Spray Drying

SPRAY DRYING TECHNIQUE

Spray Drying : A Review

Introduction[1-5]

History[1-3]

The development of spray drying equipment and techniques evolved over a period of several

decades from the 1870s through the early 1900s. The first known spray dryers used nozzle

atomizers, with rotary atomizers introduced several decades later. Because of the relatively

unsophisticated designs of the early spray dryers and practical difficulties in operating them

continuously, very little commercial use of the process was made until the 1920s.

By the second decade of the twentieth century, the evolution of spray dryer design made

commercial operations practical. This process found its earliest widespread acceptance in dairy

industry. Milk drying was the first major commercial application of the technology. Spray dryers

to produce powdered milk, whey and baby formulas are still one of the largest applications of the

technology.

Spray drying is not a new technology as far as the pharmaceutical industry is concerned, having

been used successfully for producing drug substances and various excipients since the early

1940s. It was employed primarily in manufacturing of bulk pharmaceuticals and fine chemicals,

such as antibiotics, analgesics, antacids, and vitamins.

Spray drying encapsulation has been used in the food industry since the late 1950s to provide

flavor oils with some protection against degradation / oxidation and to convert liquids into

powders. Spray drying was developed as a convenient method of drying heat-sensitive biological

materials, such as enzymes and pharmaceutical proteins, with minimal loss of activity.

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Spray drying came of age during World War II, with the sudden need to reduce the transport

weight of foods and other materials. This surge in interest led to developments in the technology

that greatly expanded the range of products that could be successfully spray dried. It has been

used in pharmaceutical technology studies to produce pharmaceuticals excipient with improved

compressibility, such as lactose, to improve flow properties, to prepare free-flowing granules for

tablet production, to improve the drug aqueous solubility and, consequently, their bioavailability.

In addition, a number of formulation processes can be accomplished in one step in a spray dryer;

these include complex formation and micro encapsulation. The fact that spray drying greatly

reduces the labor-intensive formulation, drying and granulating of solid-dose pharmaceuticals

gives cause to review the potential for this process in numerous instances. The pharmaceutical

industry, however, is coming under ever-increasing pressure to reduce manufacturing cost, while

still maintaining strict purity standards and highest level of quality control.

Concept of spray drying technique

The production of particles from the process of spraying has gained much attention in recent

years. These efforts have resulted in spray technology being applied to the manufacture of

particles to generate products ranging from pharmaceutical direct compression excipients and /

or granulations to microencapsulated flavors.

The two main spray techniques are spray drying & spray congealing. The action in spray drying

is primarily that of evaporation, whereas in spray congealing it is that of a phase change from a

liquid to a solid. The two processes are similar, except for energy flow. In the case of spray

drying, energy is applied to the droplet, forcing evaporation of the medium resulting in both

energy and mass transfer through the droplet. In spray congealing, energy only is removed from

the droplet, forcing the melted to solidify.

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Spray drying is the most widely used industrial process involving particle formation and drying.

It is highly suited for the continuous production of dry solids in either powder, granulate or

agglomerate form from liquid feedstocks as solutions, emulsions and pumpable suspensions.

Therefore, spray drying is an ideal process where the end-product must comply with precise

quality standards regarding particle size distribution, residual moisture content, bulk density, and

particle shape.

Figure - 1 Main process stages involved in spray drying process[3]

Spray drying involves the atomization of a liquid feedstock into a spray of droplets and

contacting the droplets with hot air in a drying chamber.

The sprays are produces by either rotary (wheel) or nozzle atomizers. Evaporation of moisture

from the droplets and formation of dry particles proceed under controlled temperature and

airflow conditions. Powder is discharged continuously from the drying chamber. Operating

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conditions and dryer design are selected according to the drying characteristics of the product

and powder specification.

Atomization[2, 4-6]

The atomizing device, which forms the spray, is the ´heart´ of the spray drying process.

Atomizer: Equipment that breaks bulk liquid into small droplets, forming a spray.

Prime functions of atomization are:

a. A high surface to mass ratio resulting in high evaporation rates,

b. Production of particles of the desired shape, size and density.

The aim of atomizing the concentrate is to provide a very large surface, from which the

evaporation can take place. The smaller droplets, the bigger surface, the easier evaporation, and a

better thermal efficiency of the dryer are obtained. The ideal from a drying point of view would

be a spray of drops of same size, which would mean that the drying time for all particles would

be the same for obtaining equal moisture content.

Over the years several researches have studied the mechanism by which atomization takes place

and several theories have evolved. The most widely accepted are based on the liquid jet theory

described in 1878 by Lord Rayleigh. A liquid stream accelerated by the force of gravity is pulled

apart or disintegrated into teardrop-shaped droplets. The surface tension of the liquid causes the

droplet, suspended in air, to form itself into a sphere.

In order to produce top-quality products in the most economical manner, it is crucial to select the

right atomizer. Three basic types of atomizers are used commercially:

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a. Rotary atomizer (atomization by centrifugal energy)

b. Pressure nozzle (atomization by pressure energy)

c. Two-fluid nozzle (atomization by kinetic energy)

Ultrasonic energy & vibrations have also been studied, but as yet have found few commercial

applications. The selection of a specific atomizer is made based on the properties of the feed, the

desired powder properties, the dryer type and its capacity and the atomizer capacity.

Rotary atomizers: Atomization by centrifugal energy [2, 5]

Rotary atomizer uses the energy of a high speed-rotating wheel to divide bulk liquid into

droplets. Feedstock is introduced at the center of the wheel, flows over the surface to the

periphery and disintegrates into droplets when it leaves the wheel.

Figure- 2 Rotary atomizer[5]

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Advantages of rotary atomizers:

-Great flexibility & ease of operation.

-Low pressure feed system.

-No blockage problems.

-Handling of abrasive feeds.

-Ease of droplet size control through wheel speed adjustment.

Disadvantages of rotary atomizers:

-Produce large quantities of fine particles, which can result in pollution control problems.

-High capital cost.

-Very expensive to maintain.

-Cannot be used in horizontal dryers.

