Aultons Pharmaceuticals Drying PDF
Aultons Pharmaceuticals Drying PDF
Aultons Pharmaceuticals Drying PDF
Michael E. Aulton
• Many different types of drying proces s es and of cases the ‘liquid’ will be water but also more
equipment exis t as there are numerous volatile organic solvents, such as isopropanol, may
mechanis ms by which mois ture is los t from a need to be removed in a drying process. The physical
wet product or intermediary principles of aqueous or organic solvent drying are
• The s election of the bes t drying method for a similar, regardless of the nature of the liquid, though
product is a key decis ion
volatile solvents are normally recovered by conden-
• The phenomenon of s olute migration s hould be
minimized during drying proces s es sation rather than being vented into the atmosphere.
This is for environmental and economic reasons.
Also, the toxicity and ammability of organic
Intro duc tio n solvents pose additional safety and process
considerations.
Drying is an important operation in primary phar-
maceutical manufacture (i.e. the synthesis of active
pharmaceutical ingredients or excipients) since it is Drying o f we t s o lids
usually the last stage of manufacturing before pack-
aging. It is important that the residual moisture, say
from the nal crystallization step, is rendered low
Fundamental properties
enough to prevent product deterioration during and interrelations hips
storage and ensure free- owing properties during
use. It is equally important (and probably encoun- An understanding of this operation requires some
tered more frequently) in secondary (dosage form) preliminary explanation of the following important
manufacture following the common operation of terms. To avoid confusion and repetition, these
wet granulation (see Chapter 28) during the prepa- terms will be de ned and explained in the context
ration of granules prior to tablet compaction. H ence, of water (the most commonly used pharmaceutical
stability (see Chapter 48 and 49), ow properties solvent) but the explanations and concepts are
(see Chapter 12) and compactability (see Chapter equally applicable to other relevant liquids (e.g.
30) are all in uenced by residual moisture. ethanol, isopropanol, etc.).
This chapter is concerned with drying to the ‘dry’
solid state, starting with either a wet solid or a solu- Mois ture content of wet s olids
tion or suspension. The former is usually achieved
by exposing the wet solid to moving, relatively dry The moisture content of a wet solid is expressed as
air (elevated temperatures to accelerate the process kg of moisture associated with 1 kg of the moisture-
are common). The latter is possible with equipment free or ‘bone-dry’ solid. Thus, a moisture content of
such as the spray dryer (see later in this chapter) 0.4 means that 0.4 kg of water is present per kg of
that is capable of producing a dry product from a the ‘bone-dry’ solid that will remain after complete
solution or suspension in one operation. drying. It is sometimes calculated as percentage
Most pharmaceutical materials are not com- moisture content; thus this example would be
pletely free from moisture (i.e. they are not ‘bone quoted as 40% moisture content.
dry’) but contain some residual water, the amount
of which may vary with the temperature and humid-
ity of the ambient air to which they are exposed. Tota l.mois ture .c onte nt
This is discussed in more detail in this chapter. This is the total amount of liquid associated with a
For the purpose of this chapter, drying is de ned wet solid. Some of this water can be easily removed
as the removal of all or most of the liquid associated by the simple evaporative processes employed by
with a wet pharmaceutical product. All drying pro- most pharmaceutical dryers and some cannot. The
cesses of relevance to pharmaceutical manufacturing amount of easily removable water (unbound water)
involve evaporation or sublimation of the liquid is known as the ree moisture content and the mois-
phase and the removal of the subsequent vapour. ture content of the water that is more dif cult to
The process must provide the latent heat for these remove in practice (bound water) is the equilibrium
processes without a signi cant temperature rise. moisture content. Thus, the total moisture content
Naturally the latter will enhance the potential of of a solid is equal to its free moisture content plus
thermal degradation of the product. In the majority its equilibrium moisture content.
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P A R T F IVE Do s ag e Fo rm De s ig n and Manufac ture
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equilibrium to move along the drying curve in Figure Dryers in the pharmaceutical
29.2 to the left, thus reducing the moisture content
of the solids. Phosphorus pentoxide works in an
indus try
identical manner but it has an even greater af nity
The types and variety of drying equipment have
for the water in the storage air.
reduced in recent years as pharmaceutical compa-
If dried materials are exposed to humid ambient
nies strive for standardization and globalization of
conditions they will quickly regain moisture from
manufacturing. The types of dryers that have proved
the atmosphere since this relationship is an equilib-
the most successful have become commonplace
rium. Figure 29.1 shows this. Thus it is unnecessary
and less ef cient (or more damaging) drying proc-
to ‘overdry’ a product and there is no advantage in
esses have largely disappeared. An additional trend
drying to a moisture content lower than that which
is the manufacture of ‘mini’ versions of manufac-
the material will have under the normal conditions
turing equipment to be used in formulation and
of use.
