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Drying of Pharmaceutical Products

Chapter · January 2007

DOI: 10.1201/b17208-37

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 Drying of Pharmaceutical Products
29 Zdzisław Pakowski and Arun S. Mujumdar

CONTENTS

29.1 Introduction ......................................................................................................................................... 689

29.2 Classification of Pharmaceutical Products with Respect to Dryer Selection ....................................... 690
29.3 Properties of Pharmaceutical Products ................................................................................................ 691
29.3.1 Physical Properties .................................................................................................................. 691
29.3.1.1 Particle Size ............................................................................................................. 691
29.3.2 Thermal Properties .................................................................................................................. 692
29.3.3 Sorptive Properties .................................................................................................................. 692
29.4 Dryer Types and Their Performance.................................................................................................... 693
29.4.1 Directly Heated Dryers: Batch Dryers .................................................................................... 693
29.4.1.1 Ovens....................................................................................................................... 693
29.4.1.2 Fluid Bed Dryers..................................................................................................... 693
29.4.2 Directly Heated Dryers: Continuous Dryers........................................................................... 693
29.4.2.1 Band Dryers ............................................................................................................ 693
29.4.2.2 Turbo-Tray Dryers.................................................................................................. 695
29.4.2.3 Pneumatic Dryers.................................................................................................... 695
29.4.2.4 Cyclone Dryers........................................................................................................ 695
29.4.2.5 Spouted Bed Dryers ................................................................................................ 697
29.4.2.6 Vibrated Bed Dryers ............................................................................................... 698
29.4.2.7 Fluid Bed Dryers..................................................................................................... 698
29.4.2.8 Spray Dryers ........................................................................................................... 698
29.4.3 Indirectly Heated Dryers ......................................................................................................... 698
29.4.3.1 Drum Dryers ........................................................................................................... 698
29.4.3.2 Vacuum Dryers ....................................................................................................... 698
29.4.3.3 Freeze Dryers .......................................................................................................... 702
29.4.4 Granulation and Drying.......................................................................................................... 703
29.5 Drying of Dosage Forms ..................................................................................................................... 703
29.6 Some Technological Data on Drying of Pharmaceutical Products...................................................... 704
29.7 Aseptic Conditions in Pharmaceutical Dryers ..................................................................................... 704
29.8 Solvent Recovery and Closed-Cycle Drying ........................................................................................ 710
Acknowledgments .......................................................................................................................................... 712
References ...................................................................................................................................................... 712

29.1 INTRODUCTION the Good Manufacturing Practices (GMP) for drug

The pharmaceutical industry is one in which quality
of the final product cannot be compromised. Any
deterioration of the product (e.g., by microbial infec-
tion, oxidation, thermal decomposition, contamin-
ation by metallic particles or by unremoved organic
solvent) must be avoided at any cost. In light of that
manufacture (see, e.g., Ref. [1]) put numerous de-
mands on the drying stage of the drug manufactur-
ing process. Noncontaminating dryer construction
materials are used, like polished stainless steel or
enameled iron. Closed-cycle dryers are often re-
quired as moisture removed is often an organic
solvent or their mixture. Drying must be often

ß 2006 by Taylor & Francis Group, LLC.

performed in inert gas to avoid oxidation or explo- For the first group the following types of dryers
sion if solvent is flammable. To avoid thermal de- are generally used: convective (tray, band, fluid bed,
composition in many instances vacuum and freeze flash dryers, and their modifications) or contact
drying must be employed. (vacuum dryers such as double-cone dryer-blender,
All these requirements put dryers for pharmaceut- conical dryer with rotating helical mixer, paddle
icals among the most expensive and sophisticated dryer). Pastelike materials are dried in tray dryers,
drying equipment. At the same time the wide variety band dryers equipped with extruding devices, and
of drugs produced by any pharmaceutical company spin-flash dryers. Finally, thin pastes can be dried in
(tens of thousands of individual drugs are produced spray dryers or on fluid beds or spouted beds of inert
worldwide) in many different forms causes dryers in particles. Small amounts of solutions and suspensions
the pharmaceutical industry to encompass a wide are generally freeze-dried, especially if the product is
range of types, both batch and continuous. thermolabile.
The manufacture of a drug that will be distributed Further selection of dryers is based on the drying
in nonliquid form (tablets, capsules, dragees) is kinetics, which is closely associated with the structure
carried out in three subsequent stages: as represented by their mean pore size and the type of
the moisture–material bond. Sazhin has developed a
1. Synthesis of intermediate products classification based in principle on Rebinder’s pro-
2. Final synthesis of the drug posal, which classifies all materials into four groups.
3. Manufacture of dosage forms This classification [2], which can be used to help select
a dryer, is presented in Table 29.1. Although the
After each stage the products are dried. Selection selection of the dryers is limited to dryers for granular
of a proper dryer for these products depends on the materials, this classification scheme has general valid-
properties of materials such as their form, thermal ity. The quantitative basis of the classification is the
sensitivity, tonnage, drying kinetics, and so on. Since minimum pore diameter from which moisture is to be
most pharmaceuticals are low-tonnage and high- removed during drying.
value products, considerations of energy saving are
usually of secondary importance in the selection of
the drying process.
TABLE 29.1
Classification of Granular Materials
29.2 CLASSIFICATION OF Group Pore Size Drying Time in Types of Dryers
PHARMACEUTICAL PRODUCTS WITH (nm) Suspended State Recommended
RESPECT TO DRYER SELECTION
I >100 0.5–3.0 s Cyclone dryers
From the point of view of drying technology, all Flash dryers
Two-stage
substances dried in the pharmaceutical industry can
flash dryers
be classified into three major groups:
II 100–6 3–30 s Two-stage
flash dryers
1. Granular materials: Solids in the form of indi- Fast spouted bed
vidual particles of the size approximately in the III 6–4 0.5–2 min Vortex dryers
range 0.05 to 5 mm Batch dryers
2. Pastelike materials: Solids mixed with liquid to 4–2 2–20 min Fluid bed
form a free-flowing paste; size of particles ap- Vibrated fluid bed
proximately in the range 0.1 to 50 mm Batch dryers
3. Solutions and suspensions: Solids dissolved or IV Ultramicropores, 10–60 min Vibrated fluid bed
suspended in liquid in the form of fine (10–50 particle
size 1–2 mm
mm), ultrafine (0.1–10 mm), or colloidal (<0.1
Multistage fluid bed
mm) suspensions
Batch dryers
40–90 min Batch dryers
The criteria of classification are not clear-cut here, Suspended state
and wet granular material of small particle size can as dryers not
well be classified as pastelike and a thin paste can be recommended
classified as a suspension if it is pumpable. According Particle size >90 min
to the type of the material, appropriate drying systems >2 mm
are chosen.

ß 2006 by Taylor & Francis Group, LLC.

