Pharma Tips

Sustained Release Multiple Unit Dispersible Tablets

By: Pharma Tips | Views: 11812 | Date: 06-Jul-2010

Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systematic delivery of drugs via various pharmaceutical products of different dosage forms.

Sustained Release Multiple Unit Dispersible Tablets

1. INTRODUCTION

Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systematic delivery of drugs via various pharmaceutical products of different dosage forms. The reasons that the oral route achieved such popularity may be in part attributed to its ease of administration as well as the tradition belief that by oral administration the drug is well absorbed as a food stuffs that are ingested daily. In fact the development of a pharmaceutical product for oral delivery, irrespective of its physical form (solid, liquid) involve varying extents of optimization of dosage form characteristics within the inherent constraints of gastro intestinal tract physiology.




Pharmaceutical products designed for oral delivery and currently available on the prescription and over -the-counter markets are mostly the immediate release type, which are designed for immediate release of drug for rapid adsorption Because of their clinical advantage over immediate release pharmaceutical products containing the same drugs. Sustained release pharmaceutical products, such as those formulated on the basis of spansule coating technology , have over the past decade gradually gained medical acceptance and popularity since their introduction in to the market place, recently, a new generation of pharmaceutical products , called controlled release drug delivery system is developed1.
The term “controlled release oral dosage form” is not new to most people working in various pharmaceutical research and development. In fact approximately 30 year ago, the U.S food and drug administration published regulatory requirements for controlled release products. Unfortunately, there has been a proliferation of controlled release dosage forms on the market place that may have little rationale and provide no advantages over the some drugs in conventional dosage forms2.   
Controlled release drug administration means not only prolongation of the duration of drug delivery, similar to the objective in sustained release and prolonged release, but the form also implies the predictability and reproducibility of drug release kinetics. Oral controlled release drug delivery is thus a drug delivery system that provides the continuous oral delivery of drugs as predictable and reproducible kinetics for a predetermined period throughout the course of GIT transit. Also included are systems that target the delivery of a drug to a specific region within the GI tract or either a local or systematic action.    
1.1 Multiple unit tablets:                                                       
 Today, the tablet is a dominant dosage form, since it is convenient to administer and relatively easy to mass- produce. More ever, it is the dosage form of first hand choice in the development of new drug entities. Tablets are usually prepared by applying to powder bed, there by compressing it in to a coherent compact.             
Controlled release formulations in tablet form are many but over the years the Microsphere formulations have immense popularity owing to their superiority over the former in several respects.
Controlled absorption with resultant reduction in peak to trough ratios. 
Targeted release of the drug to specific areas within the Gastro intestinal tract.
Absorption of drug irrespective of the feeding state. 
Minimal potential for dose dumping.
Facility to produce combination dosage form, etc3 
As a solid Multiple –unit dosage form, microsphere and microcapsules may be filled in to a hard gelatin capsules or be compressed in to a tablets. It is recognized that a multiple–unit controlled release tablet dosage form presents a better alternative to a single unit system for oral formulation.
An ideal multiple-unit tablet dosage form is the one, which in oral administration, disperse or disintegrate rapidly in stomach to release a large number of drug particles, granules, and spheroids. That has maintained the integrity of both cores, and their release- retarding properties such that their drug release kinetics is unaltered.
Peroral controlled-release multiple unit dosage forms (e.g., pellets, granules or microspheres, microcapsules, microparticles) are becoming more and more important on the pharmaceutical market, as they provide several advantages compared to single-unit dosage forms (e.g., tablets or capsules) . A multi-unit controlled release tablet dosage form offers several advantages in comparison to capsules.
Small size of the unit enabling the preparation to be swallowed easily (i.e. ease of esophageal transit as compared to large size capsules)
Ability to administer a portion (dose division) of such multiple-unit tablets   with out compromising their controlled release properties
Ability to incorporate large dose of drug in controlled release form in comparison to capsules.
Lesser cost of formulation and production as compared to capsules.
Feasibility of using existing tabletting capacities in the manufacturing set up.
Greater stability of drug and the formulation owing to small size and absence of gelatin shell.
Ability to formulate such tablets in a dispersible base that can be reconstituted during use to form a   suspension that can be easily swallowed and hence suitable for children and elderly.
Lesser tendency for product tampering.
Controlled- delivery or large doses of biologically active ingredient is also possible in this way and is thus advantageous in comparison to tablets and capsules,  which owing to their size will be   difficult  to swallow and in comparison to chewable tablets, where chewing would result in loss of controlled release characteristics5.
Compaction of beads, pellets or spheroids in to tablets has always been of interest the type and amount of coating the size of subunit, the surface properties of pellets, the selection of external and internal additive having a cushioning effect and the rate and magnitude or applied pressure must be carefully considered in the design of such a dosage form 6.   
 A multiple-unit dosage form has more homogenous individual plasma profiles, shorter lag time and lower variability as compared to single unit   formulations. Generally sustained release and gastric resistant preparations can be administered in a single unit dosage form, whereas Multi-component drug delivery system is available in capsules form. Multiple-unit systems also have numerous therapeutic advantages over single unit dosage form when taken orally. Multiple-unit system generally disperse freely in the gastrointestinal fluids, maximizes absorption, minimizes side effects and reduce inter and intra patient variability.
Oral controlled release multiple unit dosage forms such as beads, pellets and microparticles are becoming more popular than single unit dosage forms. These systems tend to spread uniformly throughout the gastrointestinal tract (GIT) 7. High local drug concentration and the risk of toxicity due to locally restrained tablet can be avoided. Multiple unit dosage forms avoid the vagaries of gastric emptying and different transit rates and, thereby, release the drugs more uniformly. The uniform distribution of these multiple unit dosage forms along the GIT could result in more reproducible drug absorption and reduced risk of local irritations than the use of single unit dosage forms8. The Multiparticulate can be filled into hard gelatin capsules or compressed into tablets. The compression of multiparticulate into tablets is becoming more popular, especially in the US, where the hard gelatin capsules have been tampered with Tylenol 9. Risks such as spontaneous drug release from a single-unit tablet due to damaged coating or its attachment in the stomach or intestine causing an irritation of the gastric or intestinal mucosa are reduced by the use of multiunit forms 10. After disintegration of the tablets in the stomach, single units equal to or below 2 mm in diameter and having a density lower than 2.5 g/cm3   behave like a liquid and have a short transit time through the stomach avoiding drug accumulation11. Moreover, such small single units enable a more reproducible dispersion throughout the gastrointestinal tract leading to a reduction of drug release variations and an improved bioavailability. Thus, it results in a decrease in drug dose and side effects 12, 13 .With regard to the final dosage form, the multiparticulate can be filled into hard gelatin capsules14 or be compressed into disintegrating tablets 15, 16, 17, the advantages of tabletting multiparticulates include less difficulty in esophageal transport, and thus a better patient compliance. Tablets can be prepared at a lower cost because of the higher production rate of tablets presses. The expensive control of capsule integrity after filling is also eliminated. In addition, tablets containing multiparticulates could be scored without losing the controlled release properties, which allows a more flexible dosing regimen18,19,20.

1.2 Rationale of Controlled Drug Deliver
The basic idea behind the evolution of controlled drug delivery concept is to alter the pharmacokinetics and pharmacodynamic of bioactive either by modifying the molecular structure and /or physiological parameters by an alternative selected route of administration or by using novel drug delivery systems. A desirable characteristic of controlled release delivery system is that duration of drug action should be dedicated by the design property or the inherent kinetics properties of drug molecule. Thus thorough understanding of the pharmacokinetics and pharmacodynamic of the drug molecules is necessary for optimal design of controlled released systems.
The primary objectives of controlled drug delivery are to ensure safety and enhance efficacy of drug with improved patient compliance. This could be affected by better modification and control of plasma drug levels and reduction in dosing frequency. The dose and dosing interval can be modified in case of conventional dosage forms. However, therapeutic window of plasma concentration below which no therapeutic effect is exhibited. Therapeutic index, which is defined as the ratio of median lethal dose, is the prime parameter for development of a controlled delivery system of a particular drug candidate. In an attempt to increase the dosing interval by retarding the rate of absorption the formulator must take into account the physiological constraint of a finite residence time at the absorption site as in case of GI transit time    
1.3 Selection Criteria for Drug Candidate
A number of drug characteristics need to be considered in selecting drug candidates for oral Controlled release dosage forms. 
1.3.1 Dose: In oral systems total drug dose is infrequently a limiting factor. A total dose of several grams may be administered orally as single or multiple units to obtain and maintain adequate drug levels. In general, due to bulkiness, the drugs with large doses may sometime prove difficult to formulate as extended release tablets.
Biological Half life: Drugs with an elimination half life of 2 -5 hours are the good candidates for oral controlled drug delivery. 
For the drugs with half lives shorter than 2 h, a prohibitively large dose may be required to maintain the high release rate. 
Additional factors, such as the reduced rate of absorption from the distal small intestine and colon, may also reduce the rate of drug input to less than that required for adequate drug levels. 
On the other hand, drugs with elimination half lives of over 8 hours are commonly sufficiently sustained in the body after a conventional oral dose to make sustained release unnecessary. 
Extensive binding of drugs to the plasma proteins will lead to the long half life of elimination for the drug and such drugs do not require a controlled release dosage form.
1.3.2. Therapeutic Range: The range of plasma drug levels between the minimum effective and toxic levels is known as the therapeutic range. Oral Extended release formulations are valuable for maintaining plasma levels within a narrow therapeutic range. In fact, a valid rationale for formulating drugs with longer half lives as controlled release formulations is to maintain plasma drug levels within a narrow range. By reducing the rate of drug release, it is possible to produce a flatter plasma level curve and avoid toxic drug concentration in the body. 
1.3.3. Gastro intestinal (GI) Absorption: Most SR formulations are dissolution controlled, and drug release rate from the dosage form is the rate limiting step. It is assumed that, once released, the drug is rapidly transferred from the gut lumen to blood. Therefore, efficient drug absorption from the GI tract is a prerequisite for most drugs to be considered for use in oral SR dosage form. In general, the absorption rate for most drugs decrease as the dosage form moves beyond the jejunum. For drugs that are absorbed passively, gut wall permeability shows a consistent pattern. But for compounds that are absorbed via an active transport mechanism, absorption from the GI tract may not be consistent. For such drugs an acceptable rate of absorption may exist only from a limited portion of the small intestine, which may further limit their suitability for SR systems 
1.3.4. Aqueous Solubility: It is well known that for a drug to be absorbed, it first must dissolve in the aqueous phase surrounding the site of administration and then partition into the absorbing membrane. Two of the most important physicochemical properties of a drug that influence its absorptive behavior are its aqueous solubility and if it is a weak acid or base, pKa have significance influence. These properties play an important role in performance of conventional tablet dosage forms and their role is even greater in controlled release systems.
The aqueous solubility of a drug influences its dissolution rate, which in turn establishes its concentration in solution and hence the driving force for diffusion across membranes. Dissolution rate is related to aqueous solubility as shown by the Noyes-Whitney equation.
dC/dt = kDACs          ------------1)
Where, dC/dt is the dissolution rate, 
kD is the dissolution rate constant, 
A is the total surface area of the drug particles and 
Cs is the aqueous saturation solubility of the drug. 
The dissolution rate is constant only if surface area, A remains constant but the important point to note is that the initial rate is directly proportional to aqueous solubility, Cs. Therefore, the aqueous solubility of a drug can be used as a first approximation of its dissolution rates and usually suffers oral bioavailability problems. 
The aqueous solubility of weak acids and bases is governed by the pKa of the compound and the pH of the medium.
For a weak acid,
St = So (1 + 10pH - pKa)         ------------2)
For the weak base,
St = So (1 + 10pKa - pH)        ------------3)
Where St is the total solubility of the weak acid, 
So is the solubility of the unionized form, 
pKa is the acid dissociation constant, 
H+ is the hydrogen ion concentration of the medium. 
Equation 1 and 2 predicts that the total solubility St, of a weak acid/base with a given pKa and be affected by the pH of the medium. Ideally the release of an ionizable drug from a controlled release system should be in accordance with the variation in pH of the different segments of the gastrointestinal tract so that the amount of preferentially absorbed species, and thus the plasma level of drug, will be approximately constant throughout the time course of drug action. In general, extremes in the aqueous solubility of a drug are undesirable for formulation into a controlled release product. A drug with very low solubility and a slow dissolution rate will exhibit dissolution limited absorption and yield an inherently sustained blood level. In most instances, formulation of such a drug into a controlled release system may not provide considerable benefits over conventional dosage forms. For a drug with very high solubility and rapid dissolution rate, it often is quite difficult to decrease its dissolution rate and slow its absorption. Drugs with good aqueous solubility are good candidates for extended release dosage forms. Since the GI environment changes considerably in terms of pH it is desirable that the dissolution rate be independent of such variables.
Stability to wide pH range, GI enzymes and flora: Irrespective of the system employed, an orally administered drug must be exposed to the luminal contents of the gut before it is absorbed. Stability of the drug in the GI content is therefore important to ensure a complete and reproducible drug input into the body. Unlike a conventional dosage form, ER formulation is exposed to the entire range of GI pH, enzymes and flora. Typically the drug must be stable in the pH range of 1 to 8.
1.3.5. Advantage:-                                           
1) Reduction in dosing frequency.
2) Reduced fluctuations in circulatory drug level.
3) Avoidance of night time dosing.
4) Increased Patient compliance.
5) More uniform effect.
6) Decreased effects like Reduced GI irritation
1.3.6. Disadvantage:-
1) High cost
2) Unpredictable or poor in vitro-in vivo Correction.
 3) Dose dumping 
4) Reduced potential for dosage adjustment.
 5) Increased first pas clearance
6) Poor systematic avaibility in general.