-Difficult to use with highly viscous materials.

Because of the problems and costs associated with rotary atomizers, there is interest within

segments of the spray dry industry in replacing rotary atomizers with spray nozzles.

Pressure nozzles: Atomization by pressure energy [2, 5]

Pressure nozzle is the most commonly used atomizer for spray drying. Nozzles generally

produce coarse, free flowing powders than rotary atomizers. Pressure nozzles used in spray

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drying are called “vortex” nozzles because they contain features that cause the liquid passing

through them to rotate. The rotating fluid allows the nozzle to convert the potential energy of

liquid under pressure into kinetic energy at the orifice by forming a thin, high-speed film at the

exit of the nozzle. As the unstable film leaves the nozzle, it disintegrates, forming first ligaments

and then droplets. Pressure nozzles can be used over a large range of flow rates, and can be

combined in multiple-nozzle installations to give them a great amount of flow rate and particle

size flexibility. The range of operating pressure range for pressure nozzles used in spray drying is

from about 250 PSI (17.4 bar) to about 10,000 PSI (690 bar).

Figure-3 Pressure nozzle

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Two-fluid or Pneumatic nozzles: Atomization by kinetic energy[2, 5]

Liquid feedstock and compressed air (or steam) are combined in a two-fluid nozzle. The design

utilizes the energy of compressed gas to atomize the liquid. Two advantages of the two-fluid

nozzle are its ability to produce very fine particles and to atomize highly viscous feeds.

However, two-fluid nozzles are expensive to operate because of the high cost of compressed air.

Two fluid nozzles are often used in laboratory and pilot plant spray dry applications because of

their ability to produce a wide range of flow rates and droplet sizes. The range of operating

pressure range for pressure nozzles used in spray drying is from about 250 PSI (17.4 bar) to

about 10,000 PSI (690 bar).

Figure- 4 Two fluid nozzle [4]

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Ultrasonic Atomization[3]

Recently ultrasonic energy has been used in place of pressure or centrifugal force to form

droplets. In this method, a liquid is placed on a rapidly vibrating surface at ultrasonic

frequencies. At sufficiently high amplitude, the liquid spreads, becomes unstable and collapses,

resulting in the formation of very fine droplets. These devices are excellent for droplets below 50

microns. Their use is expected to grow over the next few years.

Mixing and drying[1, 7-8]

Once the liquid is atomized it must be brought into intimate contact with the heated gas for

evaporation to take place equally from the surface of all droplets within the drying chamber. The

heated gas is introduced into the chamber by an air disperser, which ensures that the gas flows

equally to all parts of the chamber.

Air Disperser

The air disperser uses perforated plates or vaned channels through which the gas is directed,

creating a pressure drop and, thereby, equalizing the flow in all directions. It is critical that the

gas entering the air disperser is well mixed and has no temperature gradient across the duct

leading into it. This arrangement allows instant and complete mixing of the heated drying gas

with atomized cloud of droplets. To fully understand the characteristics of spray-dried powders,

one needs to examine the mechanism for drying within a single droplet. Typically, there are

many very small particles suspended in a sphere of liquid. When the droplet is first exposed to

hot gas, rapid evaporation takes place. Material dissolved in the liquid will tend to form a thin

shell at the surface of the sphere. Although the evaporation has kept the particle itself quite cool,

as the liquid concentration decreases, the particle will begin to heat. Evaporation then takes only

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as quickly as the liquid can diffuse to the surface of the sphere. This phase of the drying process

is called first-order drying or is said to be diffusion-rate-limited.

The thermal energy of the hot air is used for evaporation and the cooled air pneumatically

conveys the dried particles in the system. The contact time of the hot air and the spray droplets is

only a few seconds, during which drying is achieved and the air temperature drops

instantaneously. The dried particle never reaches the drying air temperature. This enables

efficient drying of heat sensitive materials without thermal decomposition.

Turbulence within the dryer, which is necessary for good drying, does cause some particles to be

exposed to elevated temperature. This sometimes causes a loss in activity or modification of

additives such as binders. Therefore, test work is recommended on each formulation, and the

best combination of inlet and outlet temperatures needs to be established relatively to activity

and performance of the powder in further processing

.

Figure- 5 Formation of product in spray drying [7]

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The drying chamber

The largest and most obvious part of a spray-drying system is the drying chamber. This vessel

can be taller and slander or have large diameter with a short cylinder height. Selecting these

dimensions is based on two process criteria that must be met. First, the vessel must be of

adequate volume to provide enough contact time between the atomized cloud and the heated

glass.

The second criterion is that all droplets must be sufficiently dried before they contact a surface.

This is where the vessel shape comes into play. Centrifugal atomizer requires larger diameter and

less cylinder height. Nozzles are just the opposite. Most spray dryer manufacturers can estimate,

a given powder’s mean particle size, what dimensions are needed to prevent wet deposits on the

drying chamber walls.

Drying chambers are usually constructed of stainless steel sheet metal, with stiffeners for

structural support and vessel integrity. Sheet steel finish and weld polish can be specified to meet

any requirement. Insulation is usually applied to the outside of the vessel, and stainless steel

wrapping is seam-welded over the entire vessel. This provides a thermally efficient and safe

system that is easy to clean has no crevice areas that might become contaminated.

Powder separation[1,7-8]

In almost every case, spray-drying chambers have cone bottoms to facilitate the collection of the

dried powder. When the coarse powder is to be collected, they are usually discharged directly

from the bottom of the cone through a suitable airlock, such as a rotary valve. The gas stream,

now cool and containing all the evaporate moisture, is drawn from the center of the cone above

the cone bottom and discharge through a side outlet. In effect, the chamber bottom is acting as a

cyclone separator. Because of the relatively low efficiently of collection, some fines are always

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carried with the gas stream. This must be separated in high-efficiency cyclones, followed by a

wet scrubber or in a fabric filter (bag collector). Fines are collected in the dry state (bag

collector) are often added to the larger powder stream or recycled.

