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International Journal of Universal Pharmacy and Bio Sciences 3(2): March-April 2014

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***

ICV 5.13***

Pharmaceutical Sciences REVIEW ARTICLE……!!!

A REVIEW ARTICLE ON: SUSTAINED RELEASE DRY SYRUP

Mehul Patel*, Dr. M.R.Patel, Dr K.R.Patel

Department of Pharmaceutics, B. M. Shah College of Pharmaceutical Education and Research,

Modasa, Gujarat, India.

KEYWORDS:

Pellets, Dry syrup,

Extrusion-spheronization,

Sustained Release.

For Correspondence:

Mr. Mehulkumar

Parshottambhai Patel*

Address:

Shri B. M. Shah College

of Pharmaceutical

Education and Research,

College Campus,

Modasa -383315,

Gujarat, India

Mobile- +91-8347693244

E-mail ID:

[email protected]

ABSTRACT

Mainly controlled release dosage forms are used to release drug or

API in a controlled manner to the specific site of the body. Oral route

are mainly used for controlled delivery of drug. Suspensions are

taken orally as well as other route to body. Now a day controlled

release suspension are available in market. Controlled release

suspension are prepared by various techniques like ion-exchange

resin complex, microencapsulation, Emulsion–solvent evaporation

(o/w, w/o, w/o/w), Polymerization by phase separation methods,

microspheres, extrusion-spheronization. By these techniques prepare

granules, microcapsule, pellets which have ability to give controlled

action of the drug to the specific site of the body. For preparation of

these types of granules use various types of a polymer of a specific

grade. It has a several advantages like Minimum drug accumulation

in body, Utilization of drug is better way and reduction in total

amount of drug, Reduction in fluctuation of drug level, more uniform

pharmacological response and less reduction in drug activity,

Improvement in drug therapy, uniformity of drug in blood plasma

concentration, Improve the bioavailability of some drugs etc.



INTRODUCTION:

1. Introduction to Sustained Release Drug Delivery System 1

The oral route drug delivery is the most patient convenient means of drug administration. It is widely

accepted approach of drug delivery system compared to conventional immediate release formulation of the

drug. Traditional drug delivery system has been characterized by immediate release and repeated dosing of

drug and that related to dose fluctuation and this creates the next door for sustained release drug delivery

system which provides drug release for extended period of time , enhance bioavailability constant blood

plasma concentration and that’s results in patient compliance. Numbers of sustained release dosage forms

are available as membrane controlled system, matrices with water soluble/insoluble polymers or waxes and

osmotic system. Sustained release formulation requires generally short half life of the drug.

To identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by

continuously releasing medication over an extended period of time after administration of single dose

various terms are used like sustained release, sustained action, prolonged action, controlled release,

extended action, timed release, depot and repository dosage forms etc.

In injectable dosage forms, this time may vary from days to months where as in case of orally administered

dosage forms; this period is measured in hours which depend on the residence time of the dosage form in

the gastrointestinal tract.

Sustained release systems achieve slow release of drug over an extended period of time. System which

control constant drug levels in the blood or in tissue it is considered as a controlled release system. If the

system is not achieve sustained release but extends the duration of drug release over that achieved by

conventional delivery , it is considered as a prolonged release system.

Problems occur during multiple dosing: 1

According to the drug biological property, the dosing interval between the two doses is not proper.

Half life, than it may create fluctuation of drug plasma concentration.

The drug plasma level will not remain in therapeutic range because of inappropriate dosing, results in

toxicity.

Patient’s inconveniency, that can be result in missed doses that may be non compliant to the therapy

Goal for designing sustained release system 2

The major goal set in designing sustained or controlled delivery is to:

Reduce the frequency of dosing.

Providing the uniform drug delivery.



Increase the effectiveness of the drug by localization at the site of action.

Less fluctuation in blood plasma level.

Properties of drug to be select as sustained release dosage form: 1

The following properties are to be required for the drug to formulate as sustained release delivery system:

Table 1: Physicochemical properties for drug

Parameter Preferred value

Solubility >0.1mg/ml for pH1 to pH7.8

Molecular weight <1000 Daltons

Absorption mechanism Diffusion

General absorbability From all GI segments

Apparent partition coefficient High

Release Should not be influenced by pH and

enzymes

Table 2: Pharmacokinetic properties for drug

Parameter Preferred value

Elimination half life Between 2 to 8 hrs

Elimination rate constant Required for design

Total clearance Should not be dose dependent

Absolute bioavailability Should be 75% or more

Intrinsic absorption rate Must be greater than release rate

Apparent volume of distribution (Vd) The larger (Vd) and MEC, the larger will

be the required dose size

Therapeutic concentration Css The lower Css and smaller Vd, the loss

among of drug required

Advantages of sustained release formulation: 1

Utilization of drug is better and reduction in total dose of drug.