1.4. Sustained Release Dosage Form:-
 With many drugs, the basic goal is to achieve a steady state blood level that is therapeutically effective and non toxic for the extended period of time. The design of proper dosage form is an important element to accomplishing this goal. Sustained release or prolonged release dosage forms are designed to achieve prolonged therapeutic effect by continuously releasing the drug over an extended period of time after administration of single dose. In the case of oral sustained release dosage form effect is for several hours depending upon residence time of the formulation in the gastro intestinal tract.
Physician can achieve several desirable therapeutic advantages by prescribing sustained release dosage forms. Since the frequency of drug administration is reduced. Patient compliance can be improved. and the frequency of drug administration can be made more convenient as well. The blood level oscillation characteristic of multiple dosing of conventional dosage form is reduced, because more even blood level is maintained. A less obvious advantage implicit in the design of sustained release form, is that the total amount of drug administered can be reduced. Thus maximizing availability with a minimum dose. In addition, better control of drug absorption can be attained since the high blood level peaks that may be observed after administration of a dose of a high availability drug can reduced by formulation in extended action form. The safety margin of high potency drug can be increased and the incidence of both local and systematic adverse effects can be reduced is sensitive patients. Overall increased administration of sustained release dosage form gives increased reliability10. 
Oral ingestion has been most convenient and commonly employed route of drug delivery. Because of flexibility in dosage form design and their testing, oral sustained release systems have received a great deal of attention. With most orally administered drugs, targeting is not a primary concern. And it is usually intended for drugs to permeate to the general circulation and perfuse to other body tissues. For this reason most systems employed are of the sustained release variety. It is assumed that the increasing concentration at the absorption site will increase the rate of absorption and therefore, increase circulating blood level which in turn promotes greater concentrations of drug at the site of action. If toxicity is not an tissue. Therapeutics levels can thus be extended. in essence, drug delivery by these systems usually depends on release from some type of dosage form, permeation through the biological milieu, and absorption through an epithelial membrane to the blood. There are a variety of both physiochemical and biological factors that come into play in the design of such systems.
 
Fig.1 Drug level versus time profile showing differences between zero- order controlled release, slow first- order sustained release from a conventional tablet or capsules.
Above figure shows comparative blood drug level profiles obtained from administration of conventional, controlled and sustained dosage forms as well as prolonged release dosage forms. Thus, conventional tablet or capsules provides only a single and transient burst of drug. A pharmacological effect is seen as long as the amount of drug is within the therapeutic range. Problems occur when the peak concentration is above or below this range especially for drugs with narrow therapeutic windows.
1.4.1.Advantage:-
1)Avoid patient compliance problems.
2)Minimize or eliminate local side effect and Systematic effect
3)Minimize drug accumulation with chronic dosing. 
4)Cure or control condition more promptly.
5)Improve bioavailability of some drugs.
6)Reduction in blood level fluctuations.
7)Reduction in overall health care costs.
8)Better control of drug absorption can be increased.
9)Safety of margin of high potency drugs can be increased.
1.4.2.Disadvantage:-
Administration of sustained release medication does not permit the prompt termination of therapy. Immediate changes in drug need during therapy, such as might be encountered of significant adverse effects are noted, cannot be accommodate
1)The physician has less flexibility in adjusting dosage regimens. This is fixed by the dosage form design.
2)Sustained release forms are designed for the normal population that is one the basis of   average drug biological half lives. Consequently, Disease states that alter drug dispotion, significant patient variation and so forth are not accommodated.
3)Economical factors must be assessed since more costly process and equipment are involved in manufacturing many sustained release forms.
1.5 Microencapsulation:
Microencapsulation is a rapidly expanding technology. It is the process of applying relatively thin coatings to small particles of solids or droplets of liquids and dispersions. Microencapsulation provides the means of converting liquids to solids, of altering colloidal and surface properties, of providing environmental protection and of controlling the release characteristics or availability of coated materials. Microencapsulation process receiving considerable attention fundamentally, developmentally and commercially31.
Over the last 25 years numerous patents have been taken out by pharmaceutical companies for microencapsulated drugs. The concept of miroencapsulation32 was initially utilized in carbonless copy papers. More recently it has received increasing attention in pharmaceutical and biomedical applications. The first research leading to the development of micro-encapsulation procedures for pharmaceuticals was published by Bungenburg de Jong and Kass in 1931 and dealt with the preparation of gelatin spheres and the use of gelatin coacervation process for coating. In the late 1930s, Green and co-workers of National cash register co. Dayton, Ohio, developed the gelatin coacervation process. Since then may other coating materials and processes of application have been developed by the pharmaceutical industry for the microencapsulation of medicines. 
1.5.1 Microspheres and Microcapsules  
Two general structures exist as microcapsules and microspheres. Microcapsule is a system that contain a well defined envelop.  The core can be solid, liquid or gas; the envelop is made of a continuous, porous or non-porous, polymeric phase.  Drug can be dispersed inside the microcapsules as solid particulate with regular and irregular shape.
A microsphere is a structure made of a continuous phase of one or more miscible polymer in which particular drug is dispersed, at either the particulate or molecular (dissolution) level. However difference between the two systems is the nature of the microsphere matrix in which no well defined wall of envelop exists. Different method of encapsulation results, in most cases in either a microcapsules or a microsphere. The term microcapsule is defined as a spherical particle with size varying from 50nm to 2mm, containing a core substance. Microspheres are in strict sense, spherical empty particles. However the terms microcapsule and microsphere are often used synonymously. Microspheres are synonymically called as Micropellets33 are characteristically free flowing powders consisting of proteins or synthetic polymers, which are biodegradable in nature, and ideally having a particle size less than 200m. Solid biodegradable microcapsules incorporating a drug dispersed or dissolved throughout the particle matrix have the potential for the controlled release of drug. These carries received much attention not only for prolonged release but also for the targeting of the anticancer drug to the tumor. 
1.5.2 Fundamental Considerations
Microencapsulation often involves a basic understanding of the general properties of microcapsules, Such as the nature of the core and coating materials, the stability and release characteristics of the coated materials and the microencapsulation methods. The intended physical characters of the encapsulated product and the intended use of the final product must also be considered. 
a. Core material
The core material, defined as the specific material to be coated, can be liquid or solid in nature. The composition of the core material can be varied as the liquid core can include dispersed and/or dissolved material. The solid core can be a mixture of active constituents, stabilizers, diluents, excipients and release rate retardants or accelerators. 
b. Coating materials
The coating material should be capable of forming a film that is cohesive with the core materials, be chemically compatible and non reactive with the core material and provide the desired coating properties such as strength, flexibility impermeability, optical properties and stability. The total thickness of the coatings achieved with microencapsulation techniques is microscopic in size. 
c.   Selected stability, release and other properties
Three important areas of current microencapsulation application are the stabilization of core materials, the control of the release or availability of core materials and separation of chemically reactive ingredients within a tablet or powder mixture. A wide variety of mechanisms is available to release encapsulated core materials; such as disruption of the coating can occur by pressure, shear or abrasion forces, permeability changes brought about enzymatically etc., improved gastro tolerability of drugs can be obtained by microencapsulation.  
d. Physical character of the final product 
Microcapsules should have desirable physical properties like ability to flow, to be compacted or to be suspended and the capsule wall must be capable of resisting the pressure during compression etc.
1.5.2 Coating Materials
A number of different substances both biodegradable as well as non-biodegradable have been investigated for the preparation or microcapsules. These materials include the polymers of natural and synthetic origin and also modified natural substances. Some of the polymers used in the preparation of the microcapsules are classified and listed below.
A) Synthetic Polymers
Non-biodegradable 
PMMA 
Acrolein
Glycidyl methacrylate
Epoxy polymers
Biodegradable 
Lactides and glycolides and their copolymers 
Polyalkyl cyano acrylates
Polyanhydrides
Carbopol 
B) Natural Materials 
           Proteins
Albumins 
Gelatin
Collagen
           Carbohydrates
                                  ●    Starch
Agarose
Carrageenan
Chitosan
Chemically modified carbohydrates
DEAE cellulose
Poly (acryl) dextran
Poly (acryl) starch     
1.5.3  Release from reservoir microcapsules
Release of core material from non-erodible microcapsule can occur in several ways. Diffusion of drug through such a structure may involve transport not only through an isotropic medium, such as the drug in solution but also a polymeric membrane. Transport of drug through such a membrane involves dissolution of the drug in the polymer at the high concentration of the membrane, interface and diffusion across the membrane in the direction of decreasing concentration. In addition the concentration difference across the membrane, which is taken as the driving force for drug transport, tends to decrease as the solubility of the drug on the upstream side of the membrane decreases. Therefore, the rate release remains constant as long as the internal and external concentrations of core materials and concentration gradient through the membrane are constant. Consider a spherical reservoir device where the thermodynamic activity of the core material is maintained constant within the device and coating is inert, homogeneous and of uniform thickness. The steady state release rate from Fick's law is –
dm/dt = 4DKC * r0 x r1/ r0 – r1         ------- (5)