process development. Previously, very distinctly
If low residual moisture content is necessary due
different dryers were sometimes used in labora-
to a hydrolytic instability in the material, the dried
tories but this resulted in numerous problems during
product must be ef ciently sealed during or imme-
scale-up. The use of the miniaturized production
diately after the drying process to prevent ingress of
equipment (processing just a few hundred grams)
moisture. It also worth noting that some solid phar-
will minimize later problems during the scaling up
maceutical materials perform better when they
to manufacturing batches (typically a few hundred
contain a small amount of residual water. Powders
kilograms).
will ow better; the ow of very dry powders is
inhibited by static charge. Tablet granules have
superior compaction properties with a small amount Types of pharmaceutical dryers
(1–2 %) of residual moisture.
A variety of pharmaceutical dryers are still used and
it is convenient to categorize these according to the
Type s o f drying me tho d heat transfer method that they employ, i.e. convec-
tion, conduction or radiation.
Choice of drying method
Co nve c tive drying o f
When considering how to dry a material, the follow-
ing points should be considered: we t s o lids
• heat sensitivity of the material being dried
• physical characteristics of the material Dynamic convective dryers
• nature of the liquid to be removed
• the scale of the operation Fluid ize d -b e d .d rye r
• the necessity for asepsis An excellent method of obtaining good contact
• available sources of heat (steam, electrical). between the warm drying air and wet particles is
The general principles for ef cient drying can be found in the f uidized-bed dryer. The general prin-
summarized as: ciples of the technique of f uidization will be sum-
marized before discussing its application to drying.
• large surface area for heat transfer Consider the situation in which particulate matter
• ef cient heat transfer per unit area (to provide is contained in a vessel, the base of which is perfo-
suf cient latent heat of vaporization or heat of rated, enabling a uid to pass through the bed
sublimation in the case of freeze drying) of solids from below. The uid can be liquid or gas,
• ef cient mass transfer of evaporated water but air will be assumed for the purposes of this
through any surrounding boundary layers, i.e. description, as it is directly relevant to the drying
suf cient turbulence to minimize boundary process.
layer thickness If the air velocity through the bed is increased
• ef cient vapour removal, i.e. low relative gradually and the pressure drop through the bed is
humidity air moving at adequate velocity. measured, a graph of the operation shows several
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P A R T F IVE Do s ag e Fo rm De s ig n and Manufac ture
d H / d t = hc A ∆T
(29.3)
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Dryin g C H AP TE R 2 9
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P A R T F IVE Do s ag e Fo rm De s ig n and Manufac ture
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Dryin g C H AP TE R 2 9
Ad va nta ge s .of.mic rowa ve .d rying The spray dryer provides a large surface area for heat
and mass transfer by atomizing the liquid into small
The following advantages are claimed for microwave droplets. These are sprayed into a stream of circulat-
drying: ing hot air, so that each droplet dries to an individual
1. It provides rapid drying at fairly low solid particle. Thus, particle formation and drying
temperatures. occur in the one process.
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P A R T F IVE Do s ag e Fo rm De s ig n and Manufac ture
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Dryin g C H AP TE R 2 9
experimental material from aqueous or organic solu- so that evaporation is very rapid. The actual
tion, through a pilot-scale model with a chamber drying time of a droplet is only a fraction of a
diameter of 800 mm and a height of 3 m capable of second, and the overall time in the dryer only a
evaporating 7 kg of water per hour, to a production- few seconds.
scale model that could have a chamber diameter of 2. Because evaporation is very rapid, the droplets
3.5 m and be 6 m high (or even larger) with an do not attain a high temperature. Most of the
evaporative capacity of about 50–100 kg water per heat is used as latent heat of vaporization and
hour. Larger spray dryers, with a capacity of up to the temperature of the particles is kept low by
4000 kg/ h, are used in other industries, notably in evaporative cooling.
food production. Typically, modern spray dryers 3. The characteristic particle form allows ef cient
have a 60° cone at the base of the hollow cylinder. particle packing and thus gives the product a
high bulk density. It also leads to rapid
P rod uc t dissolution because of the large surface area.