Reduction in fluctuation of drug level, more uniform pharmacological response and less reduction in

drug activity with chronic use.

Improvement in drug therapy, uniformity in blood plasma concentration.

Improve the bioavailability of some drugs, protection of drug from enzymatic inactivation by

encapsulation in polymer systems.

Reduction in gastrointestinal irritation due to decrease in local and systemic side effects.

Less frequent dosing, reduce night-time dosing, reduced patient care time that’s result in improved

patient compliance.



Disadvantages of sustained release dosage form: 1

Retrieval of drug is difficult in case of toxicity, poisoning or hy1persensitivity reactions.

Because of, increased first-pass metabolism, incomplete release, increased instability, site specific

absorption, ph dependent stability results in reduction of systemic availability rather than immediate

release dosage form.

Potential for dose adjustment of drug is reduced due to, administration is occurred in different strengths

Poor in vitro-in vivo correlation.

Factors influencing oral sustained release dosage form design: 1

A. Biological factors:

1. Biological half-life:

Drug having 2-8hrs of biological half-life, is good candidate for sustained release dosage form,

reducing dosing frequency. But, it’s limited to short half-life containing drugs that required excess

amount of drug to maintain its sustain effects. Drug with very short half-life will require large amounts

of drug to maintain sustained effects, thus making the dosage form itself to become too large to be

administered. Compounds with relatively long half lives , generally greater than 8 hours are generally

not used in sustained release dosage forms since their effect is already sustained.

GI transit time is 8-12 hrs so, drug candidate with half life greater than 8 hrs are generally not used in

sustained release dosage forms. In short drugs with shorter half life become the good candidate for

sustained release dosage form.

2. Absorption:

Absorption rate depends on the releasing rate of the drug from the formulation. If the drugs absorbed by

active transport, the intestinal absorption is limited.

Absorption of a drug can greatly affect its suitability as a sustained release product. Assuming the

transit time of most drugs and devices in the absorptive regions before release is complete. The

absorption rate constant is an apparent rate constant. It should in actuality be the release rate constant of

the drug from dosage form.

3. Distribution:

Distribution of drug into tissues is an important parameter for the drug elimination. It not only lowers

the circulating drug concentration but, it be a rate limiting step in its equilibrium with blood and extra

vascular tissue, apparent volume of distribution seems various values depending and time of drug

disposition.



4. Metabolism:

Since as long as the location, rate, and extent of metabolism are important to develop sustained release

formulation. The metabolic conversion to a drug is to be considered before converting into another

form.

Drugs that metabolized especially in the region of the small intestine can show decreased

bioavailability from slower releasing dosage forms. This happen because of saturation of intestinal wall

enzyme systems.

B. Physiological factors:

1. Dose size:

500-1000mg of dose is considered to be maximum for conventional and also to sustained release

formulation. Safety involved in administering of large amounts with narrow therapeutic range is more

important for the recommendation of dose size

2. Ionization, pka and aqueous solubility:

Most of the drugs are weak acid or base and for absorption the drug must dissolve in aqueous media

surrounding the site of administration and partition in to absorbing membrane.

The pH partition hypothesis simply states that the unchanged form of a drug species will be

preferentially absorbed through many body tissues therefore it is important to note the relationship

between pKa of the compound and its absorptive environment. For many compounds the site of

maximum absorption will also be the area in which the drug is least soluble. For conventional dosage

forms the drug can generally fully dissolve in the stomach and then be absorbed in the drug will arrive

in the small intestine in solid form. This means that the solubility of the drug is likely to change several

orders of magnitude during its release.

3. Partition coefficient:

Biological membrane is lipophilic in nature; the transport of drug across the membrane depends on the

partition coefficient of drug. Low partition coefficient of drug, poor candidate for sustained release

dosage form, eg: barbituric acid.

4. Drug stability:

When drugs are orally administered, they come across acid-base hydrolysis and enzymatic degradation.

If the drug is unstable in acid media, the system can be formulated in a way to provide drug release for

entire period of time. Instability in basic media relates to less bioavailability of drug.



Design of oral sustained release dosage form: 1

The oral route is mostly accepted route due to its design, comfortness to dosage form and patient care.