 The four groups are categorized as follows:
TABLE 29.2
Classification of Granular Pharmaceuticals
Group I: Nonporous or capillary-porous solids
According to Size (British Pharmacopoeia)
with large pore sizes. Only free moisture is re-
moved during drying. Sodium chloride and acet- Class Particle Size
ylosalicyclic acid (ASA) belong to this group. Range (mm)
Group II: Uniformly and nonuniformly porous
Coarse powder 100% <1680 40% <355
materials with pore sizes down to 6 nm. Mois-
Moderately coarse
ture removed during drying is physically or
powder 100% <1680 40% <250
physicochemically bonded. That is, it includes Moderately fine
free moisture, moisture of macro- and micro- powder 100% <355 40% <180
capillaries, and surface-adsorbed moisture. Fine powder 100% <180
Phenobarbital, methenamine (Urotropin), and Very fine powder 100% <125
sodium perborate belong to this group. Ultrafine powder 100% <50 90% <5
Group III: Microporous or colloid-capillary-
porous materials. During drying all phy-
sicochemically adsorbed moisture is removed. recommended for drying in fluid bed dryers owing
The following substances belong to this group: to their very low entrainment velocities and often
6–4 nm subgroup, glucose and sulfadimethox- poor fluidization quality due to agglomeration.
ine; 4–2 nm subgroup, calcium gluconate and
calcium glycerophosphate.
29.3 PROPERTIES OF PHARMACEUTICAL
Group IV: Ultramicroporous materials. Pore size
is comparable to the size of molecules of re- PRODUCTS
moved moisture. Moisture of ultramicropores
29.3.1 PHYSICAL PROPERTIES
is removed in intense drying, which corresponds
to moisture contents as low as 0.2–0.1% or less. 29.3.1.1 Particle Size
Chemically bonded moisture is also removed in
this case. Pharmaceuticals are usually obtained by crystallization.
Under most conditions their particle size seldom grows
Besides the pore size, which characterizes the drying larger than 1 mm. Generally, owing to their low solu-
time of individual particles, granular materials have bility, the crystals are small or very small. The particle
certain flow properties that describe among other prop- size distribution of a typical pharmaceutical as meas-
erties how easily they can be transferred into a sus- ured by sieve analysis is shown in Figure 29.1. From the
pended state. Materials that have large cohesion tend point of view of drying technology, for monodisperse
to form agglomerates and are difficult to dry in fluid materials, such as ASA and sodium p-aminosalicylate,
beds or pneumatic dryers. Agglomerates have larger the aerodynamic conditions in dryers are much easier
perimeters than individual particles, and the macro- to select. If particle size distribution is unimodal but
pores formed between particles increase the diffusional widespread (e.g., Urotropin or phenyl salicylate) or
heat and mass transfer resistance. Roughly, granular bimodal (e.g., codeine, streptomycin, or sulfanilamide),
materials are classified as free-flowing and sticky mater- the material is more difficult to dry in suspended state
ials. The degree of stickiness depends on particle size as particle segregation may occur.
and viscosity of surface moisture. Generally the smaller Materials produced in spray dryers from solutions
the particles and the more viscous the fluid the stickier and suspensions are characterized by a very small
the product will be. Selection of a dryer for a free- particle size. Particle sizes in the range 1 to 500 mm
flowing material is usually simple whereas drying of a are observed. All powders must be granulated before
sticky product may be a serious problem. Certain prod- tableting. According to Remington [3], the following
ucts not sticky at normal temperatures become sticky at granulate size should be used to produce tablets of
elevated temperatures due to plasticizing or dissolving given diameter.
in moisture. This may lead to defluidization of a bed at a
certain temperature, for instance. Tablet Diameter (in.) Granulate Size (mesh)
Granular materials are often classified by size.
0–3/16 20
According to the British Pharmacopoeia classification
7/32–5/16 16
shown in Table 29.2, they are divided into six classes.
11/32–13/32 14
This classification helps in dryer selection. Generally, >7/16 12
very fine powders and ultrafine powders are not

ß 2006 by Taylor & Francis Group, LLC.

 11 14 3
10 4 13
12
9
11
8
10

Δn/d. mm−1
Δn/d. mm−1 7 3 9
5
6 8 2
7
5
6
4 1
5
2 1
3 4
3
2
2 4
1 1
0 0
0.2 0.4 0.6 0.8 1.0 0.2 0.4 0.6 0.8 1.0
(a) d.mm (b) d.mm

FIGURE 29.1 Size distribution of typical pharmaceutical products: (a) 1, streptomycin sulfate; 2, ascorbic acid; 3, hydrate of
diaceto-2-keto-L-gulonic acid; 4, starch; 5, talcum; (b) 1, sulfanilamide; 2, acetylosalicyclic acid; 3, sodium p-aminosalicylate;
4, codeine þ terpin hydrate. (From Golubev, L.G., Sazhin, B.S., and Valashek, E.R., Drying in Chemicopharmaceutical
Industry, Meditsina, Moscow, 1978 (in Russian). With permission.)

About 10–20% of fine particles in granulate are solid. They may be found in specialized books [2,4]
generally allowed as they improve the flow properties for most common pharmaceuticals.
of the granulate.

29.3.2 THERMAL PROPERTIES 29.3.3 SORPTIVE PROPERTIES

Among thermal properties, thermal decomposition
rate is of primary interest. Usually thermal decom-
position follows a first-order reaction kinetics, that is,
c ¼ c0 ekt
where c is the actual concentration, c0 is the initial
concentration, k is the rate constant (1/s), and t is the
time (s).
The reaction rate constant depends on tempera-
ture according to Arrhenius theory:
k ¼ AeE=RT
where A is constant (1/s), E is the activation energy
(J/mol), R is the universal gas constant (J/(mol K)),
and T is temperature (K).
For example, thiamine hydrochloride in aqueous
solution has E ¼ 92.18 kJ/mol and A ¼ 9.581010
1/min. Processing such solution at 908C for 10 min
would result in c/c0 ¼ 0.949 (i.e., about 5% loss). One
has to remember that thermal decomposition is usu-
ally influenced by water content of the processed
material.
Other properties of interest include melting point
temperature, specific heat, and heat conductivity of
Sorptive properties of the pharmaceutical products as
represented by their sorption isotherms reflect their
ability to absorb water from the air and are the source
of valuable information for the selection of dryers as
well as the packaging conditions. The sorption iso-
therm is the relationship between the relative humid-
ity of the air and the moisture content of solid in
equilibrium with this air.
They are usually measured by gravimetric methods,
where a known amount of solid of known initial
moisture content is exposed to a gas of specified
relative humidity. After sufficient time, the new
weight of the sample is measured, which allows one
to calculate the actual moisture content.
In most cases the sorption isotherm produced
under conditions of increasing humidity (sorption)
differs from that produced when humidity is de-
creased (desorption). This phenomenon, known as
sorption hysteresis, can sometimes be very substan-
tial. For drying purposes only desorption isotherms
are of practical significance.
Sorption isotherms should if possible be measured
under dynamic conditions, as in a condition of fluid-
ization. The use of sorption isotherms measured
under static conditions can lead to substantial errors
when used for calculations of fluid bed, pneumatic, or

ß 2006 by Taylor & Francis Group, LLC.