Spray-dried products are easily recognizable, being 4. Provided that a suitable atomizer is used, the
uniform in their appearance. The particles have a resulting powder will have a uniform and
characteristic shape, in the form of hollow spheres controllable particle size.
sometimes with a small hole. This arises from the 5. The product is free- owing, with almost
drying process, since the droplet enters the hot air spherical particles, and is especially convenient
stream and dries on the outside to form an outer for tablet manufacture as it has excellent ow
crust with liquid still in the centre. This liquid then and compaction properties.
vaporizes and the internal vapour escapes by blowing 6. In many cases spray drying will increase the
a hole in the sphere. Figure 29.9 shows the mecha- dissolution rate and bioavailability of poorly
nism of formation of the spherical product. water-soluble drugs.
Intelligent computer control is available to control 7. Labour costs are low, the process yielding a dry,
process parameters as these, in turn, can affect par- free- owing powder from a dilute solution, in a
ticle size, bulk density, moisture content, dissolution single operation with no handling.
rate and dispersibility of the resulting product. 8. It can be used as a continuous process if
required.
Ad va nta ge s .of.the .s p ra y-d rying.p roc e s s
1. There are millions of small droplets which give Dis a d va nta ge s .of.the ..
a large surface area for heat and mass transfer, s p ra y-d rying.p roc e s s
1. The equipment is very bulky and, with the
ancillary equipment, is expensive.
2. The overall thermal ef ciency is rather low
since the air must still be hot enough when it
leaves the dryer to avoid condensation of
moisture. Also, large volumes of heated air pass
Drople t Eva pora tion Conce ntra tion through the chamber without contacting a
from s urfa ce of s olute a t
drople t s urfa ce
particle and thus not contributing directly to
the drying process.
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P A R T F IVE Do s ag e Fo rm De s ig n and Manufac ture
sodium phosphate, gelatin, starch, barium sulfate The theory and practice of freeze drying are
and calcium phosphate. The process is also used for based on an understanding and application of the
some powdered antibiotic formulations where the phase diagram for the water system.
spray-dried powder is packaged and distributed.
This is then reconstituted as a syrup at the time of
dispensing. The dry product is spray dried from a
The phas e diagram for water
formulation containing all the necessary ingredients,
The phase diagram for the water system (Fig. 29.10)
including colours and avours. Since only water is
consists of three separate areas. Each area represents
removed in the spray-drying process, these products
a single phase of water – vapour, liquid or solid. Two
must be reconstituted with pure water only.
phases can coexist along a line under the conditions
Spray drying is also capable of producing spheri-
of temperature and pressure de ned by any point
cal particles in the respirable range of 1–7 µm that
on the line. The point O is the one unique point
are necessary for the delivery of drugs from dry
where all three phases can coexist and is known as
powder inhalers (see Chapter 37).
the triple point. Its coordinates for pure water are a
It is possible to operate spray dryers aseptically
pressure of 610 Pa (as a comparison, atmospheric
using heated ltered air to dry products such as
pressure is approximately 10 5 Pa) and a temperature
serum hydrolysate. Also, some spray dryers operate
of 0.0075 °C.
in a closed circuit mode with an inert gas to mini-
The lines on the phase diagram represent the
mize oxidation of the product. Volatile solvents can
interphase equilibrium lines which show:
be recovered from such systems.
Pharmaceutical spray drying has been reviewed • the boiling point of water as it is lowered by
by Wendel & Çelik (1997) and the reader is referred reduction of the external pressure above the
to this article if additional information is required. water (BO in Fig. 29.10)
• the variation of the melting point of ice on
reduction of the external pressure above it.
Fluid ize d .s p ra y.d rye r There is a very slight rise in the melting
A development of the spray dryer is the uidized point (AO )
spray dryer (Niro). This has a small uidized bed • the reduction of the vapour pressure exerted by
mounted in the base of the cone at the point where ice as the temperature is reduced (CO ).
the product is collected. The moving air created in
the uidized bed overcomes any cohesion of spray-
dried particles after they fall into the collection A 1 B
chamber. This allows spheres with a higher moisture 10 5
content to be handled and also ones made from
stickier and more cohesive substances than were
previously possible to process.
Liquid
)
a
Fre e ze drying
P
(
e
r
S olid Va pour
u
s
s
Freeze drying is a process used to dry extremely
e
r
P
heat-sensitive materials. It can allow the drying, 2
without excessive damage, of proteins, blood prod- Triple
ucts and even microorganisms which retain a small point
but signi cant viability. 610
O
In this process, the initial liquid solution or sus-
pension is frozen, the pressure above the frozen C 3
state is reduced and the water removed by sublima- 0 0.0075 100
tion. Thus an overall liquid-to-vapour transition
Te mpe ra ture ( C)
takes place, as with all the previous dryers discussed,
but all three states of matter are involved: liquid to Fig . 29.10 • The phase diagram or water (not to scale)
solid, then solid to vapour. with reeze-drying process superimposed.