Consideration of various parameters before formulating sustained release dosage form like as, the GIT

motility, various ph in GIT, The presence of enzyme system and its effect on dosage form, and the

drug. Mechanism of action is diffusion, dissolution or combination of both. As like IV infusion,

sustained release dosage form should release the drug by zero-order mechanism which maintains

constant drug plasma concentration.

Plasma drug profile for conventional formulation, SR formulation and zero-order SR formulation are as

shown in figure1.

Figure 1: plasma drug concentration profile for conventional release, a sustained release and zero order

controlled release formulation

Figure 2: Comparison of conventional and controlled release profiles

Evaluation of sustained release formulation 4

In-vitro Data

The data is generated in a well designed reproducible in-vitro test such as dissolution test. The method

should be sensitive enough for discriminating any change in formulation parameters.



The key elements for dissolution are:

Reproducibility of the method.

Maintenance of sink condition.

Proper choice of media.

Control of solution hydrodynamics.

Selection of the most discriminating variables (media, pH, rotation speed etc.) as the basis for

dissolution test and specification.

In-vivo Data

This data consists of the following:

Evidence of reproducible in-vivo performance

Pharmacokinetic profile of the test product and reference product.

Bioavailability data either comparable to the reference dosage form with same labeling indications and

sane effects or non-equivalent to the reference dosage form with demonstration of safety and efficacy

and different labeling.

2. Introduction to Dry Syrup 6-7

Generally pediatric and geriatric patients have difficulty to swallowing solid dosage forms hence liquid

dosage forms are easy to administer. Metformin HCl is soluble in water hence formulation of a suspension

will be most suitable but product may not be physically and chemically stable because metformin HCl is

hygroscopic in nature. In the present work, attention is paid to develop a suspension dosage form of

metformin HCl.

Dry syrups are commercial dry mixtures that require the addition of water at the time of dispensing.

Antibiotics are the most commonly prepared as a dry suspension. The dry syrup is prepared commercially

using drug, colorants, flavors, sweeteners, stabilizing agents and preserving agents that may be need to

enhance the stability of the formulation.

Various commercial and official preparations are available as dry granules or dry powder mixtures which

are intended to be suspended in water or some other vehicle before administration.

Generally prepared granules are packed in sachets which must be taken as a suspension in a glass

containing needed amount of liquid, water is widely used as media.

Studies have confirmed that the dry oral suspension after reconstitution in a liquid is stable for 24 hours

after preparation, although it is recommended that the suspension should be consumed immediately after

preparation.



Advantages of dry oral suspension over liquid oral suspensions:

Advantages of dry granules:

Convenience of single dose regimen

As a single dose sachets, accurate single dosing is possible

Independent of physical factors i.e. drug dose is independent from temperature, sedimentation rate and

liquid flow properties.

A sachet which is aluminium foils packing which makes the formulation stable and easy to carry.

By adding coloring, flavoring, sweetening agent to the formulation, it is very convenient for pediatric

patients to take the medication.

Stable on storage and when constituted with ingestible liquid for administration, the corresponding

liquid suspension is stable for the time in which the therapy is necessary.

Palatable

Widely accepted in pediatric patients all over the world.

Disadvantages of liquid oral suspensions:

Inaccurate single dosing because it is available as bulk formulation

Major problem associated with this is caking upon storage.

Drug dose dependent on various physical factors of dosage form i.e. temperature of storage, liquid flow

properties- viscosity, flocculation, pour ability, redispersion.

Stability of liquid suspension mainly depends on the temperature of storage, sedimentation rate of the

formulation and content uniformity.

Administration is inconvenient.

Commonly used ingredients in dry syrup:

Commonly used ingredients in dry syrup formulation include suspending agents, wetting agents,

preservatives, sweeteners, flavor, buffer, color.

Suspending agents: suspending agents plays an important role in reconstitution.

It should be easily dispersed on shaking during reconstitution.

Microcrystalline cellulose with CMC

Acacia

Xanthan gum

Tragacanth

Car boxy methyl cellulose sodium



Propylene glycol alginate

Most commonly used suspending agent is the combination of microcrystalline cellulose and sodium CMC.

Sweeteners

Sweeteners are key ingredients in these formulations because sweeteners can mask the unpleasant taste of

the drug and also enhance patient acceptance in the pediatric patients that uses this product.

A commonly used sweetener includes mannitol, sucrose, dextrose, aspartame, sodium saccharin.

Wetting agents

Generally in suspension drugs are hydrophobic and not easily wetted which will repel water.

Surfactants are widely used to help the dispersion of hydrophobic drugs in suspension but excess wetting

agent can produce foaming and produce unpleasant taste to the formulation.

