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Spray drying: A crystallization technique : A review
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International Journal of Drug Formulation & Research Oct-Nov. 2010, Vol. 1 (II) 1-29
International Journal of Drug Formulation & Research
SPRAY DRYING: A CRYSTALLIZATION TECHNIQUE : A REVIEW
MUDIT DIXIT*, P.K.KULKARNI, ASHWINI G KINI AND H.G.SHIVAKUMAR
Department of Pharmaceutics, J.S.S College of Pharmacy, J.S.S University, S.S Nagar, Mysore-
570015, India.
ABSTRACT:
This review covers recent developments in the area of crystal engineering via spray drying. The last
decade has seen a shift from empirical formulation efforts to an engineering approach based on a better
understanding of particle formation in the spray drying process. Crystals and Micro particles with Nano scale
substructures can now be designed and their functionality has contributed significantly to stability and efficacy of
the particulate dosage form. The review provides concepts and a theoretical framework for particle design
calculations. It reviews experimental research into parameters that influence particle formation. A classification
based on dimensionless numbers is presented that can be used to estimate how excipient properties in combination
with process parameters influence the morphology of the engineered particles. A wide range of pharmaceutical
application examples—low density particles, composite particles, microencapsulation, and glass stabilization—is
discussed, with specific emphasis on the underlying particle formation mechanisms and design concepts.
KEY WORDS: spray drying, crystallization, dispensability, microencapsulation; particle formation,

stabilization.
INTRODUCTION
Many solid dosage forms in the pharmaceutical and biotech industries are based on different
form of crystals. Dry powders are inhaled as aerosols into the lung, delivered to the nose, filled
into capsules, or pressed into tablets for oral applications, or even delivered transdermally. In the
past, crystals were often viewed simply as carriers, usually crystalized dry material, without
sophisticated attributes. The primary functions of the crystallization and drying processes were to
achieve a suitable particle size and remove most of the solvent. This perspective has changed as
Available online on www.ordonearresearchlibrary.org 1

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novel drug delivery strategies were developed. More advanced therapeutic approaches have
created complex requirements for dosage forms that can only be met by crystals that are
designed for a range of functions such as stabilization of the active, transport and targeting of the
dose, or release modulation. The particle is no longer seen as a passive carrier, but rather as an
essential part of the drug delivery system. Crystals Engineering is a young discipline that
combines elements of microbiology, chemistry, formulation science, colloid and interface
science, heat and mass transfer, solid state physics, aerosol and powder science, and
nanotechnology. It provides the theoretical framework for a rational design of structured crystals
Particle engineering requires a deeper understanding of particle formation processes. Complex
structured crystals are difficult to design using an empirical approach alone because of the many
process and formulation variables that need to be tuned correctly to achieve the desired result.
Efforts to understand and control particle formation processes were intensified in the last decade,
coinciding with the development of pulmonary therapeutics that were traditionally given by
injection (1–3). The pulmonary route was found to be viable for systemic delivery of proteins
and peptides (4–6), in particular insulin (7–18), triggering the development of diverse
administration systems and particle engineering strategies (19–28). Crystallization can be
manufactured by many different processing methods like spherical agglomeration, effect of
solvent,, effect of surfactants, solid deposition, solid composition, freeze drying etc. This review
focuses exclusively on spray drying (29–35), with an emphasis on the literature of the last few
years. Wet chemistry and phase separation processes and alternative drying processes such as
spray freeze drying, or supercritical fluid technologies, have also been used widely for crystals
engineering purposes and have been reviewed elsewhere (36–41).
History of spray drying:
[42-44]
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

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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.
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

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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.
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.
Principle
There are three fundamental [42, 45-46] steps (figure 1) involved in spray drying.
1) Atomization of a liquid feed into fine droplets.
2) Mixing of these spray droplets with a heated gas stream, allowing the liquid to evaporate and
leave dried solids.
3) Dried powder is separated from the gas stream and collected.
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
conditions and dryer design are selected according to the drying characteristics of the product
and powder specification.
Atomization
The atomizing[43, 45-46] 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.

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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.
Figure - 1 : Main process stages involved in spray drying process
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:
a.Rotary atomizer (atomization by centrifugal energy)
b.Pressure nozzle (atomization by pressure energy)
c.Two-fluid nozzle (atomization by kinetic energy)

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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
Rotary atomizer[42, 45] (figure 2) 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
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.