Where,  r0 and r1 are the outside and inside radial, respectively.
D is the diffusion co-efficient of the drug molecule. 
K is the partition co-efficient and C is the concentration difference between either sides of the coating. 
Assuming all parameters on the right side of equation (5), remain constant, no change in the activity of the core material, C does not change. Integration of equation (5) over a finite period of the steady state would indicate that the drug release was zero-order. This is explained by the path length and surface area remaining constant since the membrane the drug has to traverse is of uniform thickness. If however, the thermodynamic activity of the core material does not remain constant, it indicates that the drug release was first-order.
1.5.4 Release from Monolithic Micromatrices
In a monolithic microsphere the path length does not remain constant, since the drug in the centre has a long path to travel than the drug near the surface, and therefore the rate of release decreases exponentially with time. 
Nevertheless, monolithic microspheres can be made to release drug at an approximately constant rate. The core loading of these microspheres may be increased to create structures similar to those of reservoir microscapsules. An optimum combination of particles sizes (size distribution) may be prepared to achieve a constant rate of drug release. Preparing microspheres with an erodible polymer is such a way that maximum erosion occurs in conjugation with minimum diffusion may establish a constant release rate. 
1.5.5  Prerequisites for ideal microparticulate carriers 
The materials utilized for the preparation of microparticulates should ideally fulfill the following prerequisites:
Longer duration of action 
Control of content release 
Increase of therapeutic efficiency
Protection of drug
Reduction of toxicity 
Biocompatibility
Sterilizability
Relative stability
Water solubility or dispersability
Bioresorbability 
Targetability
Polyvalent
1.5.6. Methods of Microencapsulation
Preparation of microcapsules as prolonged action dosage form can be achieved by various techniques under following headings. 
1.Coacervation phase separation 
a.By temperature change
b.By incompatible polymer addition 
c.By non-solvent addition 
d.By salt addition 
e.By polymer-polymer interaction 
f.By solvent evaporation
2.Multi orifice centrifugal process.
3.Pan coating
4.Air suspension coating
5.Spray drying and spray congealing
6.Polymerization 
7.Melt dispersion technique. 
1.Coacervation phase separation 
Microencapsulation by coacervation phase separation is generally attributed to the processes consists of three steps carried out under continuous agitation.  Formation of three immiscible chemical phases.  Disposition of the coating, and Rigidization of the coating
I.By thermal change: Phase separation of the dissolved polymer occurs in the form of immiscible liquid droplets, and if a core material is present in the system, under proper polymer concentration, temperature and agitation conditions, the liquid polymer droplets coalesce around the dispersed core material particles, thus forming the embryonic microcapsules. As the temperature decreases, one phase becomes polymer-poor (the microencapsulation vehicle phase) and the second phase. (the coating material phase) becomes polymer-rich. 
II.By incompatible polymer addition: It involves liquid phase separation of a polymers coating material and microencapsulation can be accomplished by utilizing the incompatibility of dissimilar polymers existing in a common solvent.
III.By non-solvent addition:  A liquid that is a non-solvent for a given polymer can be added to a solution of the polymer to induce phase separation. The resulting immiscible liquid polymer can be utilized to effect microencapsulation of an immiscible core material. 
IV.By salt addition:  There are two types of coacervation: simple and complex. Simple coacervation involves the use of only one colloid, e.g. gelatin in water, and involves removal of the associated water from around the dispersed colloid by agents with a greater affinity for water, such as various alcohols and salts. The dehydrated molecules of polymer tend to aggregate with surrounding molecules to form the coacervate. Complex coacervation involves the use of more than one colloid. Gelatin and acacia in water are most frequently used, and the coacervation is accomplished mainly by charge neutralization of the colloids carrying opposite charges rather than by dehydration. 
V. By polymer-polymer interaction: The interaction of oppositely charged poly electrolytes can result in the formation of a complex having such reduce solubility that phase separation occurs.           
VI. By solvent evaporation: The processes are carried out in a liquid manufacturing vehicle. The microcapsule coating is dispersed in a volatile solvent, which is dispersed in volatile solvents, which is immiscible with the liquid manufacturing vehicle phase. A core material to be microencapsulated is dissolved or dispersed in the coating polymer solution. With agitation, the core material mixture is dispersed in the liquid manufacturing vehicle phase to obtain the appropriate size microcapsule. The mixture is then heated if necessary to evaporate the solvent for the polymer. In the case in which the core material is dissolved in the coating polymer solution, matrix type microcapsules are formed. The solvent evaporation technique to product microcapsules is applicable to a wide variety of core materials. The core materials may be either water soluble or water insoluble materials.
2.Multiorifice– centrifugal process:
The South-West research institute (SWRI) has developed a mechanical process for producing microcapsules that utilizes centrifugal forces to hurl, a core material particle through an enveloping microencapsulation membrane therapy effecting mechanical microencapsulation. Processing variables include the rotational speed of the cylinder, the flow rate of the core and coating materials, the concentration and viscosity of the coating material and the viscosity and surface tension of the core material. This method is capable of microencapsulating liquids and solids of varied size ranges, with diverse coating materials. 
3.Pan coatings
The microcapsulation of relatively large particles by pan coating method has become wide spread in the pharmaceutical industry and solid particles greater than 600 µg in size are generally considered essential for effective coating. The coating is applied as a solution or as an automized spray to the desired solid core passed over the coated materials during coatings is being applied in the coating pans. 
4.Air suspension coating 
The process consists of the dispersing of solid particulate core materials in a supporting air stream and the spray coating of the air suspended particles.  Within coating chambers, particles are suspended on an upward moving air stream. The design of the chamber and its operating parameters effect a recirculating flow of the particles through the coating zone portion of the chamber, where a coating material, usually a polymer solution is spray-applied to the moving particles.
5.Spray drying and spray congealing 
Spray drying and spray congealing processes are similar in that both involve dispersing the core material in liquefied coating substance and spraying or introducing the core coating mixture into some environmental condition, whereby relatively rapid solidification of the coating is effected. The principle difference between the two methods is the means by which coating solidification is accomplished. Coating solidification in the case of spray drying is effected by rapid evaporation of solvent in which the coating material is dissolved. Coating solidification in spray congealing method, however, is accomplished by thermally congealing a molten coating material or by solidifying the dissolved coating by introducing the coating core material mixture into a nonsolvent. Removal of the nonsolvent or solvent from the coated product is then accomplished by sorption extraction or evaporation techniques. 
6.Polymerization 
The method involve the reaction of monomeric unit located at the interface existing between a core material and a continuous phase in which the core material is dispersed. The continuous or core material supporting phase is usually a liquid or gas and therefore the polymerization reaction occurs at a liquid-liquid, liquid-gas, solid-liquid or solid-gas interface e.g., microcapsules containing protein solutions by incorporating the protein in the aqueous diamine phase. 
7.Melt-dispersion technique
In this technique the coating material is melted by heating upto 80oC. The drug is suspended in it and then emulsified in water containing emulsifying agent at 80oC under stirring. Microcapsules are formed as the temperature of the system reaches to room temperature.  
1.5.7 Applications of Microencapsulation
 Pharmaceutical  
●   To mask the taste of bitter drugs.
●   To provide protection to the core material against atmospheric effects. 
  In the design of controlled and sustained release dosage form.
  To reduce gastric and other G.I. tract irritation. 
  To decrease the volatility
To reduce toxic hazards.
To reduce hygroscopicity. 
To increase flow properties. 
For the separation of incompatible substances. 
For liquid –solid conversions. 
Biomedical 
As artificial cells: to remove or convert unwanted metabolites or toxins from the body; for the treatment of chronic renal failure and congenital enzyme deficiency. 
Liposomes: entrapment of enzymes with in concentric layers of lipids; used for the entrapment of enzyme for enzyme studies, for enzyme and drug targeting.
Magnetic microcapsules: for drug targeting.
1.5.7. Evaluation of Microspheres
The characterization of microcapsule carrier is an important phenomenon, which helps to design a suitable carrier for the proteins, drug or antigen delivery. The parameters that are generally evaluated for characterization of microcapsules are:
1.5.7.1. Particle size and shape
The most widely used procedure to visualize microcapsules is conventional light microscopy, and scanning electron microscopy (SEM). Both techniques can be used to determine the shape and outer structure of microcapsule. SEM provides higher resolution in contrast to the light microscopy. It allows investigation of the microsphere surfaces and after particles are cross sectioned, it can also be used for the investigation of double walled systems. Confocal laser scanning microscopy (CLSM) is applied as a nondestructive visualization technique, which allows characterization of structures not only on surface, but also inside particle. 
1.5.7.2. Fourier trans form –infrared spectroscopy (FTIR)
FTIR is used to determine the degradation of the polymeric matrix of the carrier system, and also interaction between drug and polymer system if present.
1.5.7.3. Density determination 
The density of the microcapsule can be measured by using a multi volume pychnometer. Accurately weighed sample in a cup is placed in pychnometer; helium is introduced at a constant pressure in chamber and allowed to expand. The expansion results in a decrease in pressure within the chamber. From two pressure readings the volume and hence density of microcapsule can be determined.
1.5.7.4. Isoelectric point 
The micro electrophoresis is an apparatus used to measure electrophoretic mobility of microsphere from which the isoelectric point can be determined. The electrophoretic mobility can be related to surface contained charge, ionisable behavior or ion absorption nature of microsphere. 
1.5.7.5Capture efficiency 
The capture efficiency of microcapsule or the percent drug entrapment can be determined by allowing washed microcapsule to lyse. The lysate is then subjected to determination of active constituents as per monograph. The percent encapsulation efficiency is calculated using following equation
 
   % Entrapment == x 100 
 
1.5.7.6. Contact angle:
The angle of contact is measured to determine the wetting property of microcapsule. It determines the nature of microsphere in terms of hydrophilicity or hydrophobicity. The angle of contact is measured at the solid/air/water surface by placing a droplet in circular cell mounted above the objective of inverted microscope. Contact angle is measured at 20oC within a minute of decomposition of microsphere. 
1.5.7.7. In-vitro release studies 
Release studies for microcapsules can be carried out in different pH condition like pH 1.2 and pH 7.4 using USP rotating basket or paddle apparatus. The samples are taken at specific time intervals and are replaced by same amount of fresh medium. The samples withdrawn are analyzed as per the monograph requirement and release profile is determined using the plot of amount released as a function of time.
1.5.7.8. Kinetics of Drug Release
Release of the active constituent is an important consideration in case of microcapsules. Many theoretically possible mechanisms may be considered for the release of the drug from the microparticulates. Liberation due to polymer erosion or degradation Self diffusion through the pore release from the surface of the polymer. Pulsed delivery initiated by the application of an oscillating or sonic field. In most of the cases, a combination of more than one mechanism for drug release may operate, so the distinction amongst the mechanisms is not always trivial. The release profile from the microcapsules depends on the nature of the polymer used in the preparation as well as on the nature of the active drug. Attempts to model drug release from microcapsule have been reported and in the treatment of their data, it was assumed that drug release was confined to any of the order such as zero order or first order processes. One indication of mechanism can be obtained using a plot of log of cumulative percentage of drug remaining in the matrix against time.
First order release  would be linear as predicted by following equation.
                Log C      = Log Co - Kt /2.303 ———-—————(6)
Where, C = Amount of drug left in the matrix
            Co = Initial amount of drug in the matrix
              K = First order rate constant, (time –1)
              t = time, either in hours or minutes
 The in-vitro drug release data obtained from selected batch of microcapsules was treated according to equation (6) by plotting log of cumulative % of drug remaining against time. Next, an attempt was made to see whether the drug release is by diffusion. For system, which will release the drug by diffusion, were proposed by Higuchi .
               Q =  [DЄ/ح (2A – Є Cs) Cs t]1/2  ----------------- (7)      
Where, Q = Weight in grams of drug released per unit surface area.
                D = Diffusion co-efficient of drug in the release medium.
                ε = Porosity of the matrix.
                Cs = Solubility of drug in the microcapsule expressed as gm/ml.
                A = Total concentration of drug in matrix
                 =Tortuosity of the matrix
                t = Time 
The assumption made in the deriving equation (7) is as follows:
A pseudo steady state is maintained during release.
A >> Cs i.e., excess solute is present.
C = 0 solution at all times (perfect sink).
Drug particles are much smaller than those in the matrix.
The diffusion coefficient remain constant.
No interaction between the drug and the matrix occurs. 
For the purpose of data treatment, equation is usually reduced to,
Q = Kt1/2                    …………………………………. (8)
Therefore a plot of amount of drug released verses the square root of time should be linear if the drug release from the matrix is diffusion controlled.
 Precisely, to know the exact mechanism of drug release, whether it is by diffusion or with combination of diffusion and erosion control, the data has also been plotted according to equation as suggested by Korsemeyer , they used a simple empirical equation to describe the general solute release behavior from control release polymer matrices.