Commonly used wetting agents are polysorbate 80, sodium lauryl sulfate.

These agents are generally used in concentrations < 0.1 %.

Other ingredients

Preservatives, Buffers, Flavors & colors

Suspending agents and sweetener are good growth media for microorganisms so to overcome this problem

it is necessary to use preservatives in most suspensions. Examples: sodium benzoate, sucrose in sufficient

concentrations (60%w/w).

PH of the all ingredients are generally maintain by using appropriate buffers. Example: sodium citrate

buffer.

Various natural and artificial flavors are used in the formulation. Example: pineapple, vanilla, Raspberry.

Sometimes various natural and artificial colors are also used to make the preparation good in appearance

and more attractive. Example: Yellow No 6 and FD & C Red No 40.

Preparation of dry mixture

Granulated products

Powder blends

Combination products

Granulated products

In this wet granulation is the commonly used process and water is used as granulating fluid or an aqueous/

non aqueous binder solution.

Drug and other required materials can be dry blended or it can be dissolved or suspended in the granulating

fluid.



Solid ingredients are blended and massed with granulating fluid.

Wet mass is formed into pellets or granules forms using Extrusion spheronization machine or oscillating

granulator or mill.

Pellets or granules dried in a hot air oven

Dried pellets or granules screened in a vibratory sieve or oscillating to break up or remove aggregates or

granules.

Advantages

Improvement in appearance

Less segregation problems

Improvement in flow characteristics

Volume of dust generation during filling operations are quit less

Disadvantages

Uniformity in granule size is necessary excess of small particles will results in rapid segregation.

We can’t add Heat sensitive ingredients such as flavors before drying of granules.

More energy is required for process.

Powder blends

In this ingredients of the dry mixture are mix in powder form.

Ingredients with small quantities may need two stage mixing operation.

It should rapidly produce a homogeneous mixture.

Advantages

Less chance to have chemical and stability problems because no heat or solvents are used.

Low moisture content can be achieved

Required less energy

Disadvantages

During mixing there is a chance of loss of active ingredients

Potent drug can be used in a very low concentrations

Combination product

In this less energy and equipment for granulation may be required if majority of the diluent can be

added after granulation.

One of the advantages using this technique is, heat sensitive ingredients such as flavors can be added

after drying of granules.



In these methods first granulate some of the ingredients and blend the remaining ingredients with the

dried granules before filling into container.

Disadvantages

Uniformity in particle sizes of various fractions is the main problem here.

Recommended guidelines for processing the dry mixture

Mixing should be efficient

Determine an adequate duration of mixing time

Avoid accumulation of heat and moisture during mixing.

Limit temperature/humidity variations {70c at <40% RH}

Final batch should be protected from moisture.

3. Introduction to Extrusion Spheronization Technique

Introduction to pellet 6

In present times, the pelletization technologies are going much attention as they represent an efficient

pathway for manufacture of oral drug delivery systems. This is due to the reason that pellets offer many

therapeutic, technological as well as biopharmaceutical advantages over the conventional oral dosage

forms. Pelletization leads to an improvement in flowability, appearance and mixing properties thus

avoiding generation of excessive dust and reducing segregation, and generally, eliminating undesirable

properties and improving the physical and chemical properties of fine powders. Pellets are produced by

various techniques such as extrusion/spheronization, layering, Cryopelletization, freeze pelletization, spray

drying, spray congealing, and compression. Amongst various techniques, extrusion/spheronization

technique is the most widely utilized technique due to its high efficiency and simple and fast processing.

Pellets 6

Pellets for pharmaceutical applications are defined as spherical/semi-spherical, free flowing solid units with

a narrow size distribution, typically varying in diameter between 500 and 1500 μm. Due to their various

advantages, pellets have gained considerable attention in development of both immediate release and

modified release dosage form. In the pelletization process there is agglomeration of fine powders of drug

and excipients in to small spherical units.

Pellets should possess these ideal properties:

Spherical shape and smooth surface texture

Particle size in range of 500-1500 μm.

The quantity of the active ingredient should be maximum so as to maintain the pellet size.



Advantages of pellets

Improved appearance of product

Improved flow properties and ease of packing resulting in uniform and reproducible fill weight of

tablets and capsules

Improved safety and efficacy of active ingredient

Decreased handling hazards and easier transport

No crystallization or precipitation of solution and suspensions

High bulk density

Little abrasion and decreased friability

Uniform size with narrow size distribution

High drug loading capacity without producing extensively large particles.

When formulated as modified release preparation, pellets are less susceptible to dose dumping thus

lowering the risk of side effects.

They also reduce accumulation of drugs.

