalline cellulose (MCC) cores were coated with 10 and 20% Kollicoat SR: Eudragit NE 90:10, 70:30 and 50:50 and drug release have been measured in demineralized water. Again it significantly underestimates the resulting drug release rate, indicating the formation of cracks in these film coatings. Interestingly, the onset of crack formation is not immediate (as in the case of drug layered sugar cores), but more or less delayed. This can be explained by the lower osmotic activity of MCC compared to sugar. The drug layered MCC cores attract less water into the core than drug layered sugar cores. Thus, the hydrostatic pressure acting against the film coatings increases less rapidly. In the case of 50:50 Kollicoat SR: Eudragit NE blends, crack formation starts only after about 12 h exposure times to the release medium. Interestingly, pressure built up in these pellets pulls out parts of the drug rather rapidly upon crack formation, resulting in a partially “pulsatile” drug release profile48. Juan Wang et al., 2002 studied the mechanism of initial burst release of octreotide from loaded poly (D,L-lactide-co-glycolide) (PLGA) microspheres49.


11.2. Pore diffusion

The pores can be formed by the movement of water front towards the core of microspheres as shown in fig 7.0. The dispersed particles are dissolved in water and diffuse out through the pores or the channels created by the water.  In an earlier study, pore diffusion mechanism studied by HK. Kim et al., 2006 developed open and closed porous microspheres. Most of the entrapped rhGH quickly diffused out through the water filled pores and interconnected channels. It is likely that the sustained release of rhGH occurred via a diffusion controlled mechanism through these water filled porous channels22. In another work, Toshio Ohara et al., 2005 described dissolution mechanism of IND (indomethacin) from HPMC and Ethylcellulose. The dissolution mechanism is affected by medium pH. It is implied that the hydrophobic interaction between IND and EC occurred under lower pH region and strongly delayed the dissolution of IND50.


Figure 7.0: SEM image of porous micropshere22


11.3. Erosion mechanism

The process of erosion is initiated by change in pH and presence of enzymes. There are two ideal sequences of events for polymer erosion, namely surface (heterogeneous) and bulk (homogeneous) erosions as shown in Fig. 8.0. In bulk erosion, the microsphere has a constant diameter size and external fluid is allowed to penetrate into the microsphere, during which erosion of the polymer occurs. On the other hand, in surface erosion, the microsphere has an evolving shrinking diameter as the erosion of the polymer takes place at the external matrix boundary51. The mathematical model of surface and bulk erosion is reviewed in the literature52. V. Lemaire et al., 2003 has presented a model to describe the release of a drug immersed in a biodegradable, porous, polymeric matrix. The modeling framework is general and applicable to a wide class of porous systems, not uniquely to microspheric devices. It confirms that the relative dominance between diffusion and erosion plays a major role in the release kinetics. In particular, the velocity of erosion, the effective diffusion coefficient of the drug molecule in the wetted polymer, the average pore length, and the initial pore diameter are sensitive parameters, whereas the porosity and the effective diffusion coefficient of the drug in the solvent-filled pores are seen to have little influence, if any, on the release kinetics. A relation between the model parameters and the type of polymer is used even brought to light, allowing us to predict the shape of release curve from microspheres made of any ratios of low and high PLA53. Oliver L et al., 2004 investigated erosion-controlled drug release from different methylhydroxy ethylcellulose hydrocolloid polymers. The special polymer particle erosion mechanism, which is nearly independent from the hydrodynamic conditions in the dissolution medium, could be attributed to the existence of insoluble fibres within the polymer material. The process is used for polymer particle erosion-controlled hydrocolloid systems with the possibility to adjust the drug release rate. The fibre-containing systems show polymer particle erosion with a nearly zero order release of the incorporated drug over a period of approximately 10 h54.


Figure 8.0: drug release mechanism by surface and bulk erosion51


11.4. Mathematical models of polymer degradation

Recently numerous drug release models on surface-eroding and bulk-eroding degradable systems have been reported in the literature L. Lao et al., 2011. In general, it is easier to model drug release from surface-eroding systems because the drug is released concurrently with the layer-by-layer erosion from the outermost surface of the matrix. As the theme of this review is mainly on the bulk-degrading polymers, the focus will be on the mathematical models developed for such systems. For easy reference, the models of drug release from bulk- degrading systems are categorized according to the initial states of the drug carrier’s :( 1) non-porous and (2) porous matrices.


11.4.1. Non-porous matrices

It is generally accepted that the degradation of bulk-degrading polymers follows first order kinetics as follows:


Mw,t is the polymer molecular weight at time t, Mw,0 is the initial polymer molecular weight and k is the degradation rate constant. Many different drug release patterns have been obtained from bulk-degrading systems, mainly as a result of several factors such as polymer type, drug interactions with polymer, device geometry and size. Therefore, in the development of suitable models, various approaches have been taken. In the next two sub-sections, these approaches are sub-grouped according to the release mechanisms considered during the derivation of the models:(1)diffusion-based models, modified with time-dependent diffusivities, usually sufficient to predict mono-phasic release and (2) models that combine diffusion with erosion and/or drug dissolution and/or percolation theory, etc., usually required to describe multi-phasic release55.