Mt/M∞ =   Ktn     …………………………………    (9)    

1.6 Introduction Drug and polymer
1.6.1   Introduction of Propranolol Hydrochloride.  
Name:- Propranolol Hydrochloride
Chemical name:-  1-isopropylamine-3-(alphanaphthoxy)-2propanol-hydrochloride.      isopropylamino-3-(1-naphthyloxy) propanol hydrochloride. 
Chemical formula :- C16H21NO2HCl
Molecular Weight:- 295.84
Chemical structure:-

Category: - 
 Anti-Hypertensive agent. Beta-adrenergic receptor blocking agent Class II ant arrhythmic drug
Description:-
White, odorless crystalline powder. Only stable at acidic pH; decomposes rapidly when alkaline.  Solutions are most stable at pH 3; in aqueous solutions propranolol decomposes with oxidation of the isopropylamine side-chain. Propranolol is a racemic mixture of dextrorotary and levorotary forms.
Solubility:-  
Soluble1 in 20 of water or alcohol; slightly soluble in chloroform; practically insoluble in ether.
Storage conditions: - Store in well-closed containers, protect from light.
Melting range: - Between 162° C and 165° C
Specific rotation: - Between –1.0° & +1.0°
                                 Test solution 40 mg/ml, in water.
Residue on ignition: - Not more than 0.1 %
Pharmacokinetic:- After oral administration, propranolol is almost completely and rapidly absorbed from the gastrointestinal tract. However, because of the high first-pass metabolism and hepatic tissue binding, the absolute bioavailability is only about 30% and varies greatly between individuals. Peak plasma concentration occurs one to two hours after administration. After administration of the sustained release formulation, the peak plasma concentration occurs 7 hours after absorption. About 90 to 95 % of the drug is bound to plasma proteins.
The volume of distribution is 300 L/1.73 M2 or 3.9 L/kg (approximately 200 L in an adult). Propranolol is highly lipophilic: it crosses the blood-brain barrier and the placenta: the ratio of concentration in the blood between the fetus and the mother is 1.5. After oral administration, propranolol undergoes saturable kinetics.
The plasma half-life is 3 to 6 hours and is about 12 hours with the sustained   release forms. The total body clearance is 800 mL/minute/1.73 m2. The liver extensively metabolizes propranolol. At least one of the metabolites, the 4-hydroxypropranolol, is biologically active. The hepatic metabolism is saturable and bioavailability may be increased in overdoses. After a single oral dose, propranolol is completely eliminated in 48 hours, mainly by hepatic metabolism. Less than 0.5 % is excreted unchanged in urine.  The renal clearance is 12 mL/kg/minute. About 20% of the dose is eliminated in urine mainly as glucuronide conjugates. Propranolol is excreted in breast milk at a concentration of 50% that of blood. Dialysis clearance is about 20 mL/minute with a blood flow of 250 mL/minute.
Mechanism of action :- Propranolol is a non-cardioselective beta-blocker with no intrinsic sympathomimetic.  It has membrane stabilizing activity and is highly lipid soluble.  At toxic doses, propranolol has a pronounced negative chronotropic and inotropic effect and a quinidine-like effect on the heart: the result is a reduction of the heart rate, a decrease of the sino-atrial and atrioventricular conduction, a prolongation of the intraventricular conduction and a decrease of cardiac output. Blockade of beta-2 receptors may cause bronchospasm and hypoglycaemia.
Beta-blocking agents compete with endogenous and/or exogenous   beta-adrenergic agonists. Their specific effects depend on their selectivity for beta-1 receptors (located in the heart) or beta-2 receptors (located in bronchi, blood vessels, stomach, gut, uterus). Beta-blockers are classified according to their cardioselectivity, membrane stabilizing effect, intrinsic sympathomimetic effect and lipid solubility at therapeutic doses; propranolol slightly decreases heart rate (15%), supraventricular conduction and cardiac output (15 to 20%) Cardiac work and oxygen consumption are also decreased.  Propranolol decreases the secretion of renin.
Indications:- Propranolol, a non cardioselective beta-blocker, is mostly used in the treatment of hypertension, angina, for the prevention of re-infarction in patients who have suffered from myocardial infarction. It is also used to control symptoms of anxiety and in the treatment of supraventricular tachycardia, hypertrophic obstructive cardiomyopathy and etralogy of Fallot.        
In hyperthyroidism and thyrotoxic crisis; together with alpha blocking agents in the    preoperative treatment of phaeochromocytoma. Propranolol has also been used in the treatment of extrapyramidal disorders and in the prophylaxis of migraine headache. Propranolol may be used in acute stress reactions, somatic anxiety and panic reaction but its value   is questioned.  
Therapeutic dosage:-
Adults:- Propranolol dosing should be initiated at low doses and gradually increased until the desired therapeutic effect is achieved.  
Oral administration:- In cardiovascular diseases: the initial dose of 40 mg twice daily, may be increased at weekly intervals to a maintenance dose of 160 to 260 mg daily (some patients require 320 mg daily). In prevention of hemorrhage due to portal hypertension: 20 mg twice daily. In migraine headache: 40 to 120 mg daily 
Intravenous administration:- The optimal dose is 1 to 3 mg (inject slowly: 1    mg/minute maximum). The total dose should not exceed 5 to 10 mg.
Children¬:-
Oral administration:- 0.25 to 0.5 mg/kg/24 hours administered in divided doses (3 or 4 time daily up to 1 mg/kg/24 hours) 
Intravenous administration:- 0.025 to 0.05 mg/kg; 3 or 4 times daily under ECG control.
Contraindications:-
Absolute:- Asthma, congestive cardiac failure, atrio-ventricular block, bradycardia (below 50/minute), and treatment with amiodarone.
Relative:- Raynaud's disease, diabetes mellitus.
Interactions:- Antacids decrease the gastric absorption of propranolol. Barbiturates, phenytoïn and rifampicin increase the first-pass clearance of propranolol by hepatic enzyme induction. Plasma propranolol concentrations may be increased up to 50% by histamine H2 antagonists and oral contraceptives, which decrease hepatic metabolism by enzyme inhibition. Non-steroidal anti-inflammatory drugs decrease the antihypertensive effect of propranolol. Nifedipine might exacerbate the symptoms of beta-blocker withdrawal. Digitalis, Amiodarone, Verapamil and Diltiazem may increase bradycardia due to propranolol. Verapamil, Prenylamine, Flecainide and Disopyramide enhance the negative inotropic effect of propranolol.
Main adverse effects:- Cardiovascular: sinus bradycardia, atrioventricular block, hypotension,  increase of left ventricular failure, cardiogenic shock, intermittent claudication.
Respiratory: bronchospasm, exacerbation of asthmatic symptoms in known asthmatics, pulmonary oedema. Central nervous system: depression, psychosis, convulsions, and hallucination. Musculoskeletal: muscle weakness, aggravation of myasthenia gravis, peripheral neuropathy. Gastrointestinal: vomiting, diarrhoea, and dry mouth. Endocrine and metabolic: hypoglycaemia, hyperkalaemia, hypothyroidism, sexual dysfunction (impotence). Dermatological: urticaria, exfoliative dermatitis. Haematological: agranulocytosis (immunologic reaction), thrombocytopenia. Pregnancy: hypoglycemia and lethargy have been reported in newborn from mothers treated with propranolol before delivery.
Others: propranolol treatment may potentiate anaphylactic shock.
Precaution:- Patient should be instructed to closely follow their physician’s prescription as regards diet, dosage, and schedule for taking the drug, and should be taught to recognize promptly the early symptoms of hypertension, that generally are pain in chest, weakness, dizziness, headache, and heavy sweating, so they can contact a doctor in good time.
Official products of propranolol hydrochloride
BETABLOC (U.S.V) - Tablet 10 mg.
BETACAP   (Natco) – Tablet 40, 80, 120 mg.
CARDIMAOL (Magnet Lab.) – Tablet 10, 40 mg.
CIPLAR (Cipla) – Tablet 10, 40, 80 mg.
CORBETA (Sarabhai) – Tablet 10, 40 mg.
MIGRABETA (Pentacare)- TR Tablet 40, 60, 80 mg.
PRAL (Chemo Biological) – Tablet 10, 40 mg.
PROP- 40 (RKG Pharma) – Tablet 40 mg.
TRILOL (Triton) – Tablet- 20 mg.
INDERAL (Nicholas) – Tablet 10, 40, 80 mg.

1.6.2 Introduction of polymer
Name:- Ethyl Cellulose 
Chemical name: Cellulose ethyl ether
Molecular formula: Ethyl cellulose with complete ethoxyl substitution (DS= 3) is C12H23O6 (C12H22O5)n C12H23O5
Structural formula: The structure with complete ethoxyl substitution is
 
Ethyl Cellulose
Function category: Coating agent, flavoring agent, fixative tablet binder, tablet filler, Viscosity –increasing agent.
Description: Ethyl cellulose is a tasteless, free flowing, white to light tan colored powder.
Typical properties:
Density: (bulk): 0.4 gm/cm3
Glass transition temperature: 129-133   0 C
Solubility: Ethyl cellulose is practically insoluble in glycerin, propylene glycol, and water. Ethyl cellulose that contains less than 46.5 % of ethoxyl group is freely soluble in chloroform, methyl acetate, tetrahydrofuran, and in mixtures of aromatic hydrocarbons with   ethanol (95%). Ethyl cellulose that contains not less than 46.5% ethoxyl  group is freely soluble in chloroform, ethanol (95%) , ethyl acetate, methanol, and toluene.
Specific gravity: 1.12-1.15 gm/cm3.
Incompatibilities: Incompatible with paraffin wax and microcrystalline wax.
Safety:  Ethyl cellulose is widely used in oral and topical pharmaceutical Formulations. It is also used in food products. Ethyl cellulose is therefore a non -Caloric substance. It is generally regarded as a non-toxic, non-allergic, and Nonirritating material.
Applications in pharmaceutical formulations: 
The main use of ethyl cellulose is in Oral formulation is as a hydrophobic coating agent for tablets and granules. Ethyl cellulose coating are used to modify the release of a drug, to mask the unpleasant taste, or to improve the stability of a formulation. Modified release tablet formulation may also be produced using ethyl cellulose as a matrix former.