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-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
[42, 48]
Pressure nozzle (figure 3) is the most commonly used atomizer for spray drying. Nozzles
generally produce coarse, free flowing powders than rotary atomizers. Pressure nozzles used in
spray 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
Two-fluid or Pneumatic nozzles: Atomization by kinetic energy

Liquid feedstock and compressed air (or steam) are combined in a two-fluid nozzle [42, 48] (figure
4). 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

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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
Ultrasonic Atomization
Recently ultrasonic[43] 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.
Parameters to be controlled
The pharmaceutical spray-dried products have important properties [42, 44,60-61] like
-Uniform Particle size,
-Nearly spherical regular particle shape,
-Excellent Flowability,
-Improved Compressibility,
-Low Bulk Density,
-Better Solubility,
-Reduced Moisture Content,

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-Increased Thermal stability, and suitability for further applications.

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 and disadvantages
In the world of industrial dryers, there are few types that accept pumpable fluids as the feed
material at the inlet end of the process and produce dry particulate at the outlet.
[42,60-62]
The main advantage e of spray drying is the remarkable versatility of the technology,
evident when analyzing the multiple applications and the wide range of products that can be
obtained.
Table: 1 Parameters to be controlled
Sr. Physical properties of feed Equipment and process Spray dried product
No. parameters characteristics
1 Feed concentration increased Two fluid nozzle: 10-200 µ Particle size increased with low
or High viscosity of polymer Pressure nozzle: 20-200 µ bulk density
2 Low surface tension with Increased energy of Reduced particle size and better
smaller droplet size atomization and higher drop compressibility
velocity
3 Increased temperature of the Increased spray flow rate (to Better flow characteristics
spray solution with correct optimum level)
drop formation
4 Low concentration (<0.5% --- Improved release rate of a poorly
w/w) of hydrophilic water soluble drug
polymers such as NaCMC

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and HPMC
5 --- Increased dryer outlet Lower final product moisture
temperature content
6 --- Multistage and energy Suitability for processing heat
recovery units sensitive pharmaceuticals
Table: 2 Comparison of spray dryer at laboratory, pilot and commercial scales

Commercial
Lab scale Pilot scale
scale
Drying gas Nitrogen / Air
Type of feed Aqueous/organic solutions, suspensions or emulsions
Fit for injectables? Yes Yes Yes
Two-fluid nozzle Two-fluid nozzle
Atomization devices Two-fluid nozzle
Pressure nozzle Pressure nozzle
Nominal drying gas flow
40 80 1250
(kg/h)
Evaporating capacity
1 6 90
(in kg water/hour)
Typical batch scale (kg) 0.01 – 0.500 0.2 - 20 10 - 1000
From very fine particles (figure-5) for pulmonary delivery to big agglomerated powders for oral
dosages, from amorphous to crystalline products and the potential for one-step formulations,
spray drying offers multiple opportunities that no other single drying technology can claim. This
flexibility and reproducibility makes spray drying the process of choice for many industrial
drying operations.
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).

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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.
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.
Figure- 5 Formation of product in spray drying
Applications

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Degree of application decides the importance of process. Spray drying technology is widely
applied [42] in pharmaceutical fields as well as non-pharmaceutical fields.
Non-pharmaceutical applications
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.
Figure-6 Aseptic layout of spray drying system;
1 Air, 2 Feedstock 3 Dried product, 4 Drying chamber, 5 Cyclone, 6 Sterile filter for feed, 7
Two-fluid / Pressure nozzle, 8 Prefilter for atomizing air, 9 Prefilter for drying air, 10 Indirect air
heater, 11 HEPA filters, 12 Clean room for packing

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Pharmaceutical products
Like[42] 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
shear granulators. Spray drying technique has been used for granulating, for slow-release
granulations of magnesium carbonate, theophylline and acetaminophen. [41]
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. [63]
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.[63-64]
Modified extended release matrix tablet were produced by compressing material made by spray-
[65]
drying Theophylline 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
[66]
drying, using a Mini spray dryer . Spray-freeze-dried liposomal ciprofloxacin powder for
inhaled aerosol drug delivery had been prepared with a two-fluid nozzle. [77]
Micro crystals

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[43, 68-69]
Recently, the process received great attention in the field of micro crystals 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, nanocrystal-loaded microspheres, for drug delivery,
spray-dried powders formulated with hydrophilic polymers, biodegradable microspheres, and
spray-dried silica gel microspheres. Eudragit RL microspheres[ 70]
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.[71]
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
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.