Pellets disperse freely in GIT fluids due to their small size, providing larger surface area for drug

absorption and also reduce peak plasma level fluctuations.

Pelletization can be used for taste masking of unpalatable drugs.

In chemical industries, pelletization provides an effective method of avoiding powder dust.

Disadvantages of pellets

Pellets are rigid and so cannot be pressed into tablets.

The production of pellets is quite an expensive process due to the requirement of highly specialized

equipment and trained personnel.

The control of production process is difficult.

Pelletization 7

Pelletization can be defined as an agglomeration process for converting fine powders or granules of bulk

drugs or excipients into small, free flowing, spherical or semi-spherical units, referred to as pellets. Pellets

are oral dosage forms consisting of multiplicity of small, discrete units, each exhibiting their desired

characteristics.

Pelletization techniques11

Pelletization by extrusion spheronization

Drug layering



Cryopelletization

Freeze pelletization

Globulation

Compression

Balling

Extrusion spheronization 8,10

Compared to single-unit dosage forms, oral multi-particulate drug-delivery systems (e.g. pellets, granules)

offer biopharmaceutical advantages in terms of a more even and predictable distribution and transportation

in the gastro-intestinal tract. There are different pelletizations and granulation techniques available to

prepare drug loaded spherical particles or granules. Extrusion Spheronization is one of them and utilized in

formulation of beads and pellets.

Limitations related to bioavailability and site specific drug delivery can be overcome by this technique.

Extrusion spheronization is widely applied method for the production of multi-particulates, like pellets and

beads, for the oral controlled drug delivery system. Today this technology has gained attention because of

its simple and fast processing.

Extrusion spheronization is widely utilized in formulation of sustained release, controlled release delivery

system.

Controlled and sustained release of drug application within the pharmaceutical industry require consistent

smooth surface with a narrow size distribution, to ensure uniform coating and accurate free flow of

granules for filling operations (like capsule filling ), and this can be achieved by extrusion-spheronization

technique. It is also possible to prepare a sustained release pellets without coating of the pellets by

extrusion spheronization process.

The main objective of the extrusion-spheronization is to produce pellets/spheroids of uniform size with

high drug loading capacity. Extrusion spheronization is a multiple process of wet mass extrusion followed

by spheronization to produce uniform size spherical particles, called as spheroids, pellets, beads or matrix

pellets depending upon the material as well as process used for extrusion-spheronization. Extrusion

Spheronization has been used in agrochemicals, detergent additives, sweeteners, food and now it is used in

pharmaceuticals.

Extrusion-spheronization is primarily used for the production of multi-particulates for oral controlled

drug delivery system. It is more labor intensive than other granulation method, but it is useful when

uniform spherical shape, uniform size, good flow properties, reproducibility in packing, high strength,



low friability and smooth surface of granules is desired. Extrusion-spheronization process has gained

worldwide attention because it is a simple and fast processing technology. Any pharmaceutical

products utilize pellets or beads as a drug delivery system can be effectively produced by the extrusion

spheronization process. Wet mass extrusion and spheronization is established method for the

production of spherical pellets, and are coated effectively to achieve controlled release product. The

pellets or beads produced by the extrusion-spheronization offer the following advantages over

conventional drug delivery system.

It Produces spheroids with high loading capacity of active ingredient without producing extensively

large particles.

It produces particles of uniform size with narrow size distribution and good flow properties.

Successful coating is applied to spheroid because of its spherical shape and low surface area to volume

ratio.

Pellets composed of different drugs can be blended and formulated in single unit dosage form that

facilitates delivery of two or more chemically compatible or incompatible drug at the same or different

site in GI tract.

Pellets are frequently used in controlled release delivery system as it facilitates free dispersion of

spheroids in the GI tract and offer flexibility for further modification.

It improves the safety and efficiency of active ingredient.

It helps to increase bioavailability of drugs by controlling or modifying the release rate of drugs.

Process of extrusion and spheronization10

Extrusion spheronization follows mainly five steps that is mixing or blending, extrusion, spheronization,

coating and finally drying, which can be explained/described as

Dry mixing of ingredient to achieve homogenous powder dispersion.

Wet massing to produce a sufficient plastic mass.

Extrusion to form rod shaped particles of uniform diameter.

Spheronization to round off these rod shaped particles into spherical particles with narrow size

distribution.

Drying to achieve desired final moisture content.

And screening to obtain desired size of spheres/pellets

Extrusion/spheronization begins with extrusion process in which the wet metered mass is placed into the

extruder where it is continuously formed into cylindrical rods of uniform size and shape. Amount of



granulating fluid and uniform dispersion of fluid plays an important role in preparation of wet mass as

optimum plasticity and cohesiveness directly affect the final production of pellets.