other dryers with particles suspended in the air. Sorp-
tion isotherms for a series of selected pharmaceuticals
were tabulated by Reprintseva and Fedorovich [4].
Analysis of their sorption isotherms allows one to
classify the products and give some indications
about the selection of dryer.
Materials with intensive hysteresis for which sorp-
tion and desorption isotherms coincide only at two
points, at zero and saturation humidity, belong to
colloidal bodies according to Rebinder’s classifi-
cation. Most of the final pharmaceutical products
belong to this group. All tableting formulations con-
taining starch or gelatin are obtained by spray drying
a mixture of the drug with all other tablet compon-
ents, such as lubricants, binders, and diluents, which
are colloid in nature.
Materials that display no sorption hysteresis, or if
their hysteresis is limited (the range RH 0.2–0.9 or
over a narrower range), are classified as capillary-
porous bodies. As examples, ascorbic acid, p-amino-
benzosulfamide, and hexamethylenetetramine may be
mentioned here. Materials showing sorption iso-
therms intermediate between these two categories be-
long to the so-called capillary-colloid-porous bodies,
and they include ASA and penicillin. The energy of
the solid–moisture bond increases from capillary-
porous to colloidal bodies. Adequate drying temp-
eratures and residence times must be used for drying
such difficult to dry solids. The temperature of dry-
ing is directly proportional to the energy of the solid–
moisture bond. The drying time depends on particle
size and the amount of moisture removed.
More information can be obtained from drying
kinetics and experimental measurements. These ex-
periments provide the ultimate basis for selection of
the appropriate dryer and drying condition. Often
one may arrive at several alternate drying equipment
for drying a given product.
Some information on moisture–material bond
type is presented in Table 29.3 for selected products.
More specific information on sorption isotherms for
most common materials used in the pharmaceutical
industry together with measuring methods may be
found in Stahl [5].
29.4 DRYER TYPES AND THEIR
PERFORMANCE
High-quality standards and high price of the final
product demand high reliability and justify more so-
phisticated construction of pharmaceutical dryers
than dryers used in most other industries. Traditional
dryers of the pharmaceutical industry, such as shelf or
batch fluid bed dryers, are continuously supplemen-
ß 2006 by Taylor & Francis Group, LLC.
ted by dryers first used in other fields of application.
Increasing quantities of products may call for con-
tinuous dryers. Increased quality control and larger
production rates continuously broaden the range of
dryer types used in the pharmaceutical industry. This
chapter presents only the most widely used types of
dryers for pharmaceuticals. More information on per-
formance of industrial dryers for pharmaceuticals is
given by Simon [6]. It should be noted that most of
these dryers are discussed in greater detail elsewhere
in this handbook.
29.4.1 DIRECTLY HEATED DRYERS: BATCH DRYERS
29.4.1.1 Ovens
For small batches of pharmaceuticals, ovens are still a
good choice. They allow for placing material upon
several shelves, which can be carried by a truck. Dur-
ing drying, hot air is cross-circulated between the
shelves to permit drying of different products at the
same time. Internal circulating air filters are often
provided (Figure 29.2) to protect against cross-contam-
ination of the products. Similar ovens can be used for
thermal sterilization of vials and bottles, for example.
29.4.1.2 Fluid Bed Dryers
Small batch fluid bed dryers (Figure 29.3) are very
commonly used in the pharmaceutical industry.
Owing to better air–solid contact, drying in fluid
beds is faster than in tray ovens and because of
good mixing product uniformity is much improved.
Usually they are supplied with roll-on roll-off drying
chambers often equipped with an agitator. Air after
drying is filtered, usually in multicyclones or bag
filters. The use of bag filters is, however, troublesome
if the dryer is often used for different products as it
requires very careful cleaning.
29.4.2 DIRECTLY HEATED DRYERS: CONTINUOUS
DRYERS
29.4.2.1 Band Dryers
Relatively seldom used in the manufacture of final
pharmaceutical products, band dryers find wide use
in drying of raw materials, especially herbal and me-
dicinal plants. Usually several bands in one-above-
another configuration are used. Bands are made of
stainless steel screens or perforated plates. Band
speeds from several centimeters to about 0.5 m/min
are used. Bandwidths vary from as low as 0.5 m up to
2 m. Drying air temperatures in the range 80–1008C,
initial moisture contents of 45–100%, (d.6) and drying
rates of 5–18 kg/m2 h are usual in industrial practice.
ß 2006 by Taylor & Francis Group, LLC.

TABLE 29.3
Data on Water Sorption Properties of Selected Pharmaceutical Materials

Substance Moisture Content (% Dry Basis)

Physicochemical Bond Desorption Sorption Desorption Maximum Heat of

Hygroscopic Sorption
Physicomechanical Bond Polymolecular Adsorption Monomolecular Adsorption
Moisture (102,
Capillary Osmotic Sorption Content kJ/kmol)

Penicillin 21.4 9.6 3.0 3.6 1.0 1.0 19.0 134.0

Streptomycin 20.0 10.0 9.0 12.0 6.8 6.0 25.0 158.0
Phenylsalicylate — — — — 0.18 — 1.0 58.12
Acetylosalicyclic acid 8.5 6.0 1.5 1.7 0.5 0.5 5.8 23.50
Sodium p-aminosalicylate 20.0 12.0 8.0 10.0 2.0 2.0 20.0 —
Ascorbic acid 13.0 13.0 0.5 0.6 0.25 0.25 2.0 8.95
Talcum — — 0.1 — 0.05 — 0.35 10.36
Starch 32.0 22.0 13.6 16.0 8.2 10.0 26.0 56.35
 3 5 3 4 6 4 1
6 2

2
2

FIGURE 29.4 Turbo-tray dryer (1, shelves; 2, blades; 3,

heater; 4, fan rotors; 5, shelf and fan drive).
FIGURE 29.2 Shelf batch dryer (1, shell; 2, truck with
shelves; 3, heater; 4, fan; 5, air filters; 6, valves).
29.4.2.3 Pneumatic Dryers

In pneumatic dryers the wet feed is introduced into a

29.4.2.2 Turbo-Tray Dryers
Turbo-tray dryers, suitable for granular feeds, oper-
ate with rotating shelves and forced convection of the
air above the shelves (Figure 29.4). The product layer
fed onto the first shelf is leveled by the set of station-
ary blades, which also scratch a series of grooves onto
the layer surface. All blades are staggered so that a
new surface layer is formed by each set. This way the
layer is well mixed and dries uniformly. After travel-
ing one rotation, the material is wiped off by the last
blade and falls onto the lower shelf. The dryer can
have up to 30 trays or more and provide large resi-
dence times. Hermetic sealing of the whole dryer is
easy so that solvent recovery can be achieved.
stream of hot gas flowing with velocities of several
meters per second, usually in a vertical insulated duct.
During their cocurrent contact moisture is evapor-
ated, consuming the sensible heat of the gas. High
evaporation rates (values as high as 240–1200-kg
moisture per h and per m2 of contact area are gener-
ally met) and cocurrent contact protect the particles
from overheating. After a time of the order of a
fraction of a second to a few seconds, the dried ma-
terial and gas leave the duct and are separated in a
cyclone. Very short times of contact allow drying only
the unbound moisture from small particles.
To prolong the contact time with the same dryer
height (or length), spiral inserts may be installed inside
the dryer tube. Similar to other directly heated dryers,
they can operate in a closed cycle. A closed-cycle
pneumatic dryer is shown schematically in Figure 29.5.

6 29.4.2.4 Cyclone Dryers

Observations of pneumatic dryers proved that a con-

7
4 siderable amount of total moisture removed evapor-
ates in the cyclone separator. Several new dryer types
were constructed that apply the principle of vortex
flow. In addition, the cyclone dryers have particle
5 separation features. Centrifugal force keeps large
1 and wet particles rotating whereas small and dry
2 particles can be carried away with gas. Adjustment
6 of gas velocity can thus change the critical particle
3
size as well as residence time in the dryer.

FIGURE 29.3 Batch fluid bed dryer (1, fluidizing chamber; 29.4.2.4.1 Convex-Type Dryers
2, gas distributor; 3, plenum chamber; 4, blower; 5, heater; The construction of convex-type dryers resembles a
6, filters; 7, bag dust collector). flat cyclone without the conical bottom (Figure 29.6).

ß 2006 by Taylor & Francis Group, LLC.