Types of spray dryer systems [2]

On the basis of the type of flow

Co-current flow dryer

In the co-current flow dryer the spray is directed into the hot air entering the dryer and both pass

through the chamber in the same direction. Spray evaporation is rapid, and the temperature of the

drying air is quickly reduced by the vaporization of water. The product does not suffer from heat

degradation since once the moisture content reaches the target level, the temperature of the

particle does not increase greatly because the surrounding air is now much cooler. Dairy and

other heat-sensitive food products are preferably dried in co-current dryers.

Figure-6 Co-current flow dryer

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Counter-current flow dryer

In this dryer designthe spray and the air are introduced at opposite ends of the dryer, withthe

atomizer positioned at the top and the air entering at the bottom. A counter-current dryer offers

more rapid evaporation and higher energy efficiency than a co-current design. Because the driest

particles are in contact with hottest air, this design is not suitable for heat-sensitive products.

Counter-current dryers normally use nozzles for atomization because the energy of the spray can

be directed against the air movement. Soaps and detergents are commonly dried in counter-

current dryers.

Figure-7 Counter-current flow dryer

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Mixed flow dryer

Dryers of this type combine both co-current and counter current flow. In a mixed flow dryer, the

air enters at the top and the atomizer is located at the bottom. Like the counter-current design, a

mixed flow dryer (figure 10) exposes the driest particles to the hottest air, so this design is not

used with heat-sensitive products.

Figure-8 Mixed flow dryer

On the basis of the type of cycle

Open cycle dryer

In an open cycle dryer (figure 11), drying air is drawn from the atmosphere, heated, conveyed

through the chamber and then exhausted to the atmosphere. This is by far the most commonly

used design.

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Figure-9 Open cycle flow dryer; 1 Feed storage, 2 Pump, 3 Drying chamber, 4 Air heater,

5 Cyclone, 6 Gas scrubber, 7 Separator

Closed cycle dryer [27]

A closed cycle dryer recycles the drying gas, which may be air or more commonly, an inert gas

such as nitrogen. Closed cycle units are the dryers of choice when:

i.Feedstock consists of solids mixed with flammable organic solvents.

ii.Complete recovery of solvent is required.

iii.The products are toxic

iv.Pollution due to vapor, particulate emissions or odor is not permitted.

v.Explosion risks must be eliminated.

vi.The powder will degrade by oxidation during drying.

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Figure-10 Closed cycle dryer

Semi-closed cycle dryer

This dryer design is a cross between open and closed cycle dryers. A direct-fired heater is used

and the air entering the system is limited to that required for combustion. An amount of air equal

to the combustion air is bled from the system at the other end of the process. The gas (mainly

products of combustion) is recycled through the dryer. The recycled gas has very low oxygen

content, making it suitable for materials that cannot be exposed to oxygen, due to explosive

hazard or product degradation.

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Figure-11 Semi-closed dryer; 1 Combustion air, 2 Coolant, 3 Feedstock, 4 Heater fuel, 5

Condensed water discharge, 6 Dried product, 7 Drying chamber, 8 Cyclone, 9 Direct heater

(gas), 10 Heat exchanger, 11 Scrubber/condenser, 12. Air bleed to atmosphere

On the basis of the type of stage

Single stage dryer

In a single stage dryer, the moisture is reduced to the target (typically 2-5% by weight) in one

pass through the dryer. The single stage dryer is used in the majority of designs.

Two stage dryer

In a two stage dryer , the moisture content of product leaving the chamber is higher (5-10%) than

for the final product. After leaving the chamber, the moisture content is further reduced during a

second stage. Second stage drying may be done in afluidized bed dryer or a vibrating bed dryer.

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Two stage dryers allow the use of lower temperatures in the dryer, making the design a good

choice for products that are particularly heat sensitive.

Figure-12 Two stage dryer; 1 Air, 2 Feedstock, 3 Dried product, 4 Drying chamber, 5 Cyclone,

6 Stationary fluid bed, 7 Fluid bed cyclone, 8 Transport cyclone

On the basis of the position

Vertical dryer

The chamber of a vertical (tower) dryer has the form of a tall cylinder with a cone-shaped

bottom. Spray nozzles may be located at the top (co-current flow) or bottom (counter-current or

mixed flow) of the chamber. Inlets for the drying air may be located at the top, bottom or side of

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the chamber. Vertical spray dryers are usually large and the residence time of sprayed particles is

relatively long, allowing the use of higher flow nozzles such as the TD, which produce relatively

large particles.

Horizontal dryer

The chamber of a horizontal dryer has the form of a rectangular box with either a flat or a “V”

shaped bottom. Nozzles in a box dryer normally spray horizontally, with the dried particles

falling to the floor, where they are removed to a bagging area by a sweep conveyor or screw

conveyor. Box dryers are usually small and the particle residence time relatively short, requiring

the use of low flow nozzles, which produce relatively small particles.

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Figure-13 Horizontal dryer, 1. Drying air, 2 Feedstock, 3 Pneumatic conveyor, 4 Drying

chamber, 5 Powder conveyor, 6 Filter bags, 7 Cyclone, 8 Dust return, 9 Exhaust to atmosphere,

10 Dried powder.

Equipments[11, 12, 28]

Different Spray Dryer Models are available commercially.

Simple spray dryer

-Largest standard plant.

-For small scale production.

-Rotary wheel or nozzle atomizers.

-One-or two-point product collection.

-Can be readily modified.

-Direct-fired gas or electric heat.

-Evaporation rates to 60 kg/hr.

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Figure-14 Simple spray dryer

Minor spray dryer

-Versatile Spray Dryer for in-house research and small scale production.

-Interchangeable atomization and powder discharge systems.

-Sanitary design.

-Standard modules for a wide range of configuration.

Figure-15 Minor spray dryer

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Aseptic production minor spray dryer

-Easily sterilized.

-Electrically heated.

-HEPA filtration oninlet air.

-Positive pressure system.

-316L stainless product contact.

-Separate powder discharge box.

-Water evaporation to 18 kg/hr.