Once the extrudates are prepared, they are then taken to spheroniser where it is spheronized or rotated at

higher speed by friction plate that breaks the rod shaped particles into smaller particles and rounded them

to form spheres. The size of the spheroids is mainly depending upon the diameter of circular die that

modifies the diameter of cylindrical rods produced in extrusion stage. Based upon the type of feed

mechanism used to transfer the mass towards the die, extruders are divided in three class i.e. 1) Screw feed

extruder [axial or end plate, dome or radial].2) Gravity feed extruder [cylindrical roll, gear roll, radial] .3)

Piston feed extrude [ram] (generally utilized for experimental development.

The quality of pellets is highly influenced by the process parameters associated mainly with the extrusion

stage and is widely studied by various research scientists. When comparison studies of spheroids produced

from ram extruder and cylindrical extruder with fillers of different particle size were evaluated, it was

concluded that the different extruder influences the final spheroidal size. The studies showed that

differences in uniformity of spheroids are associated with the rate of shear and the shear stress applied by

extruder. Parameters such as morphology, size distribution, porosity, sphericity etc influences the release

profile and stability of pellets while the formulation parameters such as presence and absence of soluble or

insoluble fillers, surface active agents, pH adjusters, drug load, ratio of filler and drug influences release

profile.

Drug layering 7

Layering a suspension or a solution of a drug on a seed material (usually, a coarse crystal or non-pareil) can

produce pellets that are uniform in size distribution and generally posess very good surface morphology.

These characteristics are especially desirable when pellets will be coated for the purpose of achieving a

controlled release.

The equipment employed for this kind of processes consists of custom modified conventional coating pans

(perforated pans) and various configurations of fluidbed equipment.

There are many factors that determine the economic and performance feasibility of pellet coating. Besides

the process variables mentioned before, there are other formulation variables, such as the drug solubility in

the media used for solution layer-or the suspension concentration in solid particles for the suspension

layering of the pellets, which need to be taken into account.



Cryopelletization 6

Cryopelletization is a process whereby droplets of a liquid formulation are converted into solid spherical

particles or pellets by using liquid nitrogen as the fixing medium. The technology, which was

initially developed for lyophilization of viscous bacterial suspensions, can be used to produce drug-

loaded pellets in liquid nitrogen at -1600C.

The procedure permits instantaneous and uniform freezing of the processed material owing to the rapid

heat transfer that occurs between the droplets and liquid nitrogen. The amount of liquid nitrogen

required for manufacturing a given quantity depends on the solids content and temperature of the

solution or suspension being processed.

The equipment consists of a container equipped with: Perforated Plates a Reservoir Conveyor belt with

Transport baffles Storage Container the perforated plates generate droplets that fall and freeze

instantaneously as they come in contact with the liquid nitrogen below. The frozen pellets are

transported out of the nitrogen bath into a storage container at -600C before drying.

Freeze pelletization 6

Freeze pelletization is a novel and simple technique in which a molten solid carrier along with a dispersed

active ingredient is introduced as droplets in to an inert and immiscible column of liquid.

There are less process variables involved and also various advantages over other pelletization techniques in

terms of quality of pellets and process cost.

Pellets with a narrow size distribution can be produced with this technique.

Drying is not required as pellets are solid at room temperature.

The solid carriers are introduced as droplets in molten state into the immiscible liquid column. Depending

on their density with respect to the liquid in the column, the droplets can move either in upward or

downward direction and solidify into spherical pellets.

Two types of equipments are used

In case of freeze pelletizer I the molten solid carrier are introduced from the upper portion of the column

because density of the solid carrier is more than the density of the liquid used in the column and the carriers

solidify in the bottom portion.

In case of freeze pelletizer II the molten solid carrier is introduced from the bottom of the column because

density of the solid carrier is low as compared to the liquid used in the column and the carrier solidify at

the top.



Globulation 6

Spray Drying and Spray Congealing, also known as Globulation process, involve atomization of hot

melts, solutions, or suspensions to generate spherical particles or pellets. The droplet size in both

processes is kept small to maximize the rate of evaporation or congealing, and consequently the

particle size of the pellets produced is usually very small.

Spray Drying:

The drug entities in solution or suspension are sprayed, with or without excipients, into a hot air

stream to generate dry and highly spherical particles. As the atomized droplets come in contact

with hot air, evaporation of the application medium is initiated. This drying process continues

through a series of stages whereby the viscosity of the droplets constantly increases until finally

almost the entire application medium is driven off and solid particles are formed. Generally, spray-

dried pellets tend to be porous.