1 nitrogen
Feed
6
FIGURE 29.5 Closed-cycle pneumatic dryer in conjunction with a centrifuge (1, dryer tube; 2, cyclone; 3, blower; 4,
condenser; 5, heater; 6, centrifuge).
A fast stream of hot gas carrying suspended wet
particles is introduced tangentially into the chamber.
After several spins (i.e., helical motion within the
chamber), the gas and material escape through a
central exhaust port and are separated in a cyclone.
A characteristic feature of this type of dryer is that
only small particles can be carried away as large wet
particles are thrown by the centrifugal force toward
the periphery. This type of dryer can be designed to
FIGURE 29.6 Schematic of a convex dryer.
ß 2006 by Taylor & Francis Group, LLC.
3
2 Bleed
Make-up
Steam Coolant
5 4
Solvent
obtain a final product of required particle size. To help
disintegrate the large particles, mechanical impact
disintegrators are often built into the drying chamber.
29.4.2.4.2 Spin-Flash Dryers
The principle of separation of wet and dry particles is
applied in the design of a spin-flash dryer for sticky
and pastelike materials (Figure 29.7). In the bottom
of a cylindrical chamber a high-speed impeller disin-
tegrates the wet feed in a rapid stream of the tangen-
tially introduced heated gas stream. The swirling gas
carries away dry particles, which are then separated in
a cyclone. Partially dried particles fall back into the
impeller zone and are disintegrated. This type of dryer
is especially suitable for thick pastes as it can handle
them without dilution.
29.4.2.4.3 Countercurrent Spin Dryers
In a countercurrent spin dryer, a principle of two
coaxial cocurrent swirls of gas is applied. An exem-
plary dryer scheme working according to this prin-
ciple is shown in Figure 29.8. The cylindrical chamber
is equipped with a series of side ports that introduce
air tangentially into the chamber. The velocity of the
side airstreams varies in the range of 5–100 m/s and is
capable of producing a looser or tighter spiral, or
finally a stationary circular motion of the entrained
 Product
Feed
A
A Air
FIGURE 29.7 Schematic of a spin-flash dryer.
particles depending on the side nozzle inclination and
gas velocity. In this way particle residence time can be
controlled. Wet solids are introduced at the top of the
dryer chamber. Drying occurs as the solids descend
and finally separate from the gas, leaving the chamber
through a bottom port equipped with an airlock.
29.4.2.5 Spouted Bed Dryers
A spouted bed is essentially a conically shaped cham-
ber with a cylindrical section on top supplied with air
Vapors
Air
Feed
Product
FIGURE 29.8 Schematic of a countercurrent spin dryer.
ß 2006 by Taylor & Francis Group, LLC.
A-A
Air
through a single nozzle at the bottom (Figure 29.9).
The operational regime of the spouted bed dryer
depends on the properties of feed and the assumed
final product requirements. Polydisperse, slow-drying
granular materials are continuously added and re-
moved from the bed. Particles that undergo severe
attrition or dramatically lose weight when dry can
be carried away from the chamber with the heat
carrier. Product size and moisture content are thus
controlled by superficial air velocity in the cylindrical
part of the drying chamber. Pastelike materials can be
sprayed onto a spouted bed of inert material. Owing
to severe attrition the dry product is removed from
the particles and carried away with gas for collection
in a separator.
4
2
FIGURE 29.9 Schematic of a spouted bed dryer with an
inert bed (1, shell; 2, nozzle; 3, particle separator; 4, spray
nozzle; 5, inert bed).
29.4.2.6 Vibrated Bed Dryers
For highly polydisperse or sticky products with long
drying times, the vibrated bed type of dryer offers the
possibility of continuous operation accompanied by
gentle material handling and uniformity of the final
product moisture content. A trough vibrating in a
direction slightly inclined to the vertical at frequencies
up to 60 Hz and amplitudes up to several millimeters
offers the possibility of simultaneous material trans-
portation and vigorous mixing. In such a dryer,
granular material can be heated directly from gas
blown through a perforated trough bottom or indir-
ectly from heating surfaces immersed in the bed. Vi-
bratory action reduces material cohesion, which
makes this dryer suitable for very wet or sticky ma-
terials. Spiral construction of the trough can, if neces-
sary, extend the residence time of the material up to
30 min. These dryers can operate with virtually any
gas velocity up to the entrainment limit. The gas
velocity can be adjusted to the particle size. In direct
drying conditions, evaporation rates 30–100 kg/hm2
of grid area are observed. If the amount of heat
carried with gas is not adequate for drying, additional
contact heaters can be employed.
Radiant heating by infrared radiation (IR) radi-
ators can also be used. However, in this case only very
thin beds can be uniformly heated. For glutamic acid
with material load 15 kg/m2 and radiant heat flux 3.5
kW/m2, evaporation rates up to 4.5–9 kg/m2h have
been observed.
29.4.2.7 Fluid Bed Dryers
Continuous fluid bed dryers are generally built in two
versions: vessel-like ideally mixed dryers and trough-
like plug-flow dryers. Perfectly mixed fluid bed dryers
are characterized by a rapid decrease of the feed
moisture content as it is diluted in the large volume
of the relatively dry bed. Therefore, they can handle
relatively high initial moisture content feedstock.
Trough dryers are much more sensitive to initial
feed moisture content since the solid’s moisture de-
creases gradually with dryer length. As expected, they
provide a much better residence time distribution
(RTD) of solids in the dryer. Fluid bed dryers can
be built virtually in any required scale. Besides drying
they can be used for cooling and granulation. Their
modifications, such as vibrated, stirred, and pulsed
fluid beds, can be used to dry or process polydisperse
and relatively sticky materials.
29.4.2.8 Spray Dryers
Solutions and thin slurries of drugs can be spray dried
by contact with hot air. Particles of dry product
ß 2006 by Taylor & Francis Group, LLC.
obtained in such a way are very fine, so after mixing
with other components and granulation they can be
used directly for tableting. When the spray drying
operation is cocurrent, that is, hot air is introduced
into the dryer close to the atomizing device, there is
no danger of overheating as evaporation rates are
high (34–160 kg/hm2 of particle area). Thus, highly
heat-sensitive materials can be spray dried.
A typical arrangement of an open-cycle spray
dryer for pharmaceuticals is shown in Figure 29.10.
Gas–liquid nozzles are commonly used to spray feeds
that are solutions. However, in the production of
certain pharmaceuticals, such as antibiotics, the pow-
ders obtained by spray drying low-concentration
aqueous solutions have low bulk density. Higher
bulk density can be obtained if the feed is partly
precipitated. High bulk density antibiotics are pro-
duced from suspensions of precipitated substrates in
organic solvents; this requires the use of a closed-cycle
dryer to recuperate the solvent and also an inert gas
as drying medium to avoid the risk of ignition. Sev-
eral pharmaceutical products after filtration form
pastes that can be spray dried if they are pumpable.
Pastes that are too thick must be thinned with solv-
ents or by disintegration of their structure, as in the
case of thixotropic pastes. From a practical point of
view, disk atomizers are better capable of handling
thicker pastes than are two-fluid nozzles.
In many cases, when inert gases are used for dry-
ing or valuable solvents must be recovered, a closed-
cycle dryer can be designed according to the rules
explained in Section 29.6.
29.4.3 INDIRECTLY HEATED DRYERS
29.4.3.1 Drum Dryers
Drum dryers are frequently used for drying slurries
and thin pastes, especially those that easily adhere to
the metal surface and therefore are difficult to dry in
other dryers. The slurry or paste is fed onto the drums
by means of various types of feeders. Some of the
standard feeding arrangements and recommendations
for their use are indicated in Figure 29.11. The dry
product is removed by doctor blades. Depending on
the material properties, the product is removed in the
form of powders, flakes, or webs. The drum can be
entirely enclosed in a hood and supplied with the
necessary amount of drying gas. Thus, organic solvents
can be recovered in a closed-cycle operation.
29.4.3.2 Vacuum Dryers
Materials that are thermolabile or easily oxidizable,
especially when wet, can be dried in vacuum dryers.
 Feed

5
3

7
2

1
4
9
6

8
Product

FIGURE 29.10 Spray dryer installation (1, drying chamber; 2, atomizer; 3, air dispenser; 4, air heater; 5, feed pump; 6, main
cyclone collector; 7, wet scrubber; 8, pneumatic conveying system; 9, conveying cyclone). (Courtesy of A/S Niro Atomizer,
Soeborg, Denmark.)

2 2

3 1 1 3
3

4 4 1 1

(a) (b)

1 1 1 1

3 3
2 2
3 3
4 4 4

(c) (d)

1 1
3
3 3

4 4 4
(e) (f)
FIGURE 29.11 Some standard feeding arrangements for drum dryers: (a) nip feed, suitable for thin solutions; (b) feed roll,
suitable for glutinous materials, such as starch; (c) double applicator roll, for heat-sensitive materials; (d) splash feed, used
for slurries; (e) dip feed, for suspensions; (f) multiple applicator roll, used for increasing film thickness (1, drums; 2,
applicator rolls; 3, doctor blades; 4, conveyors). (Courtesy of R. Simon and Sons, Basford, England.)