Figure-16 Aseptic production minor spray dryer

Mini spray dryer B-290

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The Mini Spray Dryer B-290 is the laboratory equipment of your choice for the quick and gentle

drying to powder of liquid end products. The impressive features of the Spray Dryer include its

efficient performance with very short set-up times, an effective integrated nozzle cleaning

mechanism and a high degree of flexibility due to the different cylinder geometries. The B-290’s

outstanding features greatly extend the number of applications that are possible with a spray

drying process.

Figure-17 Mini spray dryer B-290

Applications:

-Spray drying from solutions

-Structure modifications

-Drying of suspensions

-Agglomeration

-Spray crystallization

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-Micro-encapsulation and coating

Fluidized spray drying

Powders with a mean particle diameter larger than 15 micron can usually be said to be free-

flowing and non dusty. Such powders can be easily fed to conventional tableting equipment,

producing equivalent, or in some cases better, quality tablets than other granulation methods.

Most of the pharmaceutical granulation is still done batch wise and usually results in larger

particles than spray dryers produce. One of the most popular of these techniques is fluid bed

spray granulation. It combines features of both spray drying and fluid bed granulation to achieve

continuous process that produces granules similar to those obtained from fluid bed granulation

process. This process is called fluidized spray drying (FSD). The Fluidized Spray Dryer is one of

the most successful designs of spray dryers ever developed

Principle

The chamber is shaped as a slender cone with a short cylindrical section. The operation is much

like conventional spray dryer. However the bottom cone of the spray dryer has been modified to

include an integral fluid bed. In the upper part of FSD , atomization and mixing with heated air

takes place as usual. However, when the partially dried particles fall from drying gas, they are

captured in fluidized bed. Controlled temperature and humidity conditions in the bed allow the

particles to stay moist enough to agglomerate. Each of these agglomerates are a cluster of

individual partially spray dried droplets. Obviously, there are going to be some droplets that dry

completely without agglomerating. In addition the fluidizing action in the fluid bed will create

some attrition. Fines from both sources will tend to be carried towards the drying gas exhaust

point. In the FSD, all drying gas from both the hot air inlet and the fluidized bed leave the drying

chamber through two exhaust ducts in the roof. As a result, fines entrained in the gas stream have

to pass through the atomized spray, affording even greater opportunity for agglomeration. Fines

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that do escape the drying chamber are collected in cyclones or a bag collector and pneumatically

re-injected into the dryer. As a result there are no fines left to recycle or discard.

Figure- 18 Fluidized spray dryer

Advantages

1.Dustless, coarse, free-flowing product with good re-dispersibility.

2.Trouble-free drying of many thermoplastic and/or hygroscopic products.

3.Very compact plant layout improves energy economy with higher inlet and lower outlet drying

temperatures.

4.Excellent for agglomerated or granulated products.

5.Aseptic and/or closed-cycle design available.

6.Drying of heat-sensitive and aromatic products without degradation.

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Spray freeze drying

It is the method, which combines processing steps common to freeze-drying and spray-drying.

Figure-19 Spray freeze drying

Potential uses

-Bioactive extracts from milk/whey.

-Freeze dried coffee/tea.

-Fruit juices.

-Pharmaceuticals/Nutraceuticals.

Major advantages

-Continuous process.

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-Greater energy efficiency.

-Much shorter drying times.

-Less labour intensive.

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The Spray Drying ProcessThe spray drying process is older than might commonly be imagined. Earliest descriptions date

from 1860 with the first patented design recorded in 1872. The basic idea of spray drying is the

production of highly dispersed powders from a fluid feed by evaporating the solvent. This is

achieved by mixing a heated gas with an atomized (sprayed) fluid of high surface-to-mass ratio

droplets, ideally of equal size, within a vessel (drying chamber), causing the solvent to evaporate

uniformly and quickly through direct contact.

Spray drying can be used in a wide range of applications where the production of a free-flowing

powder is required. This method of dehydration has become the most successful one in the

following areas:

Pharmaceuticals

Bone and tooth amalgams

Beverages

Flavours, colourings and plant extracts

Milk and egg products

Plastics, polymers and resins

Soaps and detergents

Textiles and many more

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Almost all other methods of drying, including use of ovens, freeze dryers or rotary

evaporators, produce a mass of material requiring further processing (e.g. grinding and filtering)

therefore, producing particles of irregular size and shape. Spray drying on the other hand, offers

a very flexible control over powder particle properties such as density, size, flow characteristics

and moisture content.

Design and Control

The challenges facing both designers and users are to increase production, improve powder

quality and reduce costs. This requires an understanding of the process and a robust control

implementation.

Spray drying consists of the following phases:

Feed preparation: This can be a homogenous, pumpable and free from impurities solution,

suspension or paste.

Atomization (transforming the feed into droplets): Most critical step in the process. The degree

of atomization controls the drying rate and therefore the dryer size. The most commonly used

atomization techniques are:

1. Pressure nozzle atomization: Spray created by forcing the fluid through an orifice. This is an

energy efficient method which also offers the narrowest particle size distribution.

2. Two-fluid nozzle atomization: Spray created by mixing the feed with a compressed gas. Least

energy efficient method. Useful for making extremely fine particles.

3. Centrifugal atomization: Spray created by passing the feed through or across a rotating disk.

Most resistant to wear and can generally be run for longer periods of time.

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Drying: A constant rate phase ensures moisture evaporates rapidly from the surface of the

particle. This is followed by a falling rate period where the drying is controlled by diffusion of

water to the surface of the particle.

Separation of powder from moist gas: To be carried out in an economical (e.g. recycling the

drying medium) and pollutant-free manner. Fine particles are generally removed with cyclones,

bag filters, precipitators or scrubbers.

Cooling and packaging.

A control system must therefore provide flexibility in the way in which accurate and repeatable

control of the spray drying is achieved and will include the following features:

Precise loop control with setpoint profile programming

Recipe Management System for easy parameterisation

Sequential control for complex control strategies

Secure collection of on-line data from the system for analysis and evidence

Polymer used in spray drying technique

By spray-drying Amioca® starch and Carbopol® 974P mixtures a range of potential bioadhesive

carriers was obtained with excellent bioadhesive properties.[13] Solid dispersions of theophylline

with chitosan as a carrier were prepared using a spray-drying method.[14]

Modified extended release matrix tablet were produced by compressing material made by spray-

drying Theophylline[15] slurried in an aqueous ammoniated solution of cellulose enteric polymers

such as cellulose acetate phthalate. Both enteric release and sustained release can be achieved.