2. Literature review work done :
2.1 Review work done on propranolol hydrochloride:
Patel, V. M et al 52 prepared buccal adhesive patches containing 20 mg of propranolol hydrochloride using solvent casting method. Chitosan was used as a natural bioadhesive polymer. Patches were prepared at different ratios of PVP K-30 and evaluated for various physicochemical characteristics such as weight variation, drug content uniformity, folding endurance, surface pH, ex-vivo mucoadhesive strength, ex-vivo residence time, in vitro drug release and in vitro buccal permeation study. Patches exhibited sustained release over a period of 7 hours. Optimized patches showed satisfactory bioadhesive strength and ex vivo residence time. Swelling index was proportional to PVP K-30. The surface pH of all batches was within satisfactory limit and hence patches would not cause irritation in the buccal cavity. Good correlation was observed between in vitro drug release and in vitro drug permeation with correlation coefficient of 0.9364. Stability of optimized patches was performed in natural human saliva showed that both drug and dosage forms were stable in human saliva. 
Patel VM et al53 studied mucoadhesive bilayer buccal tablets of propranolol hydrochloride by using the bioadhesive polymers sodium alginate and Corbopol 934P (CP) along with EC as an impermeable backing layer. Tablets containing Na-alginate and CP in the ratio of 5:1 had the maximum percentage of in vitro drug release without disintegration in 12 hours. The swelling index was proportional to Na-alginate content and inversely proportional to CP content. The surface pH of all tablets was found to be satisfactory, close to neutral pH; hence, buccal cavity irritation should not occur with these tablets. The mechanism of drug release was found to be non-Fickian diffusion and followed zero-order kinetics.  Optimized the formulation based on good bioadhesive strength and sustained in vitro drug permeation. 
Patel VM et al54 developed formulations and evaluated in vitro performances of buccoadhesive patches of propranolol hydrochloride using the hydrophobic polymer Eudragit L-100 as the base matrix. .A 3(2) full factorial design was employed to study the effect of independent variables like hydrophilic polymers Corbopol 934 and PVP K30, which significantly influenced characteristics like swelling index, ex vivo mucoadhesive strength, in vitro drug release, and ex vivo residence time. A stability study of optimized Eudragit patches was done in natural human saliva; it was found that both drug and buccal patches were stable in human saliva. It can be concluded that the present buccal formulation can be an ideal system to improve the bioavailability of the drug by avoiding hepatic first-pass metabolism.
Gil EC,et al55 prepared propranolol hydrochloride sustained-release matrix tablets developed and optimized. The influence of matrix forming agents and binary mixtures of them on PPL release in vitro was investigated. The sustained-release matrix tablets with good physical, mechanical and technological properties were obtained with a matrix excipient: PPL ratio of 60:40 (w/w), with a dextran: HPMC ratio of 4:1 (w/w) and with a cetyl alcohol amount of 15% (w/w). The value for the similarity factorsuggested that the dissolution profile of the present two sustained-release oral dosage forms is similar. Higuchi and Hixon-Crowell kinetic profiles were achieved and this codependent mechanism of drug release was established.
Halder A et al56 Propranolol-HCl was bound to Indion 254, a cation exchange resin, and the resulting resinate was microencapsulated with polystyrene using an oil-in-water emulsion-solvent evaporation method .The effect of various formulation parameters on the characteristics of the microcapsules was studied. The variation in the size of the microcapsules appeared to be related with the inter-facial viscosity which was influenced by the viscosity of both the aqueous dispersion medium and the organic disperse phase. The resinate encapsulation efficiency and hence the drug entrapment efficiency of the microcapsules increased with increase in the concentration of emulsion stabilizer and coat/core ratio and decreased with increase in the volume of organic disperse phase. These characteristics were found to depend on the extent of formation of fractured microcapsules and subsequent partitioning of the resinate into the aqueous dispersion medium. The prolongation of drug release was dependent on the uniformity of coating which was influenced by the formulation parameters. The drug release from the microcapsules was also found to be independent of pH of the dissolution media and increased with increase in ionic strength. Polystyrene appeared to be a suitable polymer to provide prolonged release of propranolol independent of pH of the dissolution media
Nokhodchi A et al57 determined the effects of surfactant type, its concentration and the different ratios of surfactants on the release rate of propranolol HCl. In this study, sodium lauryl sulphate (SLS) as an anionic surfactant, cetyl trimethyl ammonium bromide (CTAB) as a cationic surfactant, Tween 65 and Arlacel 60 as non-ionic surfactants were selected. The results showed that the release rate of propranolol decreased as the concentration of SLS increased. Cationic surfactant (CTAB) had little effect on the release rate of the drug. It was shown that as the ratio of CTAB: SLS increased the release rate of propranolol increased from matrices. It can be concluded that, the type and ionization of surfactant, hydrophilicity and lipophilicity of surface active agent and various ratios of surfactants are important factors in controlling the release rate of propranolol.
Takka S et al58 incorporated Eudragit L 100-55, and sodium carboxymethylcellulose with HPMC K100M to modify the drug release from HPMC matrices. The interaction between propranolol hydrochloride and anionic polymers was confirmed using the UV difference spectra method. The drug release was controlled with the type of anionic polymer and the interaction between propranolol hydrochloride and anionic polymers. The HPMC-anionic polymer ratio also influenced the drug release. The matrix containing HPMC-Eudragit L 100-55 (1:1 ratio) produced pH-independent extended.
Mohammadi-Samani S et al59 studied propranolol osmotic pump by coating the core tablets with cellulose acetate. The results showed that, when the membrane thickness increased, the release rate of propranolol decreased. The drug release follows a zero-order release when the delivery orifice is between 200 and 800 microns, but when the delivery orifice size is increased to 1000 microns, the release kinetic is abnormal. Fluid dynamics have an important effect on the delivery rate of propranolol from this device; the delivery rate increases as a function of the fluid flow. The drug release is higher under a turbulent condition with high rate of stirring.
Dabbagh MA et al60 have investigated HPMC and three viscosity grades of NaCMC, were investigated for their ability to provide a sustained release of propranolol hydrochloride from matrices. The rank order of release rate, in the absence of HPMC, was NaCMC (Blanose) < NaCMC P 800 < NaCMC P 350 for matrices containing 95-285 mg NaCMC, and was dependent on their viscosity grades. A study of the erosion rates of matrices containing polymer only indicated that NaCMC eroded more quickly than HPMC. When propranolol hydrochloride was included in matrices containing NaCMC,the erosion was reduced as a result of the insolubility of a complex formed between NaCMC and propranolol hydrochloride. The interaction between propranolol hydrochloride and NaCMC was confirmed by both dialysis and by monitoring the release of sodium ions from the matrices.
Velasco-De-Paola MV et al61 prepared controlled-release propranolol hydrochloride tablets for twice-daily administration, allowing more uniform plasmatic levels of the drug. Pharmaceutical formulations were prepared with hydrophobic Eudragit RSPO. The physical properties of the tablets were determined. Dissolution tests were performed in capsules containing the raw material using the following dissolution media: (A) distilled water, (B) simulated gastric juice without enzymes, and (C) simulated enteric juice without enzymes. A dissolution test was also performed for simulated samples (tablets) using distilled water as the dissolution medium.
Chiao CS et al62 prepared propranolol HCl encapsulated with cellulose acetate butyrate (CAB) by an emulsion-solvent evaporation method.Unencapsulated propranolol HCl powder had very rapid dissolution, as expected. Release rate from CAB microspheres increased with higher drug to polymer ratios and decreased with increasing diameter. Drug release from microspheres sizes larger than 180 microns was reasonably well described by the spherical matrix model. For microsphere size fractions between 127 and 359 microns the relationship between the 50 per cent release time and the square of the microsphere diameter was linear.
2.2 Review work done multiple unit tablets:
M.S.Patel et al63 developed sustained release Ciprofloxacin HCl dispersible tablets containing multiparticulates. Drug loaded pellets were prepared by powder layering on non–pariel seeds and sustained release pellets were prepared by coating with various grades of Eudragit and Ethylcellulose polymers.Drug release study was observed up to 12 hrs and was also capable of resisting compressional forces imparted during tableting, with cushioning agent microcrystalline cellulose and lactose (1:1). The release mechanism of Ciprofloxacin HCl from coated pellets exhibited a non-fickian release behavior controlled by combination of diffusion and chain relaxation mechanism. It can be concluded that dispersible tablets containing viscosity builders come in contact with water to form suspension. 
Tejraj M. Aminabhavi et al64prepared ampicillin (AMP) starch-based tableted microspheres cross linked with epichlorohydrin (EPI) using a modified water-in-oil (w/o) emulsification technique. The results indicated a dependence on the amount of polymer and extent of crosslinking. Release data were fitted to an empirical relation to estimate transport parameters and to understand the transport mechanism. Statistical analyses of release data was performed using analysis of variance (ANOVA) method. Suitable microspheres were selected and compressed into tablets using the directly compressible excipients. SEM photographs of the fractured part of the tablet revealed the presence of discrete microspheres in the tablets, suggesting that the system chosen is ideal for tableting. Tablets significantly lowered the initial burst effect when compared to microsphere formulations. The tablets were effective in releasing the AMP over an extended period of about 24 h.
Sirpa Tirkkonen et al 65  prepared indomethacin microencapsulated in a coacervation process using ethylcellulose and polyisobutylene as a coacervation inducing agent. The effect of compression pressure on drug release was evaluated. The release of indomethacin was also studied after effective disintegration of the tablets  by cross linked sodium carboxymethylcellulose. Release of indomethacin from plain microcapsules accelerated markedly when sodium chloride was added in the microcapsule wall. All the  tablets  without disintegrant stayed nearly intact during the dissolution test. The  tablets  of microcapsules were composed of a porous ethylcellulose matrix in which the microcapsules were separated from each other by easily wettable  tablet  adjuvants. The drug release accelerated from the  tablets  due to the mechanical destruction of microcapsule wall, which was more clearly seen after disintegration of the  tablets to the multiple  microcapsule  units.  The rupture of microcapsule films was most extensive with the  tablets  containing fragmenting dicalcium phosphate as a filler. The addition of sodium chloride in the microcapsule wall seemed to make the polymer film firmer thus reducing the destructive effect of  tablet  adjuvants. 
Bin Lu et al 66  prepared Indomethacin (IDM) encapsulated in gelatin-cellulose acetate phthalate (CAP) microcapsules (A) by complex coacervation method and simple coacervation method. The activation energy of thermal degradation for tablets A and B was calculated based on differential scanning calorimetry (DSC) to be 258.9 and 284.8 kcal/mol, respectively. In vitro release profiles showed no burst effect and release t1/2 of the two sustained-release tablets were found to be 41.30 ± 1.86 and 33.25 ±  2.84 min, respectively, while that of IDM plain tablets was 6.30 ± 0.39 min (P < 0.01). In vitro release of IDM from tablets A and B could be described by Higuchi equation and zero-order kinetics, respectively.
 Carla M. Lopes et al 67 prepared biphasic delivery system for zero-order sustained drug release. The outer layer that fills the void spaces between the mini-tablets was formulated to release the drug in a very short time (fast release), while the mini-tablets provided a prolonged release. The in vitro performance of these systems showed the desired biphasic behaviour: the drug contained in the fast releasing phase dissolved within the first 2 min, whereas the drug contained in the mini-tablets was released at different rates, depending up on formulation. it can be concluded that mini-tablets containing HPMC were particularly suitable approaching to zero-order release over 8 h time periods.
Nursin Gonul et al68 developed modified release tablet formulations containing diltiazem hydrochloride-loaded microspheres by emulsion-solvent evaporation technique. Suitable microspheres were selected and tabletted using different tabletting agents, Ludipress®, Cellactose®80, Flow-Lac®100 and excipients Compritol®888 ATO, Kollidon®SR. Tablets were evaluated from the perspective of physical and in-vitro drug release characteristics. It was seen that type and ratio of the excipients played an important role in the tabletting of the microspheres. As a result, two tablet formulations containing 180 mg diltiazem hydrochloride and using either Compritol®888 ATO or Kollidon®SR were designed successfully and maintained drug release for 24 h with zero order and Higuchi kinetics, respectively. 
Verhoeven E, et al 69 have developed mini-matrices with release-sustaining properties by hot-melt extrusion using MT as drug and ethylcellulose (EC) as sustained-release agent. Dibutyl sebacate was selected as plasticizer and its concentration was optimized to 50% (w/w) of the EC concentration. Xanthan gum, a hydrophilic polymer, was added to the formulation to increase drug release. Changing the xanthan gum concentration modified the in vitro drug release: increasing xanthan gum concentrations (1%, 2.5%, 5%, 10% and 20%, w/w) yielded a faster drug release. Raman analysis revealed that MT was homogeneously distributed in the mini-matrices, independent of screw design and processing conditions. 
Pongjanyakul et al 70 investigated the effect of different polysulfonate resins and direct compression fillers on physical properties of multiple-unit sustained-release dextromethorphan (DMP) tablets. DMP resinates were formed by a complexation of DMP and strong cation exchange resins, Dowex®50W and Amberlite®IRP69. The tablets consisted of the DMP resinates and direct compression fillers such as microcrystalline cellulose (MCC), dicalcium phosphate dihydrate (DCP), and spray dried rice starch (SDRS).Particles of Amberlite®IRP69 caused a statistical decrease in tablet hardness, whereas good tablet hardness was obtained when spherical particle of Dowex®50W was used. The plastic deformation of the fillers such as MCC and SDRS caused a little change in the release of DMP. A higher release rate constant was found in the tablets containing DCP and Dowex®50W, indicating the fracture of the resinates under compression which was due to the fragmentation of DCP. However, the release of DMP from the tablets using Amberlite®IRP69 was not significantly changed because of the higher degree of cross-linking of the resinates, which exhibited a more resistant to deformation under compression. In conclusion, the properties of polysulfonate resin, such as particle shape and degree of cross-linking, and the deformation under compaction of fillers affect the physical properties and the drug release of the resinate tablets.
S. A. Agnihotri et al71 prepared controlled release formulations of clozapine microparticulated tablets by using chitosan. SEM photographs of the fractured part of the tablet revealed the presence of discrete particles in the tablets, suggesting that the system chosen is ideal for tableting. Drug release from the tableted microparticles exhibited an initial burst effect, but the release decreased with increasing extent of cross-linking. Tablets were coated with chitosan or cellulose acetate, which significantly lowered the initial burst effect when compared to uncoated tablets. Drug release from chitosan-coated tablets was slightly higher than the tablets coated with cellulose acetate. Tablets prepared were effective in delivering clozapine over a period of 12 h.
Tejraj M. Aminabhavi et al 72 prepare microspheres loaded with nifedipine and verapamil hydrochloride using ethyl cellulose (EC) and cellulose acetate (CA) by emulsification and solvent evaporation method. Molecular level drug distribution in the microspheres was confirmed deferential scanning calorimetry. The microspheres were directly com- pressed into tablets using deferent excipients. The drug release from CA was faster than EC microspheres and, also, the VRP release was faster than NFD.The excipients used in tableting showed an effect on the release as well as the physical properties of the tablets.
C. Sajeev,et al 73 formulated and evaluated microencapsulated controlled release preparations of diclofenac sodium using EC as the retardant material to extend the release. The formulated microcapsules were then compressed into tablets to obtain controlled release oral formulations. In vitro release study of the tablet ted microcapsules in triple distilled water showed zero order release kinetics and extended release beyond 24 h. A good correlation was obtained between drug release (t60) and proportion of EC in the microecapsules. In the case of tablet ted microcapsules, very good correlation could be established between t60, proportion of EC, weight of the tablets and between release rate constant (K) and proportion of EC. All the formulations were highly stable and possessed reproducible release kinetics across the batches.