ß 2006 by Taylor & Francis Group, LLC.

 2

6
3

FIGURE 29.12 Double-cone batch vacuum dryer (1, steam jacket; 2, hatch; 3, drive; 4, vacuum ducts; 5, steam supply;
6, bearings).

Various types of vacuum dryers are in use for drying walls and mixes and transports it along the dryer
pharmaceutical products. length. Solvents can be fully recovered if a suitable
condenser for vapors is provided. Evaporation rates
29.4.3.2.1 Double-Cone Dryer-Blender of water up to 10 kg/hm2 are observed.
Operated in batch mode, the double-cone dryer-
blender dryer (Figure 29.12) is suitable for drying
wet granular materials. Owing to the intense blending
5
that occurs during the drying cycle, they can be
used for preparation of the tableting formulations. 3
Commercial double-cone dryers have capacities up 2
to 10 m3. They may be glass lined to provide high
purity of the product. They are especially suitable to 6
perform consecutive chemical reaction-drying cycles.
Reagents can be supplied through a feed tube or
through a hollow shaft. The heat necessary to evap-
orate the moisture is supplied from steam-heated
dryer walls. Drying rates observed here are in the
range 2–7 kg/hm2 of the heated area.
29.4.3.2.2 Conical Dryer with Screw Mixer
The conical dryer with screw mixer is similar in prin- 1
ciple to the double-cone dryer-blender although the
vessel is stationary and solids are mixed by epicyclic
screw mixer (Figure 29.13). For pressures from 25 to
150 mbar and wall temperatures from 40 to 608C,
Simon [6] reports evaporation rates of water up to
10 kg/hm2. Units up to 5 m3 are commercially avail-
able. The dryer has no dead spaces and is easy to clean.
29.4.3.2.3 Paddle Dryers 4

Continuously operated dryers of the paddle type

(Figure 29.14) provide drying times up to several
hours. Suitable for pastelike and granular materials, FIGURE 29.13 Conical vacuum dryer with epicyclic screw
they are steam heated. A horizontal rotating shaft mixer (1, steam jacket; 2, hatch; 3, feed tube; 4, exit port and
fitted with paddles scrapes the product from the valve; 5, motor; 6, drive arm; 7, mixing auger).

ß 2006 by Taylor & Francis Group, LLC.

 Vapors

Feed
6

4
7 3

2 5 5
Product

FIGURE 29.14 Continuous vacuum paddle dryer (1, vapor filter; 2, steam jacket; 3, shaft with paddles; 4, paddles; 5, valves;
6, shaft drive; 7, shaft oscillator).

29.4.3.2.4 Vacuum Band Dryers
Vacuum band dryers are suitable for all types of
pastelike materials. Wet material is dried as it is
transported on a moving band. Heat is supplied by
infrared low-temperature radiators or by contact with
heated bands. A multiband vacuum dryer is shown in
Figure 29.15. To allow continuous production, such
dryers are equipped with an automatic discharge
system that prevents dehermetization of the dryer
chamber. Drying chambers that provide drying sur-
face areas up to 120 m2 are available commercially.
29.4.3.2.5 Filter Dryer
The filter dryer is a combination of two operations in
one vessel. Usually it has a cylindrical form with
a bottom that serves as a filter. It is equipped with a
paddle agitator that can be heated internally or heat
may be transmitted through jacketed walls. In the

1 6

2 3 4 5 7

FIGURE 29.15 Band vacuum dryer installation (1, feed mixer; 2, filter; 3, feed pump; 4, band; 5, heating panels; 6, vapor
condenser; 7, scraper; 8, product collector system).

ß 2006 by Taylor & Francis Group, LLC.

latter case, the vessel is turned upside down after
TABLE 29.4
filtering. Units of filter area up to 15 m2 and volumes
Performance Parameter Ranges for Pharmaceutical
up to 22.5 m3 are built.
Freeze Dryers

Parameter Normal Special

29.4.3.3 Freeze Dryers Conditions Conditions

Chamber pressure (mmHg)

Freeze drying is the best method for drying highly heat-
Peak 100–200 50
sensitive or easy oxidizable materials. However, its se-
Final 20–50 5–10
lection must be governed by economic considerations. Shelf temperature (8C)
Early applications of this method were the drying of Lowest 40 50
blood plasma and serum during World War II. Highest 70 80
The high cost of freeze-drying discourages its Shelf heat-up rate (min),
wider application. In freeze-drying, solutions of phar- from 408C to 708C 90 60
maceuticals dosaged into vials are frozen and placed Shelf cool-down rate (min),
in a vacuum chamber. Ice sublimes, consuming the from 228C to 448C 90 60
latent heat of sublimation, supplied from heated Evacuation rate (min) to
reach 100 mmHg 15–30 5–10
shelves. Recently, microwave heating has also been
Vapor handling capacity
used in freeze dryers. The vapor is continuously re-
(kg H2O/hm2) 0.98 1.47
moved by a vacuum pump. After all moisture sub-
Total shelf area (m2) 11–25 0.75–3.5
limes, a very fine porous structure remains that can be
easily rehydrated. It was noticed that solutions di-
luted below 1% (weight) concentration of solids do
not produce such structure. The structure is labile and
can collapse if its temperature is raised above a cer- heated, preferably with the possibility of tem-
tain temperature of collapse. This temperature can be perature control.
as low as 408C (e.g., for glucose and fructose) or Vacuum pump: In a typical dryer with the shelf-
108C (e.g., for starches and proteins) and increases freezing feature, the vacuum pump should have
with the increase of molecular weight of the lattice a capacity of about 50 L/sm2 of the shelf area.
and its dryness. To protect against even slight rehydra- As leakage of air is inherent in any practical
tion the freeze-dried vials are immediately stoppered, vacuum system, this capacity is used to main-
preferably by internal devices without decompression tain the desired operating pressure. If, however,
of the chamber. the shelves do not have the freezing capacity,
Among other requirements that freeze dryers for the vacuum pump should have a much higher
pharmaceuticals have to fulfill, the actual trend is capacity to provide nearly instantaneous dryer
that they should provide the following range of per- evacuation.
formance parameters (Table 29.4) [7]. Under the Condenser: All freeze dryers are equipped with
conditions referred to as normal, most of the phar- condensers to remove water vapor from the
maceuticals can be dried. Under normal conditions, gases coming out of the drying chamber.
with shelves fully covered with vials at an operating Instrumentation and control: Provide monitoring
temperature of 608C, a drying rate of about 1 kg/m2h and control of pressure and temperature at stra-
may be expected. Peak evaporation rates can reach tegic points in the dryer, which includes the
1.5 kg/m2h for an operating temperature of about control of shelf temperature and often the
708C. Because of the critical drying conditions met vacuum if product sublimation is possible.
during drying of pharmaceuticals, the whole drying
system (Figure 29.16) and its components must meet Only the most sensitive and expensive products
the following requirements: are usually freeze-dried. Among these are antibi-
otics, antitoxins, antisera, certain vitamins, cancer
Chamber: Should if possible be built of easy-to- chemotherapy drugs, diagnostic reagents, and other
clean and noncorrosive materials and provided unstable and easily oxidizable materials. Because of
with a vial-stoppering facility. the high value of the dryer load, they are often
Shelf heating and cooling: In order to protect equipped with standby vacuum pumps and re-
against product melt-back, dryer shelves must frigeration units, as well as a standby electrical
be frozen during loading and chamber evacu- power supply and control instrumentation to protect
ation. Further, during drying they must be against any failure.

ß 2006 by Taylor & Francis Group, LLC.