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Figure-7 Scanning electron microscopic photographs of spray-dried chitosan microspheres;

a) Uncross-linked, b) cross-linked with d,l-glyceraldehyde.
DEFINITIONS AND THEORY CRYSTALS:

The purpose of this section is to clarify the terminology needed for a discussion of crystals
engineering. It will also provide equations that can be used to describe crystals properties and the
crystals formation process. A rigorous treatment of the physics and chemistry that form the
foundation of crystals engineering is beyond the scope of this review and the reader is referred to
several textbooks (29,45– 49) that cover this material in more detail. Rather, this section will
focus on working equations that can be used to link material properties and process parameters to
particle, aerosol, or powder properties and the resultant product attributes. An engineering
approach is used, relying on dimensionless numbers, and approximate expressions are presented

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where the exact equations are cumbersome to use.Terminology of Structured Microcrystals

Particle morphology can be described in terms of particle size, shape, internal structure, and
surface properties. The terminology used in the literature to describe structured microcrystals is
inconsistent; this review suggests the following: A core is the innermost part of the crystals. It
can be covered by one or more layers that are defined by having distinct composition or
properties. A shell is an outer layer hat is capable of bearing enough mechanical stress to
influence or determine the morphology of the crystal. In contrast, a coat is a thin layer incapable
of providing structural rigidity. The schematic in Fig. 8b shows an idealized layered sphere with
internal structure, comprising a core, a second layer, a shell and a coat. In Fig. 8a the core is
replaced with a central void. Particles can also have the cellular structure of solid, shown
schematically in Fig. 8c and e. In contrast to voids, which are simply gas-filled space, cells are
defined by a surrounding layer such as a membrane. Foam physics terminology can be used to
describe the characteristics of the cellular material: in the case of a closed cell structure (Fig. 8c)
the membranes of adjoining cells remain mostly intact, while in an open cell structure (Fig. 8e)
the membranes have ruptured, leaving a network of struts behind which are called Plateau
borders. The cells can be described as the dispersed phase and the interstitial matter between the
cells as the continuous phase. Colloid science terminology is also applicable to crystals that were
created from suspensions of solids. Fig. 8d and f show schematic examples where the dispersed
phase consists of smaller solid particles, typically nanocrystals. Two cases of particles are
shown; a carrier particle where a significant fraction of the crystals mass is in the continuous
phase with few embedded smaller crystals and the opposite case of a particle with most of the
mass in the dispersed phase. In the latter case the nanocrystals have formed a composite shell. A
large number of small, homogenously dispersed, solid nanocrystals give the crystal the nature of
a sol. Embedded nanoparticles or liquid nanodroplets may have a coat or membrane at the solid–
solid or liquid–solid phase interface. The latter case, a gel particle, is often called a dry emulsion
in the literature (51–53). Fig. 8g shows a particle with internal composition gradients which has
an irregular surface forming external voids. The term irregular is used for crystals whose primary
form deviates significantly from that of a perfect sphere, such as indented or wrinkled crystals.
Irregular crystals may still be spherical, i.e. their aspect ratio may be close to one.

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Figure-8 : Schematic representation of particle morphologies. a Layered with central core.

b Layered with central void. c Solid foam, closed cell. d Solid foam, open cell. e Particle
with embedded nanoparticles. f Composite shell. g Irregular, with external voids and
internal concentration gradients.
Particle:
Size With few exceptions, spray dried crystals are spherical and their size can be described by
their geometric diameter. This is an important parameter which influences the forces crystals
experience in fluid flows and the packing of crystals when they form a powder. The geometric
diameter is also often used as a reference, because it is in principle directly accessible by
ultramicroscopic techniques. However, the measurement of geometric diameters by image
analysis is not without difficulties. One is rarely interested in the size of just a single crystal, but
rather the size distribution of all crystal in a product. In the context of pharmaceutical
applications the mass fraction of a particulate dosage form in a certain crystal size interval is
often sought. This information can be obtained by image analysis of a sample of the dose, but
care has to be taken to ensure that a representative, statistically relevant sample is analyzed.
Usually, this can only be accomplished with the help of automated microscopy and image
analysis (54). Image analysis techniques generate count-based distributions that have to be
converted to a mass-based distribution, e.g. with the help of the Hatch Choate equations (48).
The geometric diameter of particles that are not perfect spheres depends on their orientation. In
this case an average geometric diameter can be substituted, e.g. by averaging Feret’s horizontal
and vertical diameters (54). If this is carried out on a large number of particles that are randomly