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Spray drying allowed the rapid formation of theophylline polymer micro particles without

exposing the material to high temperatures.

Microsphere

Spray drying often is used as an encapsulation technique by the food and other industries. A

substance to be encapsulated (the load) and an amphipathic carrier (usually some sort of

modified starch) are homogenized as a suspension in water (the slurry). The slurry is then fed

into a spray drier, usually a tower heated to temperatures well over the boiling point of water.

As the slurry enters the tower, it is atomized. Partly because of the high surface tension of water

and partly because of the hydrophobic/hydrophilic interactions between the amphipathic carrier,

the water, and the load, the atomized slurry forms micelles. The small size of the drops

(averaging 100 micrometers in diameter) results in a relatively large surface area which dries

quickly. As the water dries, the carrier forms a hardened shell around the load.

Load loss is usually a function of molecular weight. That is, lighter molecules tend to boil off in

larger quantities at the processing temperatures. Loss is minimized industrially by spraying into

taller towers. A larger volume of air has a lower average humidity as the process proceeds. By

the osmosis principle, water will be encouraged by its difference in fugacities in the vapor and

liquid phases to leave the micelles and enter the air. Therefore, the same percentage of water can

be dried out of the particles at lower temperatures if larger towers are used. Alternatively, the

slurry can be sprayed into a partial vacuum. Since the boiling point of a solvent is the

temperature at which the vapor pressure of the solvent is equal to the ambient pressure, reducing

pressure in the tower has the effect of lowering the boiling point of the solvent.

The application of the spray drying encapsulation technique is to prepare "dehydrated" powders

of substances which do not have any water to dehydrate. For example, instant drink mixes are

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spray dries of the various chemicals which make up the beverage. The technique was once used

to remove water from food products; for instance, in the preparation of dehydrated milk. Because

the milk was not being encapsulated and because spray drying causes thermal degradation, milk

dehydration and similar processes have been replaced by other dehydration techniques. Skim

milk powders are still widely produced using spray drying technology around the world,

typically at high solids concentration for maximum drying efficiency. Thermal degradation of

products can be overcome by using lower operating temperatures and larger chamber sizes for

increased residence times.

Recent research is now suggesting that the use of spray-drying techniques may be an alternative

method for crystallization of amorphous powders during the drying process since the temperature

effects on the amorphous powders may be significant depending on drying residence times

Nanoparticles

Spray-drying is a common technique used in pharmaceuticals to produce a dry powder from a

liquid phase [1]. This technique has also been employed as a microencapsulation method because

it can be adapted to the development of different systems, microspheres or microcapsules,

depending on the initial aqueous formulation, a solution, a suspension or an emulsion. Another

application is its use as preservation method, increasing the storage stability due to the water

elimination. Nanoparticle, submicronic colloidal carriers, is a general name to describe

nanocapsules and nanospheres. Nanocapsules correspond to a polymeric wall enveloping an oil

core, while the nanospheres consist of a polymeric matrix [3]. Nanoparticles have been

extensively studied over the last years in order to control the drug release, to increase the drug

selectivity and effectiveness, to improve drug bioavailability and decrease the drug toxicity [4,5].

Nevertheless, the full applications of polymeric nanoparticles have not been exploited due to the

lack of stability of formulations when conserved in aqueous medium for a long period [6].

During the storage, microbiological growth, polymer hydrolysis and physicochemical instability

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as a consequence of particle aggregation can take place [7]. According to Tewa-Tagne and co-

workers, efforts to develop more stable nanoparticle formulations have been unsuccessfully carry

out for many years [8]. The type and the concentration of surfactants in the formulations have

been varied, but the results shown good stability only in the short-term [9,10]. On the other hand,

the incorporation of nanoparticles in solid dosage forms resulted in phase separation after the

addition of different polymeric binders to aque-ous suspensions of nanoparticles [11]. So, the

development of an effective technique to improve the shelf life of nanoparticles is a requirement.

Microparticles are generally composed by polymeric materials and present advantages such as a

rapid and one step production, ready distribution on a large surface of the body, more constant

plasma levels, higher accuracy in reproducibility dose-by dose, less decrease in bioavailability

and minor risk of toxicity due to the dose dumping [12,13]. A modermicroparticle formulation

should be able to provide a controlled and well-defined drug release pattern.

In the last years our research group and others have been involved in the study of the potential of

the spray drying technique to stabilize polymeric nanoparticle aqueous suspensions converting

them into powders, as well as to prepare innovative nanocoated-microparticles to control the

drug release. So, this article presents a brief overview of most recent and ongoing research in the

use of spray-drying process to prepare and/or to dry polymeric nanoparticles formulations

intended for drug administration.

DRYING POLYMERIC NANOPARTICLE

Aiming to overcome the instability of nanocapsules, our group proposed for the first time in

2000 the use of the spraydrying technique to convert nanocapsule or nanospheres aqueous

formulations into powders [14]. So, we reported oral solid forms containing diclofenac-loaded

nanoparticles, prepared using colloidal silicon dioxide (AerosilR 200) as drying adjuvant (Figure

1A). The scanning electron microscopy analysis of spray-dried powders showed spherical

Page 33


microparticles, which presented the nanoparticles on their surface. The powders obtained from

the nanocapsule suspensions showed nanostructures adsorbed on the microparticles, with similar

206 S. S. Guterres et al. particle sizes (200 nm) than those determined by PCS in the suspensions

before dehydration process. the micro-powders prepared from the nanosphere suspensions

presented a reduction in the particle size which decreased from 200 nm to 60-90 nm after drying