11.4.2. Porous matrices

In an earlier study, Ehtezazi and Washington et al., 2000 developed a drug release model from porous microspheres by combining percolation theory and diffusional mass transport processes. The pores are classified into conducting (accessible) and discrete (isolated) regions. The accessible pores are connected to the exterior surface and allow mass transport to the surrounding medium whereas the isolated pores are disconnected. The percolation threshold, ρc, is a critical value below which the accessible porosity vanishes. According to the Bethe lattice theory, ρc is related to coordination number, z, as follows


After the Bethe lattice coordination number, z, is determined, the effective diffusion coefficient, Deff, is given by


where DL is the drug diffusion coefficient in the release medium and εE is the tansport coefficient of the porous structure, calculated from


C’(x) is the first derivative of an non-linear integral equation defined by Ehtezazi and Washington et al., 2000. The fraction of drug released from a microsphere, with size r, at time t is calculated by the following equation, adapted from Crank


In the case of microspheres with non-uniform sizes, the equation is modified by introducing size distribution for the microspheres. Lemaire et al., 2003 presented another model to describe drug release from porous biodegradable matrices by partitioning the matrix into multiple, identical elements. Each element is idealized as a cylinder of length L and radius R with a pore embedded coaxially in the center with radius r (r < R) and length L. As such there are two domains per element: domain (1) is a pore filled with solvent containing a drug at concentration C0 < CS (CS = solubility limit) and domain (2), lying between the two coaxial cylinders, correspond to the network of micropores (empty space between polymer chains) and contain the same drug at concentration C0. Growth of the mean pore radius due to polymer erosion is approximated to be a linear function of time


a is a velocity of erosion(of a constant value) and r0 is the initial pore radius. The symmetry about the midpoint z = L/2means the problem can be simplified by considering only half (0< z < L/2) of the element. Thus, the Equation (10) describing the evolution of the concentration C(ρ,z,t) under Fickian diffusion is given by


where ρ and z are the radial and axial axes, respectively and the diffusion coefficient D=D1 in domain (1) and D=D2 in domain (2):

DL is the drug diffusion coefficient in the solvent/liquid, is the retardation factor that reflects show the pore geometry and topology affects the diffusion and Kr is the restriction factor to account for the interactions between the drug and the polymer (D2<<D1<<DL).

Once diffusion has started, the amount of drug remaining in the element at time t, mt, is given by


Thus, the fraction of drug release at time t, Mt/M∞, is given by


As the problems involve a moving interface, the equations are solved by numerical computation55.


11.5. Mathematical models of drug release

Vijaya sankar GR et al., 2011 described the important classical equations which are useful for the subsequent model development of controlled drug delivery systems.


11.5.1. Fick’s laws of diffusion

Diffusion is the spontaneous net movement of molecules from an area of high concentration to an area of low concentration in a given volume of fluid, down the concentration gradient. Fick (1855, 1995) introduced one of the earliest analyses of this mass transport phenomenon. His work was well recognized through the two fundamental equations, called Fick’s laws of diffusion. Fick’s first law is used to describe steady state diffusion, i.e., when the concentration within the diffusion volume does not change with respect to time. Concentration is dependent only on position. In one (spatial) dimension/planar geometry, it is written as


J is the diffusion flux, i.e. amount of drug particles that passes through a unit area per unit time. C is the position-dependent drug concentration in the matrix. D is the drug diffusion coefficient and x is the position normal to the central plane of the membrane/film. The minus sign shows that diffusion takes place down the concentration gradient. Fick’s second law is used to describe non-steady or continually changing state diffusion, i.e., when the concentration within the diffusion volume changes with respect to time as well as position. In one (spatial) dimension/planar geometry, it is written as


All the parameters carry the same meanings as in Eq. (15), except that C is the time-and position-dependent drug concentration in the matrix and t is time. The main difference between the two equations lies in the fact that concentration is only a function of position in the first law while concentration is a function of both position and time in the second law. Both equations have formed the foundation of various theoretical and empirical drug release models developed in the past decades56.


11.5.2. Higuchi Model

The Higuchi model is one of the most successful theories at predicting drug release from a non-degradable monolithic system whereby drug particles are dispersed uniformly throughout the matrix by Higuchi et al., 1961, 1963. It is assumed that steady-state/pseudo-steady-state diffusion exists such that Fick’s first law can be applied. The Fick’s first law, Equation (17), can be rewritten as


Rt is the rate of diffusion; S is the cross-sectional diffusion area; D is the diffusion coefficient in the matrix; C is the concentration of drug in polymer and x is the distance measured from solvent–matrix interface.

The boundary conditions are:


Cb is drug concentration in the release medium and Cs is the saturation concentration in the matrix. K is the matrix-to-medium partition coefficient.

After substituting and series of integrations, the final equation is written as


In the sink condition, Cb is maintained at very low concentration, close to zero. If the drug loading is much higher than its solubility limit in the matrix (C0>>Cs), Equation (20) can be simplified to:


This solution is a good approximation for monolithic system with C0>>Cs under pseudo-steady state condition. Exact solutions to this diffusion problem were developed by Paul and McSpadden et al., 1976 which improved the accuracy upto11.3%if C0→Cs. Further, Lee et al., 1980 developed another model for monolithic system that can be applied at all (C0/Cs) ratios56.


11.5.3. Korsmeyer - Peppas Model

Korsmeyer et al., 1983 developed a simple, semi empirical model, relating exponentially the drug release to the elapsed time (t);


Where, a is constant incorporating structural and geometric characteristics of the drug dosage from, n is release exponent, ft  = Mt /Mis fraction release of drug. The mechanism of drug release from spherical polymeric devices may be Fickian diffusion when the value of n = 0.43 or less, anomalous (non-Fickian) transport when the value of n lies between 0.43 and 0.85, and case II transport when n = 0.85. An exponent value of  n  greater than 0.85,  signifies  supercase  II transport  mechanism (RitgerandPeppas,1987)56.


11.5.4. Power Model

In 1983, Peppas and co-workers introduced a much simpler yet more comprehensive semi-empirical model to describe drug release from polymeric systems, widely known as the power law model. The power law can be seen as a general equation that is useful to describe various mechanisms of transport including the Fickian diffusion, non-Fickian transport as well as zero-order (constant-rate) release behavior. Power law is further modified to accommodate the lag time (l) in the beginning of the drug release (Ford et al., 1991; Kimand Fassihi, 1997; PillayandFassihi, 1999) and to accommodate the possibility of a burst effect, b (Lindner and Lippold, 1995; KimandFassihi, 1997)56.