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oriented, the reported geometrical diameter is the orientation averaged Feret’s diameter. Other
common crystal sizing techniques do not measure the geometric diameter directly, but rather
derive it from the behavior of the crystals in response to the probe used in the analysis. The
reported diameters are often confused with geometric diameters, but are in fact equivalent
diameters specific to the analytical technique (53). A common example is an optical-equivalent
diameter where crystals are probed by a light source. Their scattering or absorption behavior is
compared to that of a reference geometry, usually a homogeneous sphere. The geometric
diameter of the reference sphere is only representative of the diameter of the sample crystal. if
the optical properties of the sample are close to that of the reference. For structured or irregularly
shaped crystals this is often not the case, as can easily be recognized considering the variety of
crystal types shown in Fig. 8. The optical particle size for these crystals is in reality a function of
their geometric diameter and their secondary morphological features (55, 56). Equivalent crystals
diameters based on other properties or behavior such as electrical mobility, diffusion,
sedimentation, surface or volume to surface ratio are used frequently and are described in the
literature (53,57).
PARTICLE FORMATION
Experimental Techniques
Various experimental techniques for the investigation of droplet drying and crystals formation
have been introduced. Studies using actual processing equipment are difficult to execute and
interpret, because of the complexity of the two-phase flow in spray dryers, the difficulty of
installing adequate analytical instrumentation into a development dryer, and the large number of
processing and formulation variables. Consequently, most of the techniques study more or less
simplified systems that are models of the actual situation in a dryer. Arguably the most
simplified system is a single droplet in quiescent gas. Various levitation techniques, using
optical, acoustic, or electrodynamic forces can be used to freely levitate single micro droplets
(71, 72) (Figure-5 & 8). Non-contact probing of the evaporating droplets allows measurement of
evaporation rates with minimal interference. The shortcoming of the technique is in the time-
scales that can be probed. It is difficult to introduce and levitate microdroplets in the
experimental apparatus quickly enough to allow observation of a phenomenon with a
characteristic time on the order of 10 ms. Most studies on freely levitated droplets have used

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either larger droplets or liquids with very low vapor pressure that evaporate so slowly that the
initial droplet capture and stabilization becomes short compared to the time of the measurement.
A second disadvantage of this method is that shrinking and solidifying droplets experience a
significant change in properties such as refractive index, charge state, or sphericity. This can lead
to difficulties in maintaining a stable levitation until the end of the evaporation process. An
interesting variant of single droplet levitation uses the Leidenfrost phenomenon to trap droplets
on a concave hot plate (70,73). This technique was successfully used to study shell buckling
during crystals formation. A drawback of this approach is that the flow and temperature fields
near the droplet are not to those of a free flowing droplet in a spray dryer. The latter
complication has been addressed by studying droplets suspended from thin filaments. This
technique was used to observe the particle formation process of millimetersized droplets; particle
density and morphology as a function of latent heat of crystallization, solubility, and drying rate
were investigated (74). A recent study used a similar experimental set-up with an added
capability to measure the surface adhesion of single, partially dry particles as a function of
crystal composition and moisture content (69). A refined filament suspension technique was
applied to monitor the drying process of milk droplets (75–78). The morphology of dried crystals
was studied using suspended droplets for more than forty years (62,79–84), and much useful
information has been derived from these studies. However, the use of a filament to suspend
droplets has limitations. Heat and mass transfer can be affected by heat conduction between
droplet and filament. The technique requires relatively large droplets, typically in the millimeter
diameter range. This is problematic, because the processes involved in droplet drying scale
differently with diameter. Droplet behavior observed on millimeter sized droplets may not be
representative of microdroplets that are of interest in pharmaceutical applications. Realistically
sized droplets have often been studied in small scale spray dryers (55,85). These studies have
shed light on many individual aspects of the drying process. The importance of the ratio between
droplet evaporation rate and diffusional motion of the solutes was recognized and the concept of
the Peclet number has been used to explain low density particle morphology (86). It was also
found that feed solution concentration (87) and solubility of the excipients affect crystals
morphology (88–90). Several studies show that precipitation kinetics and crystallization play an
important role and may be affected by evaporation rate (91,92). It has also been pointed out that