3. Aim of present investigation:
In the last few decades, many different types of peroral modified and controlled release formulations have been developed to decrease dosing frequency and enhance patient compliance, reduce fluctuation in circular drug levels and facilitate a more uniform effect and improve the clinical efficacy of the drug. These formulations are designed to deliver the drugs at a controlled and pre- determined rate, thus maintaining their therapeutically effective concentration in systematic circulation for prolonged period of time.
Oral multiple-unit dosage forms such as microspheres have received much attention as modified / controlled drug delivery systems. These systems distribute more uniformly in the gastrointestinal tract, thus resulting in more uniform drug absorption and reducing patient –to-patient variability.
The multiparticulate systems can be filled into hard gelatin capsules or compressed in to tablets the compression of these systems in to tablets is becoming more popular. Hard  gelatin  are very elegant dosage forms, but have the disadvantages of higher production cost, lower production rate, and tampering potential when compared to compressed tablet. Microspheres have been tabletted to control or modify the release of the drug. The manufacturing process from microspheres will create a single-unit from multi-particulate systems in order   to produce compact forms that disintegrate into many sub-units soon after ingestion to attain more uniform concentration of the drug in the body. Reduced risk of tampering, higher dose strength per unit and the higher production rate of the tablet process can be listed among the advantages of tabletting.
The model drug selected, propranolol hydrochloride a -adrenoceptor antagonist that can acutely lower the blood pressure in human by blocking β-receptors non-selectively, is typically prescribed to treat hypertension, myocardial infraction, and cardiac arrhythmias. Its short biological half-life (3.9±0.4 h). Even though propranolol hydrochloride is well absorbed from GIT, it undergoes extensive first pass metabolism and only 30 % of the doses reaches systemic circulation unchanged. The development of controlled-release dosage forms thus would clearly be advantageous. Moreover, the use of extended release products offer potential advantages like sustained blood levels, attenuation of adverse effects and improved efficacy and patient compliance. 
Multi-unit tablet disperses the sustained release multiparticulate after coming contacts with aqueous phase and allow the sustained release of drug. It provide easy administration and homogeneous plasma profile at the same time increases aesthetic value of the formulation such dosage form posses the possibility of administering large amount of drug  in convenient way .
The present research endeavour was directed towards the development and evaluation of dispersible multiple unit tablet to formation of sustained release suspension of Propranolol hydrochloride.
The present study is planned with the following objectives:
1.To prepare microspheres using EC using emulsification solvent evaporation 
       technique.
2To study the effect of variation in drug/ polymer ratio To evaluate the microspheres  
a)Scanning Electron Microscopy was performed to determine the particle size range and surface topography.
b) Sieve analysis was used to determine the particle size of microspheres
c)Entrapment efficiency and production yield was determined to estimate the amount of drug incorporated into microspheres.
d)In vitro release profile was performed to establish the release profile of propranolol hydrochloride from microspheres.
       4.  Suitable microspheres formulations were then selected and compressed into 
            tabletting using different direct tabletting agents and viscosity building agent. 
5. Evaluation of physical characterization of dispersible multiple unit tablets.
6.  In vitro release profile was performed to establish the release profile of     
    Propranolol  hydrochloride from dispersible multiple units tablet.
7. The release rate data of microspheres and dispersible multiple unit tablets were 
     investigated by using Korsmeyer, zero-order, first-order and higuchi kinetics.
8.Measurement of viscosity of suspension.
9.Stability studies of optimized batch of dispersible multiple unit tablets.

4. EXPERIMENTAL SETUP
Table 1 Material used in present investigation
IngredientsSupplier
Propranolol hydrochlorideIntasPharmaceuticals, A,bad.
Hydroxypropyl methyl cellulose (HPMC K4M)Colorcon Asia Pvt. Ltd., Goa.
Sodium carboxy methyl celluloseColorcon Asia Pvt. Ltd., Goa..
Ethyl celluloseColorcon Asia Pvt. Ltd., Goa.
Xanthan gum Gift from zydus cedilla,A’bad
Hydrochloric acid                S. D. Fine Chemicals, Mumbai.
Sodium hydroxide flakes LRS. D. Fine Chemicals, Mumbai.
Potasium dihydrogen ortho phosphate purified  LRS. D. Fine Chemicals, Mumbai.
Potassium chloride S. D. Fine Chemicals, Mumbai.
AcetoneS. D. Fine Chemicals, Mumbai.
Aerosil 200Degussa India pvt ltd , Mumbai.
Magnesium stearateS. D. Fine Chemicals, Mumbai.
Microcrystalline celluloseS. D. Fine Chemicals, Mumbai.
LactoseS. D. Fine Chemicals, Mumbai.
Sodium Starch GlycolateMaple biotech Pvt Limited, pune 
MethanolS.D.Fine Pvt Limited, pune

Table 2 Instruments
InstrumentSupplier
UV/Vis double beam SpectrophotometerShimadzu UV-1601, Kyoto, Japan.
Analytical balanceShimadzu, Japan.
Over Head stirrerRemi motor, Mumbai
Magnetic stirrerRemi motor, Mumbai
Rimek rotary tablet  machineCadmach, Ahmedabad.
Dissolution test apparatusDissolution test apparatus- TDT-06T USP-XXIV, (Electrolab-, mumbai, India)
Tablet disintegration  test machineElectrolab, Mumbai, India.
Hot air ovenElectroquip , Ahmedabad
Monsanto hardness testerElectrolab, Mumbai, India.
Roche FriabilatorElectrolab, Mumbai, India.
Sieve shakerPritec, Ambala cannt
Scanning electron microscopyLeica (S430) London, UK

4.3 Preparation of standard curve of propranolol hydrochloride
One hundred mg of propranolol HCl was transferred in 100 ml volumetric flask containing 50 ml of 1.2 pH buffer solution. The drug was dissolved in the 1.2 pH buffer solution and the volume was adjusted to 100 ml by further addition of 1.2 pH buffer solution. The 10 ml of above solution was further diluted upto 100 ml with 1.2 pH buffer solution to achieve 100 µg/ml concentration of stock solution. The resulting solution was serially diluted with 1.2 pH buffer solution to get drug concentration in range of 0-60 g/ml. The absorbance of the solutions was measured against 1.2 pH buffer solution as a blank at 290 nm using double beam UV visible spectrophotometer. The plot of absorbance v/s concentration (g/ml) was plotted and data was subjected to linear regression analysis in Microsoft Excel®.  
The similar calibration curve was also developed using 6.8 pH phosphate buffers at 289 nm.
Table 3. Standard curve of propranolol hydrochloride in pH-1.2 and Ph-6.8 
Sr. No.Concentration
(mcg/ml)Absorbance at pH 1.2
Absorbance at pH-6.8

For pH 1.2= Absorption = 0.019 x  + 0.031, Correlation Coefficient =  0.996
For PH 6.8=Absorption  = 0.019x + 0.033,   Correlation Coefficient =  0.996