11.5.5. Kinetics of drug release Zero order kinetics

Drug dissolution from pharmaceutical dosage forms that do not disaggregate and release the drug slowly and assuming that area does not change and no equilibrium conditions are obtained can be represented by the following Equation 25.


Where, Qt is amount of drug released in time‘t’, Q0 is initial amount of drug in the solution, k0 t is zero order release constant56. First order kinetics

The application of this model to drug dissolution studies is proposed by Gibaldi and Feldman et la., 1967. The following relation is expressed by model:


where, Qt is amount of drug released in time‘t’, Q0 is initial amount of drug in the solution, k1 t is first order release constant56.


12. Characterization

Floating microsphere characterization is an important phenomenon which helps in evaluation of suitability of the drug to the corresponding drug delivery system. These microspheres are characterized by following parameters.


12.1. Micromeritic properties

Micromeritic properties such as particle size, shape, tapped density, compressibility index, true density and flow properties.


12.1.1. Size analysis

Size of floating microspheres is analyzed by using optical microscopy and size distribution by sieving method36. This is useful in the determination of mean particle size with the help of calibrated ocular micrometer. The size of the beads can also be analyzed by using vernier callipers42.


12.1.2. Surface morphology

The surface morphology of floating microspheres can be analyzed by scanning electron microscopy36, fourier transform infrared spectroscopy21. Cross sections should be made in order to observe the core and internal structure of the microspheres. These studies are useful in the examination of internal and external morphology of floating microspheres.


12.1.3. Density

Density of the microspheres can be measured by using a mathematical and experimental method. Mathematically, the density of the microspheres is calculated using the weight and diameter of the microspheres. Experimental determinations of density can be determined using pycnometer27,28.


12.1.4. Compressibility index

Also called as Carr’s index (CI), is an indication of the flowability of a powder. A Carr index greater than 25 is considered to be an indication of poor flowability, and below 15, of good flowability. And it is computed according to the following Equation 2725.


Where, ρT is tapped bulk density, ρB is initial bulk density


12.2. Percentage yield of microspheres

Percentage yield of floating microspheres is calculated by the actual weight of microspheres to the total weight of all non-volatile components that are used in the preparation of floating microspheres and it is represented by the following Equation 2821.


12.3. Encapsulation efficiency

Increasing or controlling the encapsulation efficiency (EE) is desirable, it can prevent the loss of precious medication and it can help to extend the duration and dosage of treatment. The drug content of the encapsulated microspheres can be described by two quantities such as amount of the drug and amount of the unloaded drug. Drug entrapment in floating microspheres can be carried out by dissolving the weighed amount of crushed microspheres in required quantity of 0.1 N HCl and analyzed spectrophotometrically at a particular wavelength using the calibration curve. Each should be examined for drug content in a triplicate manner. The encapsulation efficiency of floating microspheres is calculated by using Equation 1.


12.4. Floating ability

Floating ability is defined as the tendency or capacity to remain a float on fluid. Required amount of the floating microspheres can be placed in the media (simulated gastric fluid (SGF, pH 2.0), phosphate buffer). It is stirred with a magnetic stirrer at 100 rpm. After a period of time, pipette out the buoyant layer of microspheres and separate by filtration. Particles in the sinking particulate layer are separated by filtration. Floating particles and sinking particles has to be dried in a desicator until constant weight is achieved. Percentage buoyancy of microspheres is determined by using Equation 2921. Floating property is also measured by using USP disintegration apparatus, USP dissolution apparatus II26 or standard BP, continuous floating monitoring system57.


Where, Qis weight of floating particles and Qs is weight of sinking particles.


12.5. Swelling index

For estimating the swelling index, required amount of the floating microspheres can be suspended in media. The particle size can be monitored by microscopy technique in different time intervals using an optical microscope. The increase in particle size of the microspheres have been noted, and the percentage of swelling can be determined at different time intervals by the difference between diameter of microspheres at time t and initial time as calculated from the following Equation 3058.


Where Dt is diameter of the microspheres at time‘t’, D0 is diameter of the microspheres at initial time.


12.6. Porosity

The porosity can be determined by mercury intrusion (Autopore 9215 II, Micromeritic, Atlanta GA). This technique based on the fact that the P pressure required to drive mercury through a pore increases as the pore diameter decreases, as described by the Washburn equation (Miller et al., 1983).


where d is the pore diameter, σ is the mercury: air interfacial tension and θ is the contact angle at the mercury: air: pores wall interface. A plot of the volume of mercury versus pressure is a common way to display the raw data. The shape of the porosimetry curve provides information about the pore morphology28.


12.7. Methods of invitro release studies

The purpose of the in-vitro release studies in the early stage of drug development is to select the optimum formulation, evaluate the active ingredient and excipients, and assess any minor changes for drug products. In invitro release studies, a weighed amount of the floating microspheres equivalent to the dose of drug is filled in hard gelatin capsule and placed in the basket of dissolution apparatus. Appropriate quantity of the simulated gastric fluid is used as the dissolution medium. It is stirred at suitable speed and maintained at 37±10c. Perfect sink condition is to be maintained during the drug release study. Samples are withdrawn at each predetermined interval, filtered and analyzed to determine the concentration of drug present in the release medium. The initial volume of the dissolution fluid should be maintained by adding the suitable volume of fresh dissolution fluid after each with drawl. All experiments have to run in triplicate6,25. Deepa kaarthikeyan et al., 2010 performed the in vitro dissolution of floating microspheres of cefpodoxime proxetil by using USP type I (38) dissolution test apparatus. 100 mg of the pure drug is used for the dissolution studies and microspheres equivalent to 273 mg of the pure drug is used for dissolution. Two mL of the aliquot samples are withdrawn at predetermined intervals and filtered and it is diluted with the 0.1 N HCl. The solution is analysed for drug content spectrophotometrically at 263 nm against suitable blank59.