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drying temperature has a strong effect on particle morphology (93,94). Some researchers have
used a chain of monodisperse free falling droplets to study heat and mass transfer, drying, and
crystals formation processes (80,95–98). With this technique the effect of drying rates on crystals
formation and the formation of internal voids in particles have been studied. The droplet
generator commonly used in this technique produces closely spaced droplets, which may lead to
droplet– droplet interactions (99–101), because the evaporation process is determined by gas
phase transport processes.
Furthermore, the studies were still carried out on relatively large droplets with a diameter >170
μm (102) (Fig-7). Recently, an improved droplet chain technique has been introduced (50) that is
based on a droplet-on-demand generator. In this technique the droplet distance is a free variable
and can be chosen so that droplets do not measurably interact. It is also capable of generating
droplets in the diameter range useful for respiratory delivery. Basic crystals formation
mechanisms have been derived with this technique,
Conclusion:
The examples given in this review show the level of sophistication that can be achieved with a
seemingly simple process such as spray drying. Even spray drying from a homogeneous solution,
if properly understood, can be used to design crystals that have a multifunctional internal
structure. Potential further advances in crystal engineering may be achieved by combining spray
drying with additional processing steps before, during, or after the drying step. The most
common modification to a simple solution spray drying process is the preparation of a
suspension or colloid prior to spray drying.
A very exciting development is the design of composite particles spray dried from dispersed
nanoparticles or even mixtures of different nanoparticles. The nanoparticles are typically
manufactured separately prior to preparation of the dispersion and retain their special properties
such as enhanced solubility or targeting capacity for the final product. Some of their
disadvantages, e.g. their tendency to agglomerate or their unfavorable aerosol transport
properties, are mitigated by the fact that they are now part of a larger microparticle. It is
interesting that the properties of the product are now determined by the primary morphology of
the composite particle, the morphology of its nanoscale substructure, and their interactions. This
highlights the importance of proper particle design in these systems. Rather complex dispersion

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systems with more than one solid dispersed phase have been studied. Calcium salts were
dispersed in an aqueous polymeric suspension and then spray dried to produce
microencapsulated crysatals . A thorough review of the large number of combination processes
where spray dried microcrystals play a role is beyond the scope of this review. It will be
interesting to follow whether the added functionality of the crystals fabricated with such
processes will justify their increased complexity in a commercial setting. It is already obvious
that the new class of engineered spray dried particles requires a shift in the thinking and structure
of pharmaceutical organizations developing them. Because both process and formulation now
equally determine key product parameters, it should be reconsidered whether separate groups
working on formulation and process development, optimization and scale-up are adequate. This
new class of products demands a unified design approach reflected in an organizational structure
that allows constant collaboration of formulators and process engineers in a single group. It also
becomes evident that purely empirical approaches to product design are doomed to fail in a
situation where the parameter space is defined by a very large number of formulation and
process variables. Successful design of engineered particles requires thorough understanding and
predictive modeling, so that the early development process can be completed in an acceptable
time with a high likelihood of success. Much of the fundamental work, including the
measurement of urgently needed material properties remains to be done.
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Spray drying: A crystallization technique : A review

Article · January 2010

Mudit Dixit Parthasarathi Kulkarni

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International Journal of Drug Formulation & Research

SPRAY DRYING: A CRYSTALLIZATION TECHNIQUE : A REVIEW

MUDIT DIXIT*, P.K.KULKARNI, ASHWINI G KINI AND H.G.SHIVAKUMAR

KEY WORDS: spray drying, crystallization, dispensability, microencapsulation; particle formation,

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Advantages of rotary atomizers:

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-Difficult to use with highly viscous materials.

Two-fluid or Pneumatic nozzles: Atomization by kinetic energy

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-Increased Thermal stability, and suitability for further applications.

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Table: 2 Comparison of spray dryer at laboratory, pilot and commercial scales

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Figure-7 Scanning electron microscopic photographs of spray-dried chitosan microspheres;

DEFINITIONS AND THEORY CRYSTALS:

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where the exact equations are cumbersome to use.Terminology of Structured Microcrystals

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Figure-8 : Schematic representation of particle morphologies. a Layered with central core.

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35. G. Lee. Spray-drying of proteins. Pharm. Biotechnol. 13:135– 158 (2002).

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52. G. Dollo, P. Le Corre, A. Guérin, F. Chevanne, J. L. Burgot, and R. Leverge. Spray-dried

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90. T. A. G. Langrish, N. Marquez, and K. Kota. An investigation and quantitative assessment of

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