 10 1 2
6 7
8 9 8
FIGURE 29.16 Freeze-drying system (1, drying chamber; 2, heated or cooled shelf; 3, ice condenser; 4, diffusion vacuum
pump; 5, rotary vacuum pump; 6, tank for cooling shelf circulating liquid; 7, tank for heating shelf circulating liquid;
8, freezing aggregate; 9, circulation pump; 10, air filter).
29.4.4 GRANULATION AND DRYING
To have proper solubility the tablets are formed from
very finely dispersed drug mixtures. However, the
process of tableting is not smooth if these powders
are fed directly to the tableting machines. Granula-
tion of the powders before tableting is usually re-
quired. Also, several pharmaceutical products, such
as glucose preparations, are sold in granulated form.
Granulation may be carried out as a dry or a wet
process. Agglomeration of particles of very fine (i.e.,
few micrometers in size) dry powders can occur owing
to van der Waals forces of attraction. Aspirin, acet-
ophenetidin, thiamine hydrochloride, ascorbic acid,
and others can be granulated using a dry process.
For wet granulation, a suitable liquid is sprayed
onto the vigorously mixed powder. Adhesion of par-
ticles takes place owing to the development of liquid
bridges and capillary forces between particles. In the
drying phase following the granulation process, solid
bridges develop owing to crystallization of dissolved
substances.
Spray granulation may be carried out in fluid beds
or vibrated fluid beds as a separate process, or this
may be performed in the dryer itself as the final stage
of the drying process. Figure 29.17 illustrates appli-
cation of a vibrated fluid bed dryer as a second stage
of a combined drying and granulation process. In
the first stage the material is spray dried. Residual
ß 2006 by Taylor & Francis Group, LLC.
3 4
moisture is removed from the powder in a vibrated
fluid bed dryer. In the same dryer the powder is spray
granulated and the granules are dried to the required
final moisture content.
In an alternate method of agglomeration, satur-
ated steam is blown for a specific period of time
through the fluid bed of cold particles. Condensation
of moisture on the particles forms agglomeration cen-
ters and allows formation of granules of the product
during fluidization.
29.5 DRYING OF DOSAGE FORMS
Final drug formulation is a mixture of active drugs
with a suitable excipient and necessary additives
(binder, color, aroma, etc.). The mixture may be
obtained directly through spray drying of solution
or suspension; otherwise, crystalline substances must
be carefully ground and blended. Powdered prepar-
ation is usually converted into granules, tablets, or
dragees. Granules obtained by wet granulation re-
quire postgranulation drying, which may be per-
formed in the same unit (see Section 29.4.4). Tablets
usually do not require drying although they contain
some water that was present in powder to im-
prove tableting. Dragees, which are essentially lac-
quered tablets, need drying as a final stage. Their
coating is sprayed usually in many layers, including
 Solution
Hot air
Vapors
1
Hot air
FIGURE 29.17 Combined spray drying–agglomerating system (1, spray dryer; 2, cyclone; 3, vibrated fluid bed dryer-
granulator).
an antioxidant layer, dissolving rate-limiting layer,
and taste and color layer. Coating layers may be
water or solvent based. Dragees may be dried in a
batch dryer with flow of air through the bed or in a
continuous fluid bed. These dryers are integral parts
of dragee-coating machines.
29.6 SOME TECHNOLOGICAL DATA
ON DRYING OF PHARMACEUTICAL
PRODUCTS
The following is a short summary of some technical
information on drying of some of the more com-
monly encountered pharmaceuticals and intermediate
products.
Table 29.5 presents a summary of the various
types of dryers, together with examples of pharma-
ceutical products for which they are used commer-
cially. It should be noted that in most cases alternate
dryers are used in practice to dry the same product.
Typical operating data for drying of selected pharma-
ceuticals are given in Table 29.6. The information
contained in Table 29.6 is derived from operating
dryer performance data as well as from laboratory-
scale experiments. Laboratory and often pilot-scale
tests are necessary before a commercial-scale dryer
ß 2006 by Taylor & Francis Group, LLC.
Vapors
Agglomerizing
liquid
Cool air Product
may be designed with confidence. For pharmaceutical
products, laboratory tests are performed to provide
data on the thermal sensitivity, oxidizability, stability,
and final product moisture content. This forms the
basis for the selection of a dryer and process param-
eters. If the product is produced in small quantities, a
batch dryer may be selected. In large-scale produc-
tion, energy losses, losses due to deterioration of the
product quality, and other losses can be quite sub-
stantial if the dryer type and operating parameters
are not optimally selected. To show how the dryer
type influences the drying kinetics, several drying
rate curves for selected pharmaceuticals are presented
in Figure 29.18.
29.7 ASEPTIC CONDITIONS IN
PHARMACEUTICAL DRYERS
The problem of maintaining aseptic conditions exists
in all stages of pharmaceutical production. The final
stages of the pharmaceutical production process, dry-
ing, tableting, and packaging, are especially suscep-
tible to microbial infection. High-sterility standards
are required for pharmaceuticals of biologic origin,
standards, laboratory reagents, and others. The two
possible sources of bacterial infection during drying
TABLE 29.5
Applications of Different Pharmaceutical Dryers

Type General Application Example Product

Directly heated
Fixed bed
Ovens Small batches of all types of pharmaceuticals Various products
Band dryers Organic raw materials, preformed pastes Various products
Turbo-shelf dryers All kinds of medium and coarse granular materials with Penicillin, ascorbic acid, mannitol,
long drying times monosodium glutamate, nicotinic acid,
riboflavin, sorbitol, starch
Suspended state
Pneumatic dryers Removal of unbound moisture, narrow particle size Ascorbic acid, hydrate of 2-keto-L-gluonic
acid, p-aminobenzosulfamide, tetracycline
sulfathiazole, aminopyrine, ASA
Cyclone dryers Removal of unbound and bound moisture, possible Thiamine bromide, phthalimidopropionitrile,
self-adjustment of particle size, longer residence times ascorbic acid, folic acid, nicotinic acid
than in pneumatic dryer
Spouted bed dryers Long drying times, increased thermal sensitivity, suitable ASA, hexamethylenetetramine, 2-amino-5-
for drying pastes on inerts ethyl-1,3,4-thiodiazole
Vibrating bed dryers Granular polydisperse materials, long residence time Nicotinic compounds, sorbose, ascorbic acid,
lactose
Fluid bed dryers Medium and coarse granular materials, possible Vitamins, lactose, glucose, sodium glutamate,
granulation Urotropin, antibiotics (oxytetracycline),
paracetamol, pancreatin powder, ASA
Spray dryers Pastes, solutions, and suspensions Aminosalicyclic acid, bacitracin, blood plasma,
blood serum, methicillin salts, culture media,
dextran, enzymes, gamma-globulin,
hormones, streptomycin, iron dextran,
lysine, casein hydrolysate, penicillin, serum
hydrolysate, penicillin, serum hydrolysate,
tetracycline vitamins, oleandomycin,
chloramphenicol succinate salts
Indirectly heated
Drum dryers Thin pastes and slurries Calcium panthothenate, streptomycin sulfate
Vacuum dryers All types of heat-sensitive materials Various products
Freeze dryers Extremely heat-sensitive materials in solutions and Antisera, antibiotics, antitoxins, vitamins,
suspensions cancer chemotherapy drugs, various
diagnostic reagents and standards

are the feed and air used for direct drying. Proper
sanitary handling of the feed must be maintained
throughout the whole production cycle. If the drug
is not thermodegradable, sterilization by superheating
can be applied. If the final product is thermolabile,
thermal sterilization of the raw materials sometimes
can be applied or chemical, ultraviolet, or radioactive
means of sterilization should be used.
For all high-sterility manufacturing operations,
class 100 air cleanliness according to U.S. Federal
Standard 209A (1966) must be maintained. High-
efficiency air filtration and laminar flow units must
be installed in packaging areas. Removal of the
airborne microbes from the air that feeds the dryers
and packaging areas is usually performed by
high-efficiency particulate air (HEPA) filters. They
are claimed to remove up to 99.97% of all particles
larger than 0.3 mm, that is, most of the known bacteria
(but not viruses).
To protect HEPA filters against premature clog-
ging, air filtration is usually multistage. At least one
prefilter is added to remove dust from the air before it
enters the HEPA filter. Figure 29.19 shows a sche-
matic diagram of a typical aseptic spray dryer system.
If drying is performed at low temperatures, air
washing with sterilizing liquid also may be used.
This is also applicable to air supplied to the packag-
ing areas. Prewashing of the air with antibac-
terial liquids can remove up to 95% of all viable
microorganisms present.