[15,16]. The polymeric nanoparticles used to coat the inorganic microparticles can be prepared

by nanoprecipitation or interfacial deposition of pre-formed polymers [17], as well as by

emulsification diffusion technique [18]. Regarding the biological effects, after oral

administration in rats, the diclofenac-loaded nanocapsule spray-dried powders dispersed in water

were valuable for reducing the gastrointestinal irritant effect of the non-steroidal anti-

inflammatory drug [19]. In parallel, a pharmacokinetic study in rats was also conducted, showing

a complete oral absorption of the drug from spray-dried powders dispersed in water [19]. In

addition, those diclofenac-loaded nanoparticle spraydried powders have been investigated after

14 months of storage at ambient temperature. The powders showed higher chemical stability than

the drug-loaded nanocapsule suspensions. Our study showed that besides the nature of the

formulation, suspension or powder, the decrease in the drug content is dependent on the type and

concentration of the surfactant system. An accelerate stability study carried out under UVC light

exposition followed by mass spectrometry analysis demonstrated that 2-(2’,6’

dichlorophenyl)aminobenzyl alcohol and N-(2’,6’-dichlorophenyl)anthranilylaldehyde were the

diclofenac degradation products [20]. Nanocapsules and nanospheres containing an anti-

inflammatory drug were freeze-dried after addition of colloidal silicon dioxide to obtain intact

dried nanoparticles [21]. The micro powder surfaces presented a homogeneous nanocoating and

satisfactory biological effect (gastrointestinal tolerance). However, in spite these promising

results, the freeze-drying technique is highly expensive and reserved for products with high

added value [22]. So, we continued our study in the use of spray-drying to dry the polymeric

nanoparticle suspensions. In the case of the nanocapsule spray-dried powders, the oil

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concentration in the suspension presented an important influence on the homogeneous

recovering of the particles. The powders prepared using low oil concentration showed two

patterns of nanoparticles on the microparticle surface [23].

Indeed, based on those results we acquired the knowledge needed for the design of homogeneous

nanocoating surfaces. The morphologic control of the micro-powder coating is determined by the

use of either polymeric spheres or vesicular nanoparticles. These studies showed the different

behavior of polymeric nanocapsules and nanospheres in the preparation of these organic-

inorganic microparticles [15,16,19,23]. The nanosphere suspension (polymeric matrix) or the

nanocapsule suspension (vesicular nanostructure) led to microparticles presenting different and

homogeneous nanocoating after the drying process [16]. It is important to note that considering

this drying strategy the drug is encapsulated in the polymeric nanoparticles. In spite the evident

advantages of the spray-drying in the presence of silicon dioxide as a strategy to dry the aqueous

suspensions, the interactions between the polymeric nanoparticles and the silicon dioxide had not

been investigated. Viewing to understand what kind of interactions takes place, Tewa-Tagne and

co-workers demonstrated that the interactions occurring in the feed are directed by hydrogen

bounds and they were more sensitive to the silica concentration than that of nanocapsules [8].

SEM analyses of the powders showed spherical separated microparticles formed by the

association of nanocapsules and silica when they are mixed at adequate concentrations in the

feed before spraydrying. On the other hand, fused agglomerated particles presenting

nanocapsules at their surface, characterized by irregular shapes and a strong adhesiveness were

prepared when the silica concentration was not sufficient. More recently, the effects of

formulations and spray-drying process variables on the powders properties has been studied in

order to optimize the process [22]. Due to the high numbers of parameters involved in the spray-

drying process, particular attention is required in the process optimization. Responses such as

temperature, moisture content, operation yield, particle size and particle densities are useful to

determine the optimal operational conditions. In the particular case of drying nanocapsules using

Page 35


silicon dioxide as an auxiliary agent, the concentrations of both determined the powder

characteristics. Besides silicon dioxide, soluble supports such as lactose, PVP-K30 and mannitol

can also be employed to dry nanocapsules [24]. Using nanocapsules at a concentration of 1%

(w/v) and lactose at 10 % (w/v), the powder had adequate morphology and ease reconstitution in

water (Figure 1B). Focusing on the size distribution after reconstitution, satisfactory result has

been observed using mannitol and PVP-K30 both at 10 % (w/v).

Physical and chemical characterization of the spray dried microparticles

The effects of spray drying conditions and composition of the microencapsulating formulation on

physical and release properties of sodium diclofenac microparticles were assessed by

determining the product moisture, size distribution, particle morphology, flow properties, total

drug load, in-vitro dissolution studies, and encapsulating efficiency. The methods used in these

determinations are presented following.

Product moisture content

The moisture content of the spray dried microparticles was determined by the oven drying

method. Samples of the microparticles with pre-defined mass were placed in a drying and

sterilization oven (Fanem Model 315 SE- Brazil) heated at 102 °C and weighed in an analytical

balance (Mettler Tolledo AG204, Switzerland) until constant mass. The product moisture content

was determined from the weight loss by averaging three measurements.

Product size distribution

The product particle size distribution was determined by optical microscopy and image analysis

with magnification of 50 times. Powder samples were dispersed on a glass sheet and images of

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the powder were obtained with the aid of an Olympus microscope (model BX60MIV) connected

to a digital camera (average of three determinations). The resulting images were analyzed with

an image analysis system (Image Pro-Plus 4.5).

Particles morphology

The morphology of the spray dried microparticles were evaluated through Scanning Electron

Microscopy (S.E.M.). Powder samples were attached to double-sided adhesive carbon tabs

mounted on S.E.M. support, coated with a thin layer of the gold, and examined with a Digital

Scanning Microscope DSM 960 Zeiss West Germany, with magnifications of 2000 and 10,000

times.

Flow properties

The flow properties (loosely packed bulk density, ρb, tapped bulk density, ρbt, the real density,

ρr, compressibility index, IC, and the Hausner ratio, HR) related directly with the behavior of the

powdered products during storage, manipulation and posterior processing. In general, the

processing parameters have significant effect on these properties. In this paper, the loosely

packed and tapped bulk densities, the Hausner ratio and the compressibility index were estimated

according to procedures presented in Prista. The real density of the spray-dried microparticles

was determined by helium picnometry, in a helium picnometer Accupic model 1330

Micromeritics. The repose angle was determined by pouring a predefined mass of spray dried

microparticles through a funnel set at a fixed height on a surface of a graph paper and measuring

the height (h) and the radius (r) of the conical pile formed. The tangent of the repose angle can be

estimated by the ratio h/r.