12.7.1. Factors affecting the drug release rate

Controlled release is an attainable and desirable characteristic for any drug delivery systems. The factors affecting the drug release rate depends on the structure of the matrix where the drug is contained and the chemical properties associated with both the polymer and the drug. The drug release is also diffusion controlled as the drug can travel through the pores formed during sphere hardening. The most desirable release profile would show a constant release rate with time. However, in many cases release profiles are more complicated and often contain two main expulsion processes: the first being an initial burst of expelled medication from the sphere surface; the second, a usually more constant stage with release rates dependent on diffusion and degradation. Polymer molecular weight, drug distribution, polymer blending, crystallinity, and other factors are important in manipulating release profiles14. Polymer molecular weight

Degradation of polymer microspheres shows a clear dependence on the molecular weight (MW) of the polymer. Zhou Hy et al., 2005 developed novel microspheres with different concentrations and molecular weight of chitosan by using w/o/w emulsion and solvent evaporation method. Loading efficiency and drug release rate is high with high molecular weight and high concentration60. F. Boury et al developed microspheres with different molecular weights of PLGA (poly (D,L-lactide-co-glycolide). A decrease in molecular weight of the polymer leads to dramatic increase in the drug content and encapsulation efficiency. The rate of drug release from particles containing higher MW polymers is initially high, followed by a decrease which is then followed again by an increase. Spheres containing high MW polymers likely undergo initial slow drug release due to diffusion, followed by the main drug release due to degradation. The drug release from the low molecular weight polymers is higher than that of high molecular weight polymer61. In another literature, S. Freiberg et al reviewed on drug release factor which depends on polymer molecular weight. By correlating observed drug release with microscopic observation of the microspheres, the drug release shows fastest for the degradation of swollen spheres14. Blends of structurally different polymers

The use of polymer blends for controlled drug delivery systems can offer major advantages, including: facilitated adjustment of desired drug release patterns, mechanical properties and drug release mechanisms. In the recent literature Muniyandy Saravanan et al., 2011 formulated floating microspheres with the blends of ethylcellulose and polyethylene glycol (PEG) using the solvent evaporation and matrix erosion method. The release of ranitidine hydrochloride from microspheres prepared with ethylcellulose alone is slow and sustained than the release from ethylcellulose/PEG microspheres. Increase in PEG content in the microspheres produce faster drug release and microspheres prepared with highest percentage of PEG released the entire drug21. F. Siepmann et al., 2008 reviewed the polymer blends for drug controlled release. Blends of GIT-insoluble and enteric polymers provide drug release profiles which is triggered by the pH of the surrounding environment along the GIT. At low pH, the drug is protonated, thus, positively charged and freely water-soluble. In contrast, at high pH the drug is deprotonated, neutral and poorly water-soluble. If the dosage form is surrounded by a conventional, pH-insensitive polymer, the resulting drug release rate can significantly decrease, because the drug concentration gradient (being the driving force for diffusion) strongly decreases. Using blends of GIT-insoluble and enteric polymers, this restriction can be overcome at low pH (within the stomach), both polymers are insoluble is leads to a relatively low permeability for the drug. This is coupled with the high drug solubility at this pH and, thus, results in an intermediate drug release rate62. Crystallinity

Polymer crystallinity is one of the important properties of all polymers. Polymer exists both in crystalline and amorphous form. Molecules are arranged in regular order. These regions are called crystalline regions. In between these ordered regions molecules are arranged in random disorganized state and these are called amorphous regions. Crystallinity in microspheres has been usually investigated by DSC or X-ray diffraction (XRD) studies. DSC can detect phase transitions including the melting of crystalline regions, whereas XRD directly detects the crystallinity properties of a material. Crystallinity in microspheres is reviewed by the Freiberg et al., 2004 which can affect the drug release. Degradation occurred first in the amorphous microsphere regions followed by a slower degradation in the crystalline regions. This suggests that the crystallinity in the polymer chains can affect the degradation rate. Furthermore at the beginning of sphere degradation, the degree of crystallinity actually increased slightly. This is attributed to the crystallization of partly degraded chains and the preferential degradation of amorphous regions14. Size distribution

The release profile is also dependent on the size of the microspheres. Size distribution can be determined by sieving the floating microspheres in standard test sieves. Ehtezazi et al., 2000 developed the porous PLA microspheres to incorporate macromolecules for controlled release. The size distributions of PLA microspheres are determined using a laser diffraction technique (Malvern Particle Sizer 2600, Malvern Instruments, UK). The microspheres are suspended in the release medium and kept at 370c­­ in the shaking incubator for 1 day and 5 ml of release to the measurements, to allow the saturation of the medium which is an aqueous solution of pore space with the release medium, and prevent floating of microspheres during the size measurements. Therefore changing pore size distribution can affect the release rate. However a coarse change in the pore size distribution is required to achieve a significant change in the release rate. Also the change in the pore size distribution mostly is one way and towards larger pores, because decreasing release rate by decreasing pore size needs to overcome technical problems of decreasing aqueous droplets of primary emulsion63. pH controlled release

Added control over drug delivery can be achieved by employing pH-triggered release. Researchers also demonstrated that controlled release is possible for acrylamide-based microsphere system which is pH and temperature-sensitive. Nuran Isıklan et al., 2011 developed the pH responsive ictanoic acid grafted alginate microsphere containing the drug as nifedipine. The amount of drug release decreases with an increase in the concentration of alginate-g-poly (itaconic acid) (NaAlg-g-PIA). As increase in the concentration of the NaAlg-g-PIA, hydrophilic functional groups in the microsphere preparation solution increase. Therefore, more functional groups cross-linked with the –CHO groups of the glutaraldehyde (GA), which result in decrease of nifedipine release15.