5. Experimental Work: 
5.1 Preparation of microspheres
        The microspheres were prepared by the emulsion–solvent evaporation technique. Ethyl cellulose was dissolved in acetone by stirring at 500 rpm with magnetic stirrer. Accurately weighed amount of propranolol hydrochloride and Caster oil were dispersed in this solution and stirred at the same rate with magnetic stir at a temperature of less than 200C. This mixture was rapidly poured into liquid paraffin. The resultant emulsion was continuously agitated at room temperature using a three blade propeller stirrer at 1200 rpm for 5hrs and acetone was removed completely by evaporation. The solidify microsphere were filtered and washed twice with 200mi n-hexane and then under vacuum at room temperature for 12 hrs. Final microspheres were stored in a desiccator. In this study, the drug/ polymer ratio (1:1, 1:2, 1:3, and 1:4) was varied, maintaining a constant amount of polymer and solvent volume, but decreasing the amount of the drug in all formulation. The composition of each microsphere formulation prepared is given in table1. Span 80 was used as an emulsifier for stabilizing the outer phase in the amount of 1.5 % which was calculated from the volume of the dispersing medium (w/v %). The concentration of castor oil (10%), which was used as a plasticizer, was calculated from the amount (w/w %)       
Table: 4. Composition of Microsphere Formulation coded F1-F4.
CompositionF1F2F3F4
Propranolol Hydrochloride(gm)3.61.81.20.9
Ethyl Cellulose (gm)3.63.63.63.6
Caster oil (ml)0.360.360.360.36
Span 80 (ml)3.03.03.03.0
Acetone (ml)60606060
Liquid Paraffin (ml)200200200200
Drug : Polymer1:11:21:31:4
Emulsifier (%)1.51.51.51.5

5.2 Assay of propranolol hydrochloride
Propranolol HCl estimated by Ultraviolet visible (UV/Vis) spectrophotometric method (Simatzu-1608 UV/Vis double beam spectrophotometer, Japan).  Aqueous solution of Propranolol was prepared in pH 1.2 and absorbance was measured on UV/Vis spectrophotometer at 290 nm.The method was validated for linearity, accuracy, and precision. The method obeys Beer’s Law in the concentration range was 10 to 50 µg/ml. When a standard drug solution was analyzed repeatedly (n=3), the mean error (accuracy) and relative standard deviation (precision) were found to be 0.84 % and 1.2 % respectively.
 5.3 Determination of production yield and encapsulation efficiency.
Production yield of the microspheres was determined by accurately                        calculating the initial weight of the raw material (WR) and the last weight of the microspheres (WM) obtained. The ratio of WM to WR was then calculated and multiplied by 100 and expressed as a percentage. Encapsulation efficiency of the microspheres was estimated by dissolving accurately weighted portion from each batch in methanol and the actual drug content was determined using a UV –visible spectrophotometer (Simatzu 1608 UV/Vis double beam spectrophotometer) at a wavelength of 290 nm.
The percentage of en capsulation efficiency was calculated using equation (1) and (2)
  
 5.4 Particle size analysis of microsphere.
The mean particle size and size distribution of microspheres were determined by sieve analysis method. Sieve analysis was performed by shaking 16/22, 22/30, 30/44, 44/60, 60/80 Mesh arranged on a rotap sieve shaker at a frequently of 60 Hz for 5 minutes with a load of 10 gm of Microspheres on the top most sieve. Weight fiction retained on each sieve was noted. Size distribution was observed by % weight fraction passed from one sieve and retained on order.
The mean microspheres diameter was calculated by the method of meshali et al. microspheres diameter of fraction that is retained on each sieve was calculated by following formula.

Dm = 1/ (ΣXi/Di)
Where,
Dm= mean diameter of microsphere
Xi = the weight of a given fraction (in grams)
Di =the mean geometrical diameters of the microspheres of a given fraction which is equal to √D1 D2
Where,
D1 and D2    are opening size of the two sieves retaining in between a given size fraction.
5.5 Scanning electron microscopy.
Scanning electron microscopy was used to examine the shape and surface morphology of the ethyl cellulose microspheres. Samples of microspheres were dusted onto double –sided tape on an aluminum stub. The stubs were then coated with gold using a cold sputter coater to a thickness of 400 0A. The samples were imaged using a 20kV electron beam.   
5.6 Kinetic treatment of dissolution profiles74-78
5.6.1 Zero-Order:
In many of the modified release dosages forms, particularly controlled or sustained release dosages forms (those dosage forms that release the drug in planned, predicated and slower than normal manner), is zero-order kinetics.
m = k * t
Where, k is zero-order constant, m is % drug unreleased and t is the time. The plot of % drug released versus time is linear.

5.6.2 First-Order: 
Most conventional dosage form exhibits this dissolution mechanism. Some modified release preparations, particularly prolonged release formulations, adhere to this type of dissolution pattern.
m = ea * e-bt
Where, a is the intercept and b is the slope.
It assumes that the drug molecules diffuse out through a gel like layer formed around the drug during the dissolution process. A plot of log % drug released versus time is linear. 
5.6.3 Higuchi Model: 
A large number of modified release dosage form contain some sort of matrix system. In such instances, the drug dissolves from this matrix. The dissolution pattern of the drug is dictated by water penetration rate (diffusion controlled) and thus the following relationship applies:
m = 100-q * square root of time
Where, q is the Higuchi constant (% per square root of time). In Higuchi model, a plot of % drug unreleased (released) versus square root of time is linear.   
5.6.4 Korsmeyers and Pappas Model
The dissolution profiles obtained are treated with Korsmeyer and Peppas equation to get kinetic parameters , . A simple, semi-empirical equation was used to analyze data of controlled release of drugs from polymer matrices (Eq. 1).
Mt/M∞ = ktn
Where Mt is amount of drug release at time t, M∞ is total amount of drug present in formulation, k is release rate constant depend on geometry of dosage form and n is diffusion exponent indicating the mechanism of drug release, where for cylinder value of n is 0.45 indicate fickian diffusion, between 0.45 and 0.89 indicate anomalous transport and 0.89 indicate case-II transport.

Table: 5. Mathematical modeling and drug release kinetics of propranolol     
               hydrochloride from ethylcellulose microspheres and dispersible multiple 
               unit tablet formulations.
Batch
Code
Kinetic model
Zero-orderFirst-orderKorsmeyer
modelHiguchi
(Q√t)KnOrder of release
r 2R 2r 2r 2
F10.99690.98210.98940.99240.27880.4690Fickian
F20.99520.98480.98620.99360.24850.5122Non fickian
F30.99570.98490.98610.98420.24030.5209Non-fickian
F40.99430.98460.98480.98190.22920.5384Non- fickian
T10.99690.98120.99010.99280.27750.4718Fickian
T20.99570.97930.99030.99230.26100.4853Fickian
T30.99570.98150.98870.99020.24850.4987Fickian
T40.99380.97790.98940.99000.24230.5039Non fickian
T50.99690.98210.98960.99160.26980.4758Fickian 
T60.99770.98470.98800.99060.26390.4844Fickian
T70.99740.98490.98710.99000.25660.4853Fickian
T80.99770.98410.98830.99100.24080.5012Non fickian


5.7 Preparation of Dispersible multiple units Tablet. 
The microsphere formulations coded F1 was selected for tablet dosage forms based on their loading efficiency. Fight different batches of dispersible tablet containing varying concentrations of excipients and viscosity building agents were prepared (Table 3). Microsphere batch F1 (120mg propranolol hydrochloride) were mixed with Microcrystalline cellulose: Lactose (1:1) and sodium starch glycolate (40 #) in a polythene bag. The blend was thoroughly mixed with viscosity-building agent (sodium carboxymethylcellulose, Xanthan gum1 to 4 %) and other excipients like magnesium stearate(2%), aerosil 200(1%) (Table 3) for 1 min. The final mixture was compressed into tablets using 12-mm flat faced punch in Rimek rotary press. (Cadmech Machinery Ltd., Ahmedabad). The average weight of the tablets was 650mg and compression pressure was adjusted during tabletting of each formula upto 6 kg/cm2. 

Table:6. Composition of Tablet formulation Coded T1- T8
CompositionCoded and Quantity per Tablet (mg)
T1T2T3T4T5T6T7T8
Microsphere298298298298298298298298
MCC+ Lactose298285278.5272298285278.5272
SSG32.532.532.532.532.532.532.532.5
Sodium CMC6.51319.526----
Xanthan Gum--------6.51319.526
Magnesium stearate1313131313131313
Aerosil 2006.56.56.56.56.56.56.56.5

5.8 Evaluation of dispersible multiple unit tablets: 
         Hardness of prepared tablets was determined using Monsanto hardness tester (Shital Scientific Industries, Mumbai). The results are the average of 10 determinations. Friability was evaluated as the percentage weight loss of 20 tablets tumbled in a friabilator (model EF2, Electrolab, Mumbai) for 4 min at 25 rpm. The tablets then were dedusted, and the loss in weight caused by fracture or abrasion was recorded as percentage friability. Disintegration test was performed in a disintegration apparatus (model ED2, Electrolab, Mumbai, India) at 37ºC in 900 ml of distilled water for 6 tablets in accordance with the USP 24. The drug content of six formulations was calculated from the standard curve. Individually, assayed tablet should be within 95% to 105 % for propranolol hydrochloride of the labeled claim as per the standard compendium.
        
Table: 7. Physical characterization of multiple unit dispersible tablets

BatchHardness
(kg /cm2)Weight Variation (mg)Disintegration Time (Sec.)Friability
(%)Drug Content
(%)
T15.2651±0.43630.52100.3
T24.9650±0.41590.6899.12
T34.5        649±0.34650.62101.3
T45.2652±0.25580.71100.0
T55.9648± 0.21760.65103.4
T65.5651±0.11600.7099.28
T75.2649±0.32650.51100.1
T85.9650 ±0.41560.6799.97

5.8 In-vitro Drug Release Studies of dispersible multiple unit tablets
Dissolution study was carried out using type II (Paddle type) Electrolab TDT-06T dissolution test apparatus USP XXIV. The 900 ml of pH1.2 buffer was used as dissolution media for 2 h followed by 12 h study in 6.8 pH phosphate buffer. The pH of the medium was adjusted to 6.8 after 2 h by adding 4.32 g of sodium hydroxide and 6.08 g of potassium dihydrogen phosphate dissolved in 5 ml water. Temperature was maintained constant at 37 + 0.50 C. The stirring speed was kept at 100 RPM. Five milliliters of sample was withdrawn at specific time intervals, suitably diluted and filtered through whatman filter paper (0.7 μ size). The volume of the dissolution fluid was adjusted by replacing 5 ml of suitable dissolution medium after each sampling. The volume of the withdrawn samples was measured at 227 nm and concentration of the drug was calculated using standard curve equation. 

Table:8.Cumulative % drug release of ethylcellulose  microspheres batches F1 to F4
Time in hrF1F2F3F4
129.8826.6725.9224.88
238.1235.5234.533.12
343.0440.7339.3238.04
449.9746.2945.2343.97
559.5457.0756.1855.54
665.3260.0959.3958.32
769.0665.2364.4863.06
876.8577.3676.0675.85
981.6382.6281.1780.63
1086.4584.8384.9283.45
1190.1387.0286.6385.13
1295.1892.2391.1689.18
  

5.9 Stability studies of optimized batch of dispersible multiple unit tablets.
In order to determine the change in performance of dosage form on storage, stability study of optimized batch of dispersible multiple unit tablets was carried out at 40°C in a humidity jar having 75 % RH according to ICH35. Samples were withdrawn after three month and evaluated for change in drug release pattern. The similarity (f2) and dissimilarity (f1) factor was applied to study the effect of storage on batch .The release profile of sample put on stability study was depicted in Table 8 and Figure
5.10 Measurement of viscosity of suspension 
Dispersible tablet containing sustained release microcapsules and viscosity-building agent in contact with water disintegrate and form a uniform viscous suspension. For measurements of viscosity of different batches of tablet, Brook field Viscometer was used and the reading were recorded. Viscosity of the suspension was determined by using (LV) Brookfield Viscometer. As the system is non-newtonian, spindle no.3 was used. Viscosity was measured for the fixed time 2 minute for 6 RPM.
                             Dial reading x Factor = Viscosity (cps).