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Total drug load

Known amounts of spray-dried microparticles were assayed by spectrophotometry at wavelength

of 276 nm in phosphate buffer (pH 6.8) in a UV–VIS HP 8453 spectrophotometer to determine

the total drug load in the spray dried microparticles. The absorbance results were correlated with

drug concentration through a calibration curve determined earlier.

In-vitro dissolution profiles

In vitro dissolution studies of pure drug and spray dried microparticles were conducted according

to USP XXIII “in vitro testing requirements” Method A (paddle method, rotation of 100 RPM

and temperature fixed at 37 °C). The assays were carried out in a dissolution test station Hanson

Research, model SR8 PLUS. The dissolution mediums were 0.1 N HCl solution and a pH 6.8

phosphate buffer solution, following the pH change dissolution procedure specified in USP: 2 h

of exposure to 750 mL of 0.1 N HCl followed by testing in 1000 mL of pH 6.8 phosphate buffer,

the pH being adjusted with 250 mL of 0.2 M tribasic sodium phosphate solution. The released

amount of sodium diclofenac was periodically determined by UV spectrophotometry at

wavelength of 276 nm, using the spectrophotometer UV–VIS HP 8453. The percentage of the

drug released was determined at 60, 120, 180, 240, 300 and 360 min (average of three

determinations). Due to the low solubility of the sodium diclofenac in acid the medium, the sink

conditions were not reached in the 0.1 N HCl solution. However, the dissolution tests were also

performed in this medium in order to simulate the product performance after oral administration.

Encapsulation efficiency

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In this paper, the microencapsulation efficiency was estimated indirectly through the analysis of

the dissolution profiles obtained in 2.4.6 (indirect method). This parameter was assumed as the

percentile inhibition of the drug released at 180 min (60 min in the buffer stage) promoted by

themicroencapsulation process. Eq. (1) was used in this determination, where CD refers to the

free drug and CM to the microencapsulated drug (CD) release. Encapsulation efficiency ð%Þ ¼

100d

CD − CM

CD _ _180min ð1Þ

Parameters to be controlled[2, 4, 9-10]

The pharmaceutical spray-dried products have important properties like

-Uniform Particle size,

-Nearly spherical regular particle shape,

-Excellent Flowability,

-Improved Compressibility,

-Low Bulk Density,

-Better Solubility,

-Reduced Moisture Content,

-Increased Thermal stability, and suitability for further applications.

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Such product characteristics majorly depend on the physical properties of feed, equipment

components and processing parameters (Table 1). By modifying the spray drying process, it is

possible to alter and control the mentioned properties of spray-dried powders. It is certainly very

useful for the development of drug delivery systems.

With the latest developments on spray drying technologies and with the increasing demand for

highly defined particles properties in the pharmaceutical industry, there have been developed a

range of spray drying units (Table 2) able to operate under the most stringent cGMP conditions.

All spray dryers units operate with nitrogen as the drying gas and are fit to handle both aqueous

and organic feeds (solutions, emulsions and pumpable suspensions).

Advantages of spray drying

1. Able to operate in applications that range from aseptic pharmaceutical processing to ceramic

powder production.

2. It can be designed to virtually any capacity required. (Feed rates range from a few pounds per

hour to over 100 tons per hour).

3. The actual spray drying process is very rapid, with the major portion of evaporation taking

place in less than a few seconds.

4. Adaptable to fully automated control system that allows continuous monitoring and recording

of very large number of process variables simultaneously.

5. Wide ranges of spray dryer designs are available to meet various product specifications.

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6. It has few moving parts and careful selection of various components can result in a system

having no moving parts in direct contact with the product, thereby reducing corrosion problems.

7. It can be used with both heat-resistant and heat sensitive products.

8. As long as they are can be pumped, the feedstock can be in solution, slurry, paste, gel,

suspension or melt form.

9. Offers high precision control over Particle size, Bulk density, Degree of crystallinity, organic

volatile impurities and residual solvents.

10. Powder quality remains constant during the entire run of the dryer. Nearly spherical particles

can be produced, uniform in size and frequently hollow, thus reducing the bulk density of the

product.

Disadvantages of spray drying

1. The equipment is very bulky and with the ancillary equipment is expensive.

2. The overall thermal efficiency is low, as the large volumes of heated air pass through the

chamber without contacting a particle, thus not contributing directly to the drying.

Applications

Degree of application decides the importance of process. Spray drying technology is widely

applied in pharmaceutical fields as well as non-pharmaceutical fields.

Non-pharmaceutical applications[2]

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Chemical industry, Ceramic materials, Detergents, soaps and surface-active agents, Pesticides,

herbicides, fungicides and insecticides, Dyestuffs, pigments, fertilizers, mineral floatation

concentrates, inorganic chemicals, organic chemicals, spray concentration (purification), milk

products, egg products, food and plant products, fruits, vegetables, carbohydrates and similar

products, slaughterhouse products, fish products and many others.

Pharmaceutical applications

Many pharmaceutical and biochemical products are spray dried, including antibiotics, enzymes,

vitamins, yeasts, vaccines, and plasma. The spray drying capacity required for these products

ranges from high, in the case of yeasts to low, as in the case of plasma. Spray drying of most

pharmaceutical and biochemical products is done using two-fluid or pressure nozzle atomizers.

Spray drying systems used for pharmaceutical/biochemical applications include: Open-cycle,

aseptic open-cycle (figure 6) and closed-cycle.

Pharmaceutical products[2]

Algae, antibiotics and moulds, bacitracin, penicillin, streptomycin, sulphathiazole, tetracycline,

dextran, enzymes, hormones, lysine (amino acids), pharmaceutical gums, sera, spores, tableting

constituents, vaccines, vitamins, yeast products, tannin products, etc.