12.8. Methods of invivo studies

The study of residence in gastrointestinal transit time became necessary to evaluate the drug-release pattern at various levels of GIT by tracking the location of the dosage form. This provided the insight for formulation of a programmable drug dosage form, which would then release the drug at specific levels of the GIT. The invivo gastric retentive of floating dosage form is usually investigated by g-scintigraphy, gastroscopy, ultrasonography, radiology and magnetic resonance imaging57.


12.8.1. Gamma Scintigraphy

Scintigraphy is a form of diagnostic test used in nuclear medicine, wherein radio isotopes are taken internally, and the emitted radiation is captured by external detectors (gamma cameras) to form two dimensional images. Presently, in vivo evaluation of floating dosage forms is done by gamma scintigraphy (GS). GS is a technique, whereby the transit of a dosage form through its intended site of delivery can be noninvasively imaged in vivo via the judicious introduction of an appropriate short-lived gamma-emitting radioisotope. The observed transit of the dosage form can then be correlated with the rate and extent of drug absorption. Information such as the site of disintegration or dispersion can also be obtained. It helps to locate the dosage form in the GIT, by which one can predict and correlate the gastric emptying time and the passage of the dosage form in the GIT. Gamma emitting radio isotopes can be incorporated into the controlled release dosage form has become the state of art for the evaluation of gastroretentive formulation in healthy volunteers. A small amount of stable isotope is incorporated into the controlled release dosage form during the preparation26. Ninan Ma et al., 2008 developed floating microspheres and non-floating microspheres to incorporate the radio labelled isotope. This is investigated by using g - scintigraphy technique. Pertechnetate (99mTcO-4)  is used as a gamma emitting radio isotope which is  formulated into the dosage forms and administered to the healthy volunteers. The gamma images can be recorded using an online computer system64.


12.8.2. Ultrasonography

Ultrasonography is a radiologic technique in which deep structures of the body are visualized by the reflections of the ultrasonic waves directed into the deep tissues. Ultrasonic waves reflected substantially different acoustic impedances across interface enable the imaging of some abdominal organs24.


12.8.3. Radiology

Radiology is a medical speciality that employs the use of imaging to both diagnosis and treats disease visualized within the body. This method is state of art in preclinical evaluation of gastroretentivity. Their major advantage is simplicity and cost. Using of X-rays is prohibited due to high exposure and often requirement in high quantity. A commonly used contrast agent is barium sulphate24.



Table 3.0. Marketed products of non porous floating microspheres57

S. No

Brand name

Active ingredient

Company name





Ranbaxy, India

Colloidal gel forming FDDS


Cytotec ®



Bilayer capsule



Al-Mg Antacid

Pierre Fabre Drug, France

Floating liquid alginate preparation


Modapar ®

Levodopa, 100mg, Benserzide, 25mg

Roche products, (USA)

Floating CR capsule


Liq. Gaviscon

Al(OH)3 (95mg),

MgCO3 (358mg)

GlaxoSmithKline, India

Effervescent floating liquid alginate preparation


Valrelease ®

Diazepam (15mg)

Hoffmann-LaRoche, (USA)

Floating capsule

Al-Mg=aluminum-magnesium; Al(OH)3= aluminum hydroxide; MgCO3=magnesium carbonate; CR=controlled release; FeSO4=ferrous sulphate


Table 4.0: Physicochemical parameters of various drugs suitable for floating microspheres


Mol wt

t1/2 hours

Protein binding


H2O solubility

log p


Absorption ranging from GIT













































well absorbed

P-nitro aniline


























rapid, uniform

mol wt=molecular weight, t1/2=half life, m.p=melting point, pka=partition coefficient, log p= lipophilicity



13. Non-porous floating microspheres

Alarmingly, no marketed products of porous floating microspheres are available in the market. So, there is a great potential to develop such products for suitable drugs. Some of the marketed formulations are listed in Table 3.0


14. Drugs commonly used for floating microspheres

Most of the floating systems reported in literature are single-unit systems, such as the HBS and floating tablets. These systems are unreliable and irreproducible in prolonging residence time in the stomach when orally administered, owing to their all-or-nothing emptying process. On the other hand, multiple- unit dosage forms appear to be better suited since they are claimed to reduce the intersubject variability in absorption and lower the probability of dose-dumping. The list of various drugs with their physicochemical properties is given in table 4.0 such as molecular weight, half life, protein binding, melting point, solubility and absorption range etc, can be suitable for the development of floating microsphere1.


15. Applications of floating microspheres

Floating microspheres are especially effective in delivery of sparingly soluble and insoluble drugs. It is known that as the solubility of a drug decreases, the time available for drug dissolution becomes less adequate and thus the transit time becomes a significant factor affecting drug absorption. The gastro-retentive floating microspheres will alter beneficially the absorption profile of the active agent, thus enhancing its bioavailability. Drugs that have poor bioavailability because of their limited absorption to the upper gastrointestinal tract can also be delivered efficiently thereby maximizing their absorption and improving the bioavailability65.



15.1. Sustained drug delivery

Sustained drug delivery system is capable of drug release of an active agent over a period of time, allowing for a sustained effect. Floating microspheres can float in the stomach either by effervescent and non-effervescent techniques which release the drug in controlled manner for prolonged period of time. These systems are very effective for various drugs which have shorter residence time in the stomach. These systems have a bulk density lowers than the gastric fluid and which they can float in the stomach.  For example sustained release of Diltiazem hydrochloride floating microsphere is developed and evaluated in volunteer64. A non-steroidal anti-inflammatory drug such as Indomethacin is very effective for controlled release and also reduces the gastric irritation25.