Spray Congealing:

This process consists of suspending the particles in a molten coating material and pumping the

resultant slurry into a spray dryer in which cold air is circulated. The slurry droplets congeal on contact

with the air. The coating agents normally employed is low melting materials such as waxes. The

congealing process require higher ratio of coating agents to active material than does the spray drying,

because only the molten coating agent constitutes the liquid phase.

Compression 6

Compression is one type of compaction technique for preparing pellets. Pellets of definite sizes and shapes

are prepared by compacting mixtures or blends of active ingredients and excipients under pressure. The

formulation and process variables controlling the quantity of pellets prepared are similar to those used in

tablet manufacturing.

Balling 6

Balling is the pelletization process in which pellets are formed by a continuous rolling and tumbling motion

in pans, discs, drums or mixtures. The process consists of conversion of finely divided particles into

spherical particles upon addition of appropriate amounts of liquid.

LITERATURE REVIEW

1. literature review on sustained release drug delivery system

Basak SC.et al12

Designed and released Characteristics of sustained release tablet containing metformin

HCl. The release of water soluble drug, metformin HCl exhibited diffusion dominated mechanism. The



wax and cetyl alcohol ration plays an important role in overall release of the drug. The hydrophobic wax

matrix tablet is a promising approach to achieve appropriate sustained release dosage.

Savaser A.et al13

Preparation and in vitro evaluation of sustained release tablet formulations of diclofenac

sodium. Prepared by using HPMC and Chitosan. In vitro studies showed that 20% HPMC contained SR

formulation with direct compression method is the optimum formulation due to its better targeting profile

in terms of release.

Prabhu LS.et al14

Formulated and evaluated of oral sustained release of Diltiazem HCl using as matrix

forming material. Prepared by direct compression method using rosin as matrix forming material in

different proportions and with different diluent combinations.

Ghosh S et al15

preparation and evaluation of aceclofenac sustained release formulation and comparison of

formulated and marketed product. The formulation and production technology of aceclofenac 200 mg

hydrophilic matrix tablets have been developed, which produced SR formulation with good physical

characteristics, predictable and reproducible drug release profile similar to the marketed reference product.

This study demonstrated that Methocel K4 MCR provides a reliable sustained matrix formulation

recommendation for high dose and BCS II class drugs such as aceclofenac.

Shalger S Vet al16

preparation and evaluation of sustained release matrix tablets of propranolol

hydrochloride. Sustained release matrix tablets of propranolol hydrochloride can be prepared using HPMC

K100M to achieve a desired drug release rates over a period of 12 hours, which can help to reduce the dose

and frequency.

Khachane KN et al17

Novel Sustained Release Drug Delivery System: Review, development of sustained

release oral dosage forms is beneficial for optimal therapy regarding efficiency, safety patient compliance.

In case of sustained release (SR) dosage forms the release of the active agent, although, is lower than the

conventional formulations, however, it is still substantially affected by the external environments into

which it is released.

Chugh I et al18

Oral Sustained Release Drug Delivery System: An Overview, oral ingestion has been the

most convenient and commonly employed route of drug delivery. Indeed, for sustained release systems, the

oral route of administration has by far received the most attention with respect to research on physiological

and drug constraints. Sustained release dosage forms are designed to release a drug at a predetermined rate

by maintaining a constant drug level for a specific period of time with minimum side effects.

Thirupathi Reddy et al19

prepared cefixime trihydrate sustained release matrix tablet. Matrix tablets of

cefixime trihydrate were prepared by using polymers like hydroxyl propylmethylcellulose (HPMC K15M,



HPMC K100 and HPMC 4M), xanthan gum, polymethacrylate and different diluents like microcrystalline

cellulose, Ethyl cellulose, sodium starch glycolate, and talc as glident. Amongst all the formulations , the

release profile of formula F16 having SSG 2% and MCC 82 mg and F20 HPMC K 100-190mg and MCC

190 mg gave optimum results., it was concluded that for cefixime trihydrate sustained release matrix

tablets, the same batch is successful formulation and can be manufactured with reproducible characteristics

of batch to batch.

Mandal U et al20

designed formulation and optimization of sustain release tablet of Metformin HCl 500mg

using response surface methodology. The hydrophilic matrix tablets of metformin HCl, prepared using

HPMC K 15M and PVP K 30, can successfully be employed as once a day oral controlled release drug

delivery system.