Granulation and tabletting

When compared with other granulation methods, spray drying stands out as unique in several

ways. Because the feed to a spray dryer is a homogenous liquid, it eliminates the concern over

blending of dry components with liquids.

Although it is the application of shear forces in the centrifugal atomizer that creates a spray, this

form of energy generally will not destroy microencapsulated material as can happen in high

Page 42


shear granulators. Spray drying technique has been used for granulating, for slow-release

granulations of magnesium carbonate, theophylline and acetaminophen.[1]

The spherical composite particles consisting of amorphous lactose and sodium alginate were

prepared by spray drying their aqueous solutions using rotary atomizing spray-dryer. The SD

composite particles had good compactibility and excellent micrometric properties as filler for

direct tableting of controlled release matrix tablets.[12]

By spray-drying Amioca® starch and Carbopol® 974P mixtures a range of potential bioadhesive

carriers was obtained with excellent bioadhesive properties.[13] Solid dispersions of theophylline

with chitosan as a carrier were prepared using a spray-drying method.[14]

Modified extended release matrix tablet were produced by compressing material made by spray-

drying Theophylline[15] slurried in an aqueous ammoniated solution of cellulose enteric polymers

such as cellulose acetate phthalate. Both enteric release and sustained release can be achieved.

Spray drying allowed the rapid formation of theophylline polymer micro particles without

exposing the material to high temperatures.

Aerosol formulation

Salbutamol sulphate particles, for use in dry powder aerosol formulation, were prepared by spray

drying, using a Mini spray dryer[16]. Spray-freeze-dried liposomal ciprofloxacin powder for

inhaled aerosol drug delivery had been prepared with a two-fluid nozzle.[17]

Micro particles

Page 43



Recently, the process received great attention in the field of micro particles [3, 18-19] for the

preparation of dried liposomes, amorphous drugs, mucoadhesive microspheres, drying of

preformed microcapsules, Gastroresistant microspheres, and controlled-release systems.

Comprehensive studies have been performed on the preparation of microspheres by spray drying

techniques for different purposes, like modification of biopharmaceutical properties, formulation

of dry emulsions, spray dried phospholipids, nanoparticle-loaded microspheres, for drug

delivery, spray-dried powders formulated with hydrophilic polymers, biodegradable

microspheres, and spray-dried silica gel microspheres. Eudragit RL microspheres [20] containing

vitamin C were prepared by Spray drying method.Spray-drying was useful for the preparation of

Paracetamol encapsulating Eudragit RS/RL or Ethylcellulose microspheres.[21]

The spray drying technique has been widely applied to prepare micro-particles of drug with

polymer. When a drug crystal suspension of a polymer solution is spray-dried, microcapsulated

particles are prepared, whereas spray drying of solution of polymer containing dissolved drug

leads to formation of drug-containing microspheres in which the drug can be dispersed in a

molecular state or as micro crystals. In both cases, the particles tend to have a spherical shape

and are free flowing. These properties are preferable pharmaceutical manufacturing process such

as tabletting and capsule filling.

Controlling microsphere size is an important process variable that can affect product

performance. Scanning Electron microscope (SEM) is used to characterize the size of

microspheres (figure 7). The conventional method of sizing involves periodic sampling and

subsequent analysis using off-line techniques, but these have limitations such as late feedback

response times, sampling errors and lacks the sensitivity required for it to be used in the

detection of fluctuations. Using PAT as an in-process monitor during spray drying could offer

Page 44


better process control and improved product quality resulting in products of greater value. Thus,

PAT serves as a useful tool to provide real time information about process and product size.[22]

Micro particles of diltiazem hydrochloride with ethyl cellulose (EC) were prepared by using

spray drying technique. Drug was dispersed in benzene solution of EC or dissolved in methanol

solution of EC with 1:1-1:5 drug EC ratio, followed by spray drying. A microcapsule structure

was obtained in the suspension system, while a microsphere structure, while the drug was in an

amorphous state, was formed in the solution system.

Coating applications

Spray drying has proved extremely useful in the coating and encapsulation of both solids and

liquids. Spray-dried micro particles of theophylline were prepared with a coating polymer [23] in

an aqueous system. Hydroxypropyl methylcellulose (1.25%w/v) and the drug (0.25w/v) were

dissolved in water and spray-dried using a laboratory spray dryer equipped with a two-fluid

pressure nozzle.

The spray drying method can produce discrete particles coated with an aqueous coating solution

or dispersion from spray droplets of the aqueous solution or suspension of drug and coating

polymer when sprayed into a drying chamber. As the solvent is evaporated the coating material

envelops the suspended particle. The coating provides such valuable characteristics as taste and

odour masking, improvement in stability, enteric coating and sustained release. Oily liquids may

be encapsulated by emulsification in water with the aid of a gum such as acacia, or starch, and

subsequent spray drying. As the water evaporates, the oil is entrapped in a shell of the gum. This

process is used for the preparation of “dry” flavor oils[24].

Dry emulsions and dry elixirs

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Dry emulsions[25]were prepared by spray drying various liquid o/w emulsions containing

fractionated coconut oil dispersed in aqueous solutions of HPMC (solid carrier). Flurbiprofen

(FP) dry elixir[26] prepared by the spray-drying technique showed good flowability and was

spherical in shape, having a geometric mean diameter of about 13 μm. Dry elixir is a solid form

of microcapsules simultaneously containing ethanol and drug in water-soluble polymer shell.

The dry elixir was produced when a solution of water-soluble dextrin and drug dissolved in an

ethanol-water co-solvent system was spray-dried. The final solutions were delivered to the

nozzle at a flow rate of 5 ml/min using a peristaltic pump and thereafter spray-dried.

Inlet and outlet temperatures were maintained at 90 and 55°C respectively. The poorly water-

soluble drugs encapsulated in the dry elixir are readily dispersed and dissolved in aqueous media

as a result of the co-solvent effect of ethanol, resulting in enhanceddissolution rate &

bioavailability.

Page 46

http://www.pharmainfo.net/tablet-evaluation-tests/dissolution


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http://www.niroinc.com/pharma_systems/pharmaceutical_spray_dryer.asp/

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