15.2. Site specific drug delivery

Site specific drug delivery allows for higher drug concentrations at the site, which can often reduce side effects, increase quality of life for patients. These systems are suitable for drugs which are absorbed from the stomach or proximal part of the small intestine. This delivery system delivers the drug at specific site by providing the intimate contact with the absorbing membrane to treat the gastric and duodenal ulcers, gastritis and oesophagitis. These systems are assessed the location of dosage form in the stomach in volunteers by X-ray radiography and magnetic resonance imaging technology. Eg: riboflavin17, ranitidine hydrochloride23, cefpodoxime proxetil59.


15.3. Absorption modification

Drugs that have poor bioavailability because of its site specific absorption from the upper gastrointestinal tract are suitable drugs for to be formulated as floating delivery systems, thereby maximizing their absorption. Eg: Cefpodoxime proxetil59.

Table 5.0: List of various drugs along with the constituents used in non porous floating microspheres

S. No






Gelrite gellan gum

S. Maiti et al., 2011




Ling Zhao et al., 2010


Metformin HCl66


Ghodake et al., 2010




D. kaarthikeyan et al., 2010



HPMC, N a alginate

M. Vani et al., 2010



Pectin, Na alginate

EM. Elmowafy et al., 2009



Na alginate, Eudragit RS 30 D, chitosan

N. Ma et al., 2008



Chitosan, EC

Wei .YM  et al., 2008


Acetohydroxamic acid44

Gellan, chitosan

Rajinikanth et al., 2007


Anhy. Theophylline13


S, Sungthongjeen et al., 2006



Chitosan, cellulose acetate

Zhou HY et al., 2005



Eudragit S 100, HPMC

Y. Sato et al., 2004



Alginate, EC

Y. Murat et al., 2003



Alginate, chitosan

Y. Murata et al., 2000

RHCl–ranitidine hydrochloride; EC-ethylcellulose; CP-cefpodoxime proxetil; PEG- polyethylene glycol; HPMC- hydroxy propyl methyl cellulose; PVP- polyvinyl pyrrolidone; Na- sodium; AT- amoxicillin trihydrate; DTZ-diltiazem hydrochloride; MCC-microcrystalline cellulose; MTZ-metronidazole


Table 5.1: List of various drugs along with the constituents used in porous floating microspheres.

S. No






EC 18 – 22cps

M. Saravanan et al., 2011




M.V. Dhoka et al., 2011




Anand P. Gadad et al., 2009




Mastiholimath et al., 2008



Sodium alginate, dextran

S.K. Bajpai et al., 2007



Sodium alginate, HPMC

Shishu et al., 2007


Vitamin B239


Bajpai S.K et al ., 2007


Diclofenac Na30


Badve S.S et al., 2007



Low density polypropylene, accurel MP 1000

Praveen sher., 2007



Na alginate, HPMC

B.Y. Choi et al., 2002




N.J. Joseph et al., 2002



Na alginate, amylose

L. Whitehead et al., 2000


Fluorescein sodium salt28

Casein, gelatin

E. Bulgarelli., et al 1999

RHCl–ranitidine hydrochloride; EC-ethylcellulose; CP-cefpodoxime proxetil; PEG- polyethylene glycol; HPMC- hydroxy propyl methyl cellulose; PVP- polyvinyl pyrrolidone; Na- sodium; AT- amoxicillin trihydrate


15.4. As carriers

Carriers are used in this system to prolong the invivo drug actions, decrease drug metabolism and reduce drug toxicity. Floating microspheres can be used as carriers for drugs with so-called absorption windows, these substances, for example antiviral, antifungal and antibiotic agents (Sulphonamides, Quionolones, Penicillin’s, Cephalosporin’s, Amino glycosides and Tetracycline’s) are taken up only from specific sites of the GI mucosa25.


16. Recent advances in development and formulation of Porous and non porous floating microspheres:

In recent years, authors have focussed in the development of floating microspheres with different polymers and drugs. The concept of non porous and porous floating microspheres is a new trend to obtain prolonged and uniform release of drug in the stomach either for effective local action or enhanced bioavailability. Porous network decides the floating time, dissolution and diffusion of drugs. Non porous and porous floating microspheres are developed with the different polymers as controlled release systems and few of them are shown in Table 5.0 and Table 5.1.



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9.        Yunying Tao, Yifan Lu, Yinjing Sun, Bing Gu, Weiyue Lu, Jun Pan., Development of mucoadhesive microspheres of acyclovir with enhanced bioavailability. International journal of pharmaceutics 378 (2009) 30–36.

10.     Zhepeng Liu, Weiyue Lu, Lisheng Qian, Xuhui Zhang, Pengyun Zeng, Jun Pan, In vitro and in vivo studies on mucoadhesive microspheres of amoxicillin. Journal of controlled release 102 (2005) 135–144.

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13.     Srisagul Sungthongjeen, Ornlaksana Paeratakul, Sontaya Limmatvapirat, Satit Puttipipatkhachorn, Preparation and in vitro evaluation of a multiple-unit floating drug delivery system based on gas formation technique. International journal of pharmaceutics 324 (2006) 136–143.

14.     S. Freiberg, X.X. Zhu, Review: Polymer microspheres for Controlled drug release, International journal of pharmaceutics 282 (2004) 1–18.

15.     Nuran Isiklan, Murat Inal, Fatma Kursum, Gulden Ercan., pH responsive itaconic acid grafted alginate microspheres for the controlled release of nifedipine. Carbohydrate polymers 84 (2011) 933–943.

16.     Jaspreet Kaur Vasir, Kaustubh Tambwekar, Sanjay Garg, Review: Bioadhesive microspheres as a controlled drug delivery system. International journal of pharmaceutics 255 (2003) 13–32.