2. literature review on dry syrup

SB Sateesha et al21

prepared stable and palatable Norfloxacin suspension formulation for oral

administration. The aim of this work is to prepare stable and palatable Norfloxacin suspension formulation

for oral administration. Hence an attempt is made to develop Norfloxacin dry syrup. Methods employed for

formulations are: a) preparation of Norfloxacin granules by coating with different levels of Acrycoat E100-

40 and b) preparation of Norfloxacin microspheres using Eudragit E100 and subsequent adsorption on

different carriers such as lactose, microcrystalline cellulose and mannitol. The microspheres were smoother

and more regular in their shape compared to granules. Stability studies of dry suspension formulation

conducted at 40± 2⁰C for three months were found to be stable and percentages of drug remaining were

higher than 98% of initial concentration.

Palekar shanbhag pradnya et al22

developed oral reconstitutable system of cephalexin as dry suspension,

to be reconstituted with water. Cephalexin, a cephalosporin antibiotic was chosen as the model drug

candidate to obtain a dosage form with improved stability, palatability and attractive pediatric elegance,

cost effective and with ease of administration. All the formulations showed good organoleptic properties

with enhanced sedimentation and rheological behavior with T90% within two hours. The powder mixture

gave a rapid release of 10-30 minutes.

D.K Jain et al23

Development dry suspensions for reconstitution like Azithromycin and Ambroxol HCl

using powder blends techniques. Suspensions were evaluated for flow properties, rheological and

sedimentation behavior. The reconstitution oral suspensions of Azithromycin and Ambroxol HCl were

found to be stable over its intended shelf life of 15 days after reconstitution. Formulation with xanthan gum

(1.5% and 0.75%) showed excellent sedimentation volume and degree of flocculation nearing 1. This was



due to the presence of anti caking agents or the granule disintegrants added to the formulations. Also

formulation with Acacia (3% and 1.5%) showed good redispersibility.

SB Sateesha et al24

Developed taste masked Cefetamet Pivoxil (CPH) dry powder suspension. Because of

its intense bitter taste and susceptibility to moisture CPH is presently available only in the form of tablet.

The aim of this study was to develop taste masked CPH dry powder suspension. Methods employed for

formulations were: a) Film coating of CPH using Eudragit E100 and subsequent adsorption on different

carriers such as spray-dried lactose, sodium starch glycolate and spray-dried mannitol and b) complexation

of CPH with three different ion exchange resins Indion 234, Amberlite IRP64 and Amberlite IRP69.

Suspensions prepared using Amberlite IRP64 and Amberlite IRP69 was extremely palatable with no bitter

after taste. The suspension made with Indion 234 was palatable with slight or no bitter after taste.

J.M. Hempen stall et al25

prepared diluted antibiotic syrups. The penicillin content and stability of diluted

antibiotic syrups, prepared according to the manufacturers recommendations and other, non-approved,

methods have been investigated. The choice of diluent controls the stability of the preparation.

Phenoxymethylpenicillin syrups become less stable as the sucrose content increase. This is not always true

with Ampicillin syrups where the manufacturer’s instructions are not always the most stable, the effect of

different diluents on the stability of syrups, especially suspensions, suggests that syrups should always be

reconstituted and diluted according to the directions with the product.

M. Gabriel’s et al26

developed a dry suspension, containing one of the Artemisinin derivatives, namely

Artesunate, Artemether and Dihydroartemisinin using fast wetting suspension, containing one of the

Artemisinin derivatives i.e. Artesunate, Artemether, and Dihydroartemisinin using fast wetting suspending

agents, i.e. xanthan gum and Avicel®CL11. Based on the results of selection tests for the colourant,

sweetener and taste masking agent, the following composition was proposed for a suitable dry powder with

Artemether(AM) as active compound to prepare 100 ml reconstituted suspension.

T.N. Patel et al27

prepared a taste masked complex of topiramate with ion exchange resin. Mask the taste

of Topiramate by using ion exchange resin technique. Topiramate is an anti-epileptic drug used in partial

onset seizure. But its bitter taste becomes a critical issue which strongly demanded to mask the taste.

Different types of ion exchange resins like Kyron T-104, Kyron T-114, Kyron T-134, Doshion p 542 were

used to form complex with topiramate. Ion exchange resin to drug ratio, effect of ph, effect of temperature,

effect of resin soaking time, effect of stirring time on complex formation were optimized. Drug resin

complex was evaluated for swelling, particle size analysis and drug release from drug-resin complex. Upon



exercising with various ion exchange resins Kyron T-114 with drug-resin ratio of 1:3 was found to offer a

best masking agent.

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