ß 2006 by Taylor & Francis Group, LLC.

ß 2006 by Taylor & Francis Group, LLC.

TABLE 29.6
Process Parameters for Drying of Selected Pharmaceuticals

Materiala Dryer Type, Moistureb Initial Final Initial Air Final Air Dryer Evaporation Residence or Unit Air
Bed Height Moisture Moisture Temperature Temperature Throughput Rate Drying Consumption
Content Content (˚C) (˚C) (kg/h) (kg/m2h) Time (kg air/kg material)
(3102 kg/kg) (3102 kg/kg)

AET Batch fluid bed 17–18.6 0.5 150–155

Batch fluid bed, 20–23.5 0.5–1 90–95
100 mm
Batch fluid bed, 110–115
100 mm
Aminopyrine Combinedd 15 0.68 95 45 86 83c
Antibiotics Batch fluid bed 19.3 0.8 70 80 min
ASA Batch fluid bed 15 1 40 20 min
Ascorbic acid Combined 6.34 0.06 170 60 35.7
Vortex Ethanol 12 0.35 90 55 45 s 10.3
Azorybitylamine Combined 50 0.5 160 65 252
Barbituric acid Combined 30 0.2 250 65 109.7
Biomycin Pulsed fluid bed 25–48 0.05 1–1.5 h
DKGA Combined fast 15 0.5 45 38 65.3 117c
spouted bed
11 0.2 55 10 s
Folic acid Vortex 20 0.4 80 50 52 s 10.6
Nicotinic acid Combined 20.9 0.005 100 60
Vortex 20 0.55 120 80 36 s 16.6
Vortex 27 0.34 130 78 38 s 15.0
ß 2006 by Taylor & Francis Group, LLC.

Vortex 28 0.54 130 80 42 s 14.0

Vortex 27.6 0.36 150 98 57 s 13.6
Vortex 27.8 0.43 160 105 62 s 12.0
Oxytetracycline Pulsed fluid bed 18–24 3–5 1.5–2 h
Phthalimidopropionitrite Vortex 18 0.3 80 52 45 s 10.2
Piperazine Combined 30–5 5–0.5 90–160 50–80 40–79 30–50c
Riboflavine Combined 40 0.75 130 80 150
Sorbose Combined 6 0.2 124.7 32.8 62.7 29.2
Sulfaguanidine Pneumatic 14.8 8.93 0.3–0.5 h
Terpin hydrate Pulsed fluid bed 20–28 0.1–0.3 130 50 80.1 58.8c
Tetracycline Combined 30 18 130 20
Pneumatic 30–35 15–12 0.3–0.35 h
Granulated Pulsed fluid bed 24–26 12–14 0.4–0.5 h
Hydrochloride Pulsed fluid bed 17–21 1–2
Thiamine bromide Vortex Ethanol 15 2 65 46
16 1.8 80 50 38 s 13
18 1.5 90 55 36 s 12
20 0.6 100 70 23 s 11
20 0.4 100 75 42 s 10
Vitamins Turbo-tray 20 5 90 30 s 8
a
AET, 2-amino-5-ethyl-1,3,4-thiodiaz ASA, acetylosaloicyclic acid; DKGA, hydrate of 2-keto-L-gluonic acid.
b
Moisture removed is water if not otherwise indicated.
c
In kg air/kg water evaporated.
d
Free fall of extruded particles in countercurrent with air and fluid bed.
 4
4
12
16

X,%
10 3 1
8

N, %/min
8 2 12
3
X,%
4
6 1 8
5 5
4
40 60 80 4
2 t, min 4

(a) 2 4 6 8 10 4 8 12 16
t, min X,%

1
8 4
7 8
6 3 6
X,%

N, %/min
4 3
5 5 4
X,%

2
4 2 2 2
3 1
40 80 120 3
2 t, min 1
5 4
1

(b) 4 12 20 28 36 44 2 4 6 8
t, min X,%

FIGURE 29.18 Drying kinetic data for (a) penicillin; (b) ascorbic acid (1, countercurrent spin dryer; 2, flash dryer with
impacting streams of gas; 3, spouted bed dryer; 4, gas filtration in stationary bed; 5, fluid bed; X, moisture content; t, time; N,
drying rate).

Feed
8

7
2 9
3

4 5 6
6
Atomizing 7
air 9
Exhaust 1
air

4
10
Drying
11 air

Pro-
duct

FIGURE 29.19 Aseptic open spray drying system (1, drying chamber; 2, air dispenser; 3, atomizer; 4, prefilter; 5, filter;
6, heater; 7, HEPA filter; 8, sterile feed filter; 9, feed pump; 10, cyclone collector; 11, packing room). (Courtesy of A/S Niro
Atomizer, Soeborg, Denmark.)

ß 2006 by Taylor & Francis Group, LLC.

 The packaging areas should be provided with
laminar flow units supplied with filtered or washed
air. All personnel and ancillary equipment must be
placed downstream from the sterile product. A sche-
matic of the packaging area of a typical spray dryer
for aseptic operation is shown in Figure 29.20. In
general, for aseptic noncontaminating drying oper-
ation, rotating or sliding parts should be avoided in
dryer installations. Dryers themselves and their duct-
work can be easily sterilized by maintaining the in-
stallation at elevated temperatures for specified
periods. The U.S. Pharmacopoeia specifies heating at
160–1708C for 2–4 h. However, most aseptic dryers
are sterilized at temperatures in the range 200 to
2508C for several hours in practice.
Effectiveness of thermal sterilization may be
tested by placing samples of test bacteria (Bacillus
subtilis for hot air and spores of Bacillus stearother-
mophilus for steam sterilization) in strategic locations
in the installation. After sterilization, samples are
sown onto culture media in petri dishes and observed
for growth. Absence of any growth indicates that
sterilization was successful.
To maintain high-purity standards of the product,
several precautions must also be taken in the design of
the drying chamber and installation [8].
The installation must be leakproof and must op-
erate under slight overpressure.
All inside surfaces must be as smooth as possible;
all corners must be rounded to guard against
material deposition.
All ductwork should be as short as possible to
prevent product buildup.
All locations where mechanical friction of parts
take place should be eliminated as they can
produce small metallic contaminations in the
product. Rotating or sliding parts should be
avoided.
Aseptic dryers with an open drying cycle provide
satisfactory protection against microbial infec-
tion. Nevertheless, closed-cycle dryers offer a
much better possibility of maintaining proper
sanitary conditions. Unfortunately, their higher
costs make them justified only in some special
cases.

Feed Sterile feed filter

Feed pump

Pre-filter I Pre-filter II Hepa filter

Two fluid nozzle

Air blower Heater

Atomizing air Fan Pre-filter

Hepa filter Heater
Drying air

Outlet air Drying chamber

Cyclone
Fan Pre-filter

Hepa filter

Clean room with

laminar flow

Bottles out Bottles in

Filling machine Bottle sterilizer

FIGURE 29.20 Aseptic spray dryer and packaging area. (Courtesy of A/S Niro Atomizer, Soeborg, Denmark.)

ß 2006 by Taylor & Francis Group, LLC.