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18.     Praveen Sher, Ganesh Ingavle, Surendra Ponrathnam, Atmaram P. Pawar, Low density porous carrier based conceptual drug delivery system. Microporous and mesoporous materials 102 (2007) 290–298.

19.     M. Vani, A. Meena, F. Godwin Savio, Mohana Priya, Nancy, Design and evaluation of gastro retentive floating beads of ranitidine hydrochloride. Int J Pharm biomed sci 2010, 1(1), 1-4, ISSN no: 0976-5263.

20.     Sunil k. Jain, Govind P, Agrawal and Narendra K. Jain., Evaluation of porous carrier-based floating orlistat microspheres for gastric delivery. Submitted: march 24, 2006; accepted: june 8, 2006; published: november 10, 2006.

21.     Muniyandy Saravanana, Boddapati Anupama., Development and evaluation of ethylcellulose floating microspheres loaded with ranitidine hydrochloride by novel solvent evaporation-matrix erosion method. Carbohydrate polymers, Accepted (2011).

22.     Hong Kee Kim, Hyun Jung Chung, Tae Gwan Park., Biodegradable polymeric microspheres with “open/closed pores for sustained release of human growth hormone. Journal of controlled release 112 (2006) 167 – 174.

23.     Wei YM, Zhao L., In vitro and in vivo evaluation of ranitidine hydrochloride loaded hollow microspheres in rabbits. Arch pharm res. 2008 oct;31(10):1369-77. Epub 2008 oct 29.

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25.     Sachin B Somwanshi, Ramdas T Dolas, Vikarant K Nikam, Vinayak M Gaware, Kiran B Kotade, Kiran B Dhamak and Atul N Khadse. Floating multiparticulate oral sustained release drug delivery system. J. Chem. Pharm. Res., 2011, 3(1):536-547.

26.     Swapnila d.Vanshiv, Hemant P Joshi, Atul P Sherje,Sanjivani AA Phale, Shalaka P Dhat., Gastroretentive drug delivery system: review. Journal of pharmacy research vol.2.issue 12.december 2009.

27.     Frances Stops, John T. Fell, John H. Collett , Luigi G. Martini, Floating dosage forms to prolong gastro-retention—the characterization of calcium alginate beads. International journal of pharmaceutics 350 (2008) 301–311.

28.     E. Bulgarelli, F. Forni, M.T. Bernabei, Effect of matrix composition and process conditions on casein–gelatin beads floating properties. International journal of pharmaceutics 198 (2000) 157–165.

29.     Enas M. Elmowafy, Gehanne A.S. Awad, Samar Mansour, Abd El-Hamid A. El-shamy, Ionotropically emulsion gelled polysaccharides beads: preparation, in vitro and in vivo evaluation. Carbohydrate polymers 75 (2009) 135–142.

30.     Badve SS, Sher P, Korde A, Pawar AP, Development of  hollow/porous calcium pectinate beads for floating- pulsatile drug delivery .

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32.     Amit kumar Nayak, Ruma Maji, Biswarup Das, Gastroretentive drug delivery systems: a review. Asian journal of pharmaceutical and clinical research, vol.3 issue 1, january-march 2010. ISSN 0974-2441.

33.     Singh Bandana, Kanoujia Jovita, Pandey Manisha, Saraf Shubhini A, Formulation and evaluation of floating microspheres of famotidine. Int.j. Pharmtech res.2010,2(2), ISSN: 0974-4304.

34.     Ling Zhao L, Wei YM, Yu Y, Zheng WW, Polymer blends used to prepare nifedipine loaded hollow microspheres for a floating type oral drug delivery system: invitro evaluation. Arch Pharm Res. 2010 Mar; 33(3):443-50. Epub 2010 Mar 30.

35.     N.J. Joseph, S. Lakshmi, A. Jayakrishnan., A floating-type oral dosage form for piroxicam based on hollow polycarbonate microspheres: in vitro and in vivo evaluation in rabbits. Journal of controlled release 79 (2002) 71–79.

36.     Yuveraj Singh Tanwar, Pushpendra Singh Naruka, Garima Rani Ojha, Development and evaluation of floating microspheres of verapamil hydrochloride, RBCF, Brazilian journal of pharmaceutical sciences, vol. 43, n. 4, out./dez., 2007.

37.     Bibaswan Mishra, Susijit Sahoo, Prasanta Kumar Biswal, Sunit Kumar Sahu, Bhupen Chandra Behera, Goutam Kumar Jana., Formulation and evaluation of torsemide intragastric buoyant sustained release microspheres. Journal of pharmacy research 2010, 3(4),742-746.

38.     Sahoo S.K, Mohapatra S:Dhal S.K, Behera B.C, Barik B.B., Formulation of floating microspheres of ciprofloxacin hydrochloride by crosslinking technique. 2007, vol. 6, no.58, pp. 65-68 [4 page(s) (article).

39.     Bajpai, S. K; Dubey, Seema., Dynamic release of vitamin B2 from floating barium alginate beads for gastric delivery. Journal of macromolecular science, part a: pure and applied chemistry, volume 44, number 9, september 2007 , pp. 1005-1011(7).

40.     Sunil kumar Bajpai,  Rasika Tankhiwale., Preparation, characterization and preliminary calcium release study of floating sodium alginate/dextran-based hydrogel beads: part i. Article first published online: 27 jun 2007 doi: 10.1002/pi.2311.

41.     Sriamornsak Pornsak; Sungthongjeen Srisagul; Puttipipatkhachorn Satit., Use of pectin as a carrier for intragastric floating drug delivery : carbonate salt contained beads. 2007, vol. 67, no3, pp. 436-445 [10 page(s) (article)] (1/2 p.)