6. RESULT AND DISCUSSION 
6.1. Preparation of Microsphere
The emulsion –solvent evaporation method was used to prepare propranolol hydrochloride microsphere. Liquid paraffin was selected as a outer phase, since ethyl cellulose were very slightly soluble in liquid paraffin 80, 82. Acetone with a dielectric constant of 20.7 was chosen as a disperse (inner) phase because solvents with dielectric constants between 10-40 show poor compactability with liquid paraffin and the system of these solvents/ liquid paraffin was reported to a applicable to the micro encapsulation process 79,80,82,83. Emulsifying agents span80 was used in this study to reduce the inter-facial tension and prevent electrification ranged and flocculation during the preparation of the microspheres79, 83, 85, 86. Castor oil was used as a plasticizer in the microsphere formulations.87.
6.2 Determination of Production yield and encapsulation efficiency.
The encapsulation efficiency and production yield of propranolol hydrochloride-loaded ethyl cellulose microsphere are shown in table No.9 and figure No All microspheres formulations were produced with high production yield and encapsulation efficiency. The yield of the production ranged from 93.2-96.66. The encapsulation efficiency of microspheres was between 75.05- 80.40. The overall results have shown that ethyl cellulose is a suitable polymer for the encapsulation of a hydrophilic drug.    
When the production yield and encapsulation efficiency of the microspheres were investigated based on variation of the drug/polymer ratio .The encapsulation efficiency of the microspheres prepared with span 80 was not affected by variation in the drug/ polymer ratio. As the polymer amount was increased, the encapsulation efficiency of the microspheres decreased. This phenomenon was due to the fact that higher polymer amounts produced smaller size droplets and since smaller droplets have a larger total surface area, the diffusion of the drug from them is faster and more of the drug is lost, resulting in the formulation of microspheres with a lower drug contents84. 

Table: 9 Properties of microsphere formulations.
CodeTheoretical drug yield  (w/w)Actual drug yield  (w/w)Encapsulation efficiency (%)Production yield (%)Mean Diameter (µm)
F15040.280.4093.2500.18
F233.3325.6676.9894.6465.5
F325.0018.2172.8496.66395.7
F420.0014.271.0595.88390.1

 Table: 10.Dissolution profiles for dispersible multiple unit tablet T1-T8
Time (hr)Cumulative percentage release
T1T2T3T4T5T6T7T8
00000000000000000
129.6827.8826.8825.8828.8828.5827.8826.18
238.0236.1234.1234.137.1236.1235.1233.12
343.1441.0440.0439.0442.0441.5840.0438.87
449.9747.9745.9744.9748.9747.9746.9744.34
559.5957.5455.5454.5458.5457.4455.5453.23
665.3263.3262.3262.1263.3263.3262.3260.36
769.0866.0664.0663.0667.0667.0665.0664.19
876.8874.8573.8572.8575.8575.8573.8571.38
981.6478.6377.6375.6380.6380.6378.6375.76
1085.5683.4582.4581.4584.4583.4582.4580.11
1191.488.1387.1386.1390.1389.1386.13  84.78
1297.5895.1893.6894.1896.1894.1892.1890.18

6.3 Particle size analysis of microspheres
Mean particle sizes of all microspheres are shown in Table. Particle size analysis of the ethyl cellulose microspheres propranolol hydrochloride showed that the mean microsphere diameter was affected by the drug/polymer ratio for all formulations. A reduction in microsphere size was observed with increasing polymer ratio and decreasing drug amount. Increasing the ratio of the polymer caused a decrease in the particle size of microspheres. As the drug amount was increased and the polymer ratio decreased (drug/polymer ratio 1/1), a more viscous internal phase occurred. During the emulsification process, the internal phase was hardly dispersed in the outer phase and larger microspheres were produced. When the drug amount was decreased as the polymer ratio increased (drug/polymer ratio 1/2, 1/3, 1/4), the size of microspheres decreased due to the reduced viscosity of the internal phase. These findings are similar to the results reported previously79,81.
The particle size distribution of the microspheres prepared with emulsifying agents, Span 80 is shown in Figure and Table 3. 
6.4 Scanning electron microscopy
The shape and surface characteristics of the microsphere formulations coded F1 is shown in Figures7.The drug-loaded ethyl cellulose microspheres were spherical in shape and no drug crystals were found on the microsphere surface. The microspheres prepared with a 1/4 drug/polymer ratio had a smoother surface than that of the microspheres prepared with a 1/1 drug/polymer ratio. Irregular surfaces and larger sizes were observed in the microspheres prepared with a drug/polymer ratio of 1/1.
This result showed that the drug/polymer ratio extensively affected the morphological characteristics of the ehylcellulose microspheres. As the polymer ratio was increased, more spherical microspheres with a smooth surface were obtained. This result is similar to that mentioned previously 79.
The shape and surface characteristics of microspheres prepared with Span 80 are shown in Figures 7. The microspheres had a compact structure and smooth surface.
 6.5 In vitro release study
The release profiles of propranolol hydrochloride microspheres prepared with Span 80 was depicted Figure 6. As the polymer concentration increased from 1/1 through 1/4, the drug release rate decreased dramatically, depending on the drug-to-polymer ratio. Increasing the polymer amount in the formulation resulted in a decrease in the dissolution rate, thereby increasing the distance that the drug passed through the surface of the microspheres. This finding is in agreement with previous works79, 80.82,88,89.
In order to obtain meaningful information for the release models, the drug release data were kinetically evaluated and the fitness of the release profiles to the four different kinetic models, zero order, first order, krosmeyers and Higuchi (Qpt) was investigated. The selection was based on the comparison of higher determination coefficient. The release profiles for all microsphere formulations were best characterized by the Zero order model. When the microspheres were immersed into the dissolution medium, they swelled with absorption of water into their matrix and formed a gel diffusion layer. This layer hindered the outward transport of the drug, producing a diffusion controlled release effect90. The release profiles for all dispersible multiple unit tablet formulations were best characterized by the Zero order model. Drug release kinetics of propranolol hydrochloride from ethylcellulose microspheres and dispersible multiple unit tablet formulations were depicted in table 5.
6.6 Dispersible multiple unit tablets 
Propranolol hydrochloride microspheres were tabletted using MCC, Lactose and sodium starch glycolate (5%). Propranolol hydrochloride microspheres and fillers like MCC and lactose (1:1) were given the good cushioning effect on mcrospheres of dispersible multiple unit tablet without creating any picking and sticking problem. The results of in vitro release studies are shown in figure and table. The release data showed that the release from dispersible multiple unit tablets were reducing with increasing the concentration of suspending agent. This is because of the reason that an increase in concentration of suspending agent increase viscosity, which in turn reduces the rate of diffusion. All the dispersible tablet formulation (T1-T8) showed uniformity of drug release within 12 hrs. The dispersible multiple unit tablets prepared with 4 % concentration of Xanthan gum showed maximum sustaining effect and release only 90.18 of drug at the end of the 12h. All the batches of tablets not observed significance difference in drug release. Dispersible multiple unit tablets also contain suspending agents like Sodium CMC, Xanthan gum, (1 to 4%) were used. Dispersible multiple unit tablets are formed which is rapidly disintegrated with the contact with the aqueous phase and form viscous colloidal suspension of drug microspheres. Viscosity of all the tables batches were depicted. Dispersible multiple unit tablets contining  1%, 2%, 3% suspending agent shows lower viscosity and 4% suspending agent gives excellent viscosity with the contact with  aqueous phase. Among them 4% xanthan gum, gives excellent viscosity (875 cps) with water and form a viscous suspension contains drug microspheres that avoid the settle down of microspheres in the suspension up to 30 minutes.The present formulation may reduce the disadvantages imposed by other drug delivery systems and conveniently administer to the patient like children and elders. All the parameters regarding to evaluation of dispersible multiple unit tablets as hardness, disintegration time, Friability, and drug content were in acceptable range.

Table: 11. Viscosity measurement of different formulation batches.
Formulation CodeViscosity in CPS
T1248
T2421
T3502
T4578
T5345
T6546
T7685
T8875

6.7 Optimized batch from dispersible multiple unit tablet.
The selection of the best batch depends on disintegration time, tablets forms uniform suspension, drug release of dispersible tablet, Among the eight batches of the dispersible multiple tablet, batch T8 showed uniformity of drug release of 90.18 within 12 hrs and rapidly disintegrates within 57 second and gave excellent viscosity with the contact aqueous phase and form a viscous suspension contains drug –resinate microsphere that batch considered as ideal formulation for the stability studies.
6.8 Stability study of optimized batch
Amongst tablet batches of microspheres, batch T8 have more desirable tablet demonstrate 90.18 % release during the 12 hour release study. The value of diffusion exponent was 0.512 which indicate that the release was anomalous diffusion based and the release during the first hour of dissolution study was 26.58 %. Hence the dispersible multiple unit tablet of batch T8 was considered as promising batch for accelerated stability study. From the results of stability study, it was observed that the batch T8 dispersible multiple unit tablets was stable for the three months at 400C, 75 % relative humidity as specified by the ICH guidelines (Table 12). Comparing the dissolution profile of freshly prepared batch with the dissolution profile of the tablet stored for the three months, the f1 and f2 value were found to be 2.30 and 87.23 respectively. The low value of f1 and f2 value between 50 and 100 indicates the good correlation between the two batches.
 Table:12. Dissolution profiles of batch T8 evaluated for stability study

Time in hrsCumulative percentage drug release

Fresh  sampleAfter 3 month
126.1827.12
233.1235.24
338.8739.03
444.3445.43
553.2354.22
660.3661.34
764.1966.01
871.3873.08
975.7677.87
1080.1183.08
1184.7888.45
1290.1895.34

7. CONCLUSION:
Present study was undertaken to provide an oral composition, which overcomes the drawbacks of conventional oral formulations of active substances by combining particles containing an active substance with a gelling or swelling agent, which is hydrated in the presence of an aqueous solution to form a viscous medium surrounding the particles. Such a dispersible tablet is formed which is rapidly disintegrates in contact with water and forms viscous colloidal suspension of sustained release microspheres. Dispersible tablet containing F1 formulation sustained the release effects up to 12 hours and was capable to resist deformation imparted by the compression forces at the time of tableting, with use of cushioning agent MCC:Lactose (1:1).The release mechanism of propranolol hydrochloride  from microspheres and tablets shows values of n lies between 0.489 to 0.528 in the formulation exhibiting a non-fickian release behavior controlled by combination of diffusion and chain relaxation mechanism.  Dispersible multiple unit    Tablet batch-T8 give containing 4% Xanthan gum as a viscosity building agent, which gives excellent viscosity with water and form a viscous suspension containing sustained release pellets that avoid the settle down of pellets in the suspension up to 30 minutes. The present formulation may reduce the disadvantages imposed by other drug delivery systems and conveniently administer to the patient like children and elders.

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muath  |  13-Nov-2010 03:12:45 IST
i want to participate in this good subject
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