29.8 SOLVENT RECOVERY AND
CLOSED-CYCLE DRYING
A large portion of all pharmaceuticals is obtained
from nonwater solutions. The solvent is either a single
component solvent (i.e., ethanol, methanol, acetone,
etc.); however it is often a mixture of solvents. Table
29.7, containing some information selected from
Pakowski [9], presents exemplary drugs with moisture
that is a solvent mixture.
These solvents, due to their high cost and detrimen-
tal influence on the environment, may not be disposed
off into atmosphere even at very low concentrations. In
vacuum dryers solvent vapors after filtering in dust
collectors undergo condensation in single or multistage
condensers. In convective drying the presence of solv-
ents and powders can produce an explosive mixture
with air, which calls for inert gas as the heat carrier. It
is then necessary to close the drying cycle.
In closed-cycle drying the spent gas, after separ-
ated from the dried material, is dehumidified and
after reheating returned to the dryer.
A closed-cycle dryer is justified in the following
cases:
Flammable, toxic, or valuable organic solvent
is used. In this case the solvent will be fully
recuperated.
Inert gas is used as drying medium, which is
recommended if flammable solvent or solid is
dealt with. Easy oxidization of the product also
requires inert gas drying.
Solids or its solvent or vapors produced during
drying are toxic, have an unpleasant odor, or
can by other means pollute the atmosphere.
Inert gas, usually nitrogen, circulating in the cycle
is continuously supplied with a fresh makeup gas. For
a spray dryer with evaporation rate of acetone, 110
kg/h, approximately 3 m3/h makeup nitrogen is ne-
cessary during normal operation. Purging of the in-
stallation after washing and sterilization requires
approximately 75 m3 nitrogen.
A closed-cycle spray dryer is shown in Figure
29.21. Essentially the same elements of installation
are used as for normal open-cycle dryers; however,
disk or liquid-nozzle atomizers are preferred as they
do not require gas for spraying. Solvent evaporates
into the stream of inert gas, usually nitrogen, leaving
the material dry. Most of the particles then formed
are separated in the dryer; the rest are recovered in
high-efficiency cyclones. Hot and humid effluent gas
is contacted with cooled solvent in a scrubber where
the solvent vapors partially condense. Dehumidified
gas is reheated and returned to the dryer. Another
solution for water-based solids is a self-inertizing

TABLE 29.7
Some Pharmaceuticals Containing Multicomponent Moisture

Total Moisture Content, wt%

Solid Moisture Composition, wt% Initial Final

Raw vitamin C 1,2-Dichloroethane 68 20 0.1

Trichloroethylene 20
Acetone 10
Ethanol 2
Commercial vitamin C Methanol
Water
Vitamin B6 Ethanol 80 10.6 0.5
Water 20
Dibromobenzene Acetic acid 11 20 0.3
Water 89
Pancreatin Acetone 60 0.3
Water
Trichloroethylene
Steroids Methanol 30 0.2
Ethanol
Water
Multivitamin Ethanol 85 13 1.5
Water 15
Antibiotics Isopropanol 40 0.3
Acetone

ß 2006 by Taylor & Francis Group, LLC.

 Feed 9

10 8

3
2 Cooling
6 7 liquid
1

Solvent
5 recovery

Product
FIGURE 29.21 Closed-cycle spray dryer system (1, drying chamber; 2, atomizer; 3, gas dispenser; 4, cyclone collector; 5, inert
gas supply; 6, scrubber-condenser; 7, heat exchanger; 8, vent for purging dryer; 9, gas heater (indirect); 10, feed pump).
(Courtesy of A/S Niro Atomizer, Soeborg, Denmark.)

dryer (Figure 29.22) in which oxygen concentration in
drying air is lowered to 4–5% in a directly fired
gas heater.
The throughput of closed-cycle dryers is generally
limited by the volume of the scrubber used for cooling
and condensation. The dimensions of the scrubber
increase with the amount of gas used for drying;
however, closing the cycle of even such extensively
gas-consuming dryers as pneumatic or fluid bed
dryers was found justified.
Among the pharmaceuticals dried in closed-cycle
spray dryers, antibiotics and antibiotic by-products
can be mentioned. Coating of powders with poly-
meric coating material dissolved in the feed or so-
called microencapsulation is a new application of
closed-cycle spray dryers. For dryers using very
high gas flow rates, such as fluid bed dryers, the
following principle may be used. The outcoming
gas from the drying chamber is split into two
parts. One part is heated and recirculated whereas
the second part is sent to a condenser; after solvent
removal it is mixed with the recycle stream and
returned to the drying chamber. This allows oper-
ation at high gas flow rates in the drying chamber

4 2
3

1
3

10

FIGURE 29.22 Self-inertizing closed-cycle dryer (1, feed tank; 2, direct heater; 3, atomizer; 4, atomizer drive; 5, scrubber;
6, drying chamber; 7, pumps; 8, cyclone; 9, fans; 10, cooler). (Courtesy of APV Pasilac Anhydro, Soeborg, Denmark.)

ß 2006 by Taylor & Francis Group, LLC.

 Feed
3 4
2
FIGURE 29.23 Closed-cycle batch fluid bed dryer (1, drying chamber; 2, bag filter; 3, blower; 4, heater; 5, condenser;
6, pump; 7, product collector).
and also relatively high solvent concentrations in
the exit streams, which makes condensation more
efficient. In the falling rate period, when the concen-
tration of the solvent in the exit gas decreases, re-
moval of moisture usually requires lowering the
temperature of the cooling medium in order to ob-
tain condensation at the required concentration of
solvent. Figure 29.23 shows schematically a batch
fluid bed dryer working in a closed-cycle opera-
tion [10]. Two condensers operating at different
temperatures are used; this arrangement is espe-
cially appropriate when condensing a mixture of
two different solvents.
Traces of solvents in gas vented to atmosphere
from closed-cycle dryers are usually removed by in-
cineration in gas or catalytic burners. This method
may also be used for deodorization of exhaust gas.
Chlorine-containing solvents cannot be burned and
must be adsorbed on a suitable sorbent.
ACKNOWLEDGMENTS
We are grateful to A/S Niro Atomizer and APV
Pasilac Anhydro, both of Soeborg, Denmark, and
R. Simon and Sons, Basford, England, for granting
permission to reproduce some of their copyrighted
material.
ß 2006 by Taylor & Francis Group, LLC.
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REFERENCES
1. Basic Standards of Good Manufacturing Practice for
Pharmaceutical Products, Document PH 3/83, EFTA
Secretariat, Geneva, 1983.
2. L.G. Golubev, B.S. Sazhin, and E.R. Valashek, Drying
in Chemicopharmaceutical Industry, Meditsina, Mos-
cow, 1978 (in Russian).
3. J.P. Remington, Remington’s Pharmaceutical Sciences,
16th ed., Mack Publishing Company, Easton, 1980.
4. S.M. Reprintseva and N.V. Fedorovich, New Methods
of Thermal Processing and Drying of Pharmaceuticals,
Nauka i Tekhnika, Moscow, 1979 (in Russian).
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tischen Technologie (Moisture and Drying in the Pharma-
ceutical Technology), Dr. Detrich Steinkopff Verlag,
Darmstadt, 1980 (in German).
6. E. Simon, Industrielle Trocknung von Arzneimitteln
und ihren Vorstufen (Industrial Drying of Drugs and
Their Intermediate Products). In Trocknung und Trock-
ner in der Produktion, Vol. 3 (K. Kröll and W. Kast,
Eds.), Springer-Verlag, Berlin, 1989 (in German).
7. S.L. Morgan and M.R. Spotts, Pharmaceutical Tech-
nology, 11 1979, pp. 94–101, 114.
8. K. Masters and I. Vestergaard, Process Biochemistry, 1
1975, pp. 3–6.
9. Z. Pakowski, Drying of solids containing multicompo-
nent moisture. In Advances in Drying, Vol. 5 (A.S.
Mujumdar, Ed.), Hemisphere Publishing Company,
New York, 1992.
10. E.I. Simon, Khim. Farm. Zhurn., 11 1978, pp. 121–128.