42.     Baljit singh, Vikrant Sharma, Dimpal Chauhan, Gastroretentive floating sterculia–alginate beads for use in antiulcer drug delivery. Chemical engineering research and design 88 (2 0 1 0) 997–1012.

43.     Shishu, Gupta N, Aggarwal N., Stomach-specific drug delivery of 5-fluorouracil using floating alginate beads. Aaps pharmscitech. 2007 jun 22;8(2):article 48.

44.     Rajinikanth PS, Mishra B., Preparation and in vitro characterization of gellan based floating beads of acetohydroxamic acid for eradication of H. Pylori. Acta pharm. 2007 dec;57(4):413-27.

45.     Madhura V. Dhoka, Umesh A. Nimbalkar, Amol Pande, Preparation of cefpodoxime proxetil - polymeric microspheres by the emulsion solvent diffusion method for taste masking. Int.j. Pharmtech res.2011, 3(1) ISSN : 0974-4304.

46.     Jia Yu, Xiaomei Wang, Xing Tang, Hongyao Zhang., Formulation and in vitro evaluation of biodegradable microspheres of dexamethasone acetate. Biodegradable microspheres of dexamethasone acetate/Asian Journal of Pharmaceutical Sciences 2007, 2 (6): 260-268.

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49.     Juan Wang, Barbara M. Wang, Steven P. Schwendeman., Characterization of the initial burst release of a model peptide from poly (d,l-lactide-co-glycolide) microspheres. Journal of controlled release 82 (2002) 289–307.

50.     Toshio Ohara, Satoshi Kitamura, Teruyuki Kitagawa, Katsuhide Terada., Dissolution mechanism of poorly water-soluble drug from extended release solid dispersion system with ethylcellulose and hydroxypropylmethylcellulose. International journal of pharmaceutics 302 (2005) 95–102.

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52.     Davis Yohanes Arifin, Lai Yeng Lee, Chi-hwa Wang., Mathematical modeling and simulation of drug release from microspheres: implications to drug delivery systems. Advanced drug delivery reviews 58 (2006) 1274–1325.

53.     V. Lemaire, J. Bélair, P. Hildgen., Structural modeling of drug release from biodegradable porous matrices based on a combined diffusion/erosion process. International journal of pharmaceutics 258 (2003) 95–107.

54.     Oliver l. Freichel, Bernhard C. Lippold., Artificially induced polymer particle erosion of oral hydrocolloid systems by the addition of insoluble cellulose fibres to fibre-free methylhydroxy ethylcellulose. European journal of pharmaceutics and biopharmaceutics 57 (2004) 527–532.

55.     Luciana Lisa Lao, Nicholas A.Peppas, Freddy Yinchiang Boey, Subbu S.Venkatraman., Modeling of drug release from bulk-degrading polymers. International journal of pharmaceutics. Accepted (2011).

56.     Vijaya sankar GR, Naveen kumar Jakki, Suresh AG, Packialakshmi M., Formulation and evaluation of captopril gastroretentive floating drug delivery system. International journal of pharmacy and industrial research, Volume 01/ Issue 01/ Jan – Mar 2011.

57.     Jm Patil, RS Hirlekar, PS Gide and VJ Kadam., Trends in floating drug delivery systems. Journal of scientific and industrial research.  Vol. 65, January 2006, pp. 11-21.

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64.     Ninan Ma, Lu Xu, Qifang Wang, Xiangrong Zhang, Wenji Zhang, Yang Li, Lingyu Jin, Sanming Li., Development and evaluation of new sustained-release floating microspheres. International journal of pharmaceutics 358 (2008) 82–90.

65.     Zaware S. R, Gaikwad P.D, Bankar V.H, Pawar S.P, A review on floating drug delivery system. Int.j.ph.sci.,sep-dec,2010;2(3):834-847.

66.     Ghodake J.D, Vidhate J.S, Shinde D.A, Kadam A.N., Formulation and evaluation of floating microsphere containing anti-diabetic (metformin hydrochloride) drug. Int.j. Pharmtech res.2010,2(1).

67.     Yasunori Sato, Yoshiaki Kawashima, Hirofumi Takeuchi, Hiromitsu Yamamoto, Yasuhisa Fujibayashi, Pharmacoscintigraphic evaluation of riboflavin-containing microballoons for a floating controlled drug delivery system in healthy humans, Journal of controlled release 98 (2004) 75– 85.

68.     Murata Y, Kofuji K, Kawashima S., Preparation of floating alginate gel beads for drug delivery to the gastric mucosa. J biomater sci polym ed. 2003;14(6):581-8.

69.     Y. Murata, N. Sasaki, E. Miyamoto, S. Kawashima., Use of floating alginate gel beads for stomach-specific drug delivery. European journal of pharmaceutics and biopharmaceutics 50 (2000) 221-226.

70.     Anand P. Gadad, Mrityunjaya B. Patil, Suma N. Naduvinamani Vinayak S. Mastiholimath, Panchaxari M. Dandagi, Anandrao R. Kulkarni., Sodium alginate polymeric floating beads for the delivery of cefpodoxime proxetil. Article first published online: 30 jun 2009.

71.     Mastiholimath VS, Dandagi PM, Gadad AP, Mathews R, Kulkarni AR, In vitro and in vivo evaluation of ranitidine hydrochloride ethyl cellulose floating microparticles. J microencapsul. 2008 Aug;25(5):307-14.

72.     B.Y. Choi, H.J. Park, S.J. Hwang, J.B. Park, Preparation of alginate beads for floating drug delivery system: effects of co2 gas-forming agents. International journal of pharmaceutics 239 (2002) 81–91.

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Received on 21.06.2011          Modified on 29.06.2011

Accepted on 08.07.2011         © RJPT All right reserved

Research J. Pharm. and Tech. 4(9): Sept. 2011; Page 1340-1357