498
Dryin g C H AP TE R 2 9
O n heating ice at atmospheric pressure, it will melt to produce a large frozen surface to speed up
when the temperature rises to 0 °C, i.e. at this tem- that later stage.
perature the ice will change to liquid water. Contin- Shell freezing. This is employed for fairly large
ued heating at atmospheric pressure will raise the volumes such as blood products. The bottles are
temperature of the water to 100 °C. If heating is rotated slowly and almost horizontally in a refriger-
continued, the liquid water will be converted into ated bath. The liquid freezes in a thin shell around
water vapour at 100 °C. the inner circumference of the bottle. Freezing is
If, however, solid ice is maintained at a pressure slow and large ice crystals form, which is a drawback
below the triple point then on heating, the ice of this method as they may damage blood cells and
will sublime and pass directly to water vapour reduce the viability of microbial cultures.
without passing through the liquid phase. This In vertical spin freezing, the bottles are spun indi-
sublimation, and therefore drying, will only occur vidually in a vertical position so that centrifugal
at a temperature below that of the triple point. force forms a circumferential layer of solution which
Thus it will only happen if the pressure is pre- is cooled by a blast of cold air. The solution super-
vented from rising above the triple point pressure cools and freezes rapidly with the formation of small
during the process. To ensure that this is so, the ice crystals.
vapour evolved must be removed as fast as it is
Centr ifuga l eva por a tive freezing. This is a
formed.
similar method where the solution is spun in small
containers within a centrifuge. This prevents foaming
Ap p lic a tion.of.the .p ha s e .d ia gra m.of. when a vacuum is applied. The vacuum causes
boiling at room temperature and this removes so
wa te r.to.fre e ze .d rying
much latent heat that the solution cools quickly and
The process of freeze drying is superimposed on the ‘snap’ freezes. About 20% of the water is removed
phase diagram for water in Figure 29.10. In its basic prior to freeze drying and there is no need for sepa-
form freeze drying comprises three steps: rate refrigeration. Ampoules are usually frozen in
1. freezing the solution this way, a number being spun in an angled position
2. reducing the atmospheric pressure above the (approximately 30° to the horizontal) in a special
ice to below that of the triple point of centrifuge head so that the liquid is thrown
the product outwards and freezes as a wedge with a larger
3. adding heat to the system to raise the surface area.
temperature to the sublimation curve (CO in
Fig. 29.10) to provide the latent heat of Va c uum.a p p lic a tion.s ta ge
sublimation.
The containers and the frozen material must be con-
These are discussed in detail below. nected to a source of vacuum suf cient to drop the
pressure below the triple point and remove the large
volumes of low-pressure vapour formed during
Stages of the freeze-drying drying. Again, an excess vacuum is normal in prac-
proces s tice to ensure that the product in question is below
the triple point of the formulation.
Fre e zing.s ta ge Commonly a number of bottles or vials are
attached to individual outlets of a manifold which is
The liquid material is frozen before the application connected to vacuum.
of a vacuum to avoid frothing. The depression of the
freezing point caused by the presence of dissolved
solutes means that the solution must be cooled to Sub lima tion.s ta ge
well below the normal freezing temperature for pure H eat of sublimation must be supplied. It may be
water and it is usual to work in the range –10 to thought that, as the process takes place at a low
–30 °C, typically below –18 °C. The presence of dis- temperature, the additional heat needed to sublime
solved solutes will shift the pure-water phase the ice will be small. In fact, the latent heat of sub-
diagram. Since the subsequent stage of sublimation limation of ice is 2900 kJ kg–1, appreciably larger
is slow, several methods are used at this stage than the latent heat of evaporation of water at
499
P A R T F IVE Do s ag e Fo rm De s ig n and Manufac ture
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Dryin g C H AP TE R 2 9
for example, are sealed on the manifold while still strains to be stored for long periods with viability of
under vacuum. O therwise, the closing must be about 10% on reconstitution.
carried out under controlled atmospheric condi-
tions. The dry material often needs to be sterile.
So lute mig ratio n during drying
Ad va nta ge s .of.fre e ze .d rying Solute migration is the phenomenon that can occur
Freeze drying, as a result of the character of the during drying which results from the movement of
process, has certain special advantages: a solution within a wet system. The solvent moves
1. Drying takes place at very low temperatures, so towards the surface of a solid (from where it evapo-
that enzyme action is inhibited and chemical rates), taking any dissolved solute with it. Many
decomposition, particularly hydrolysis, is drugs and binding agents are soluble in granulating
minimized. uid and during the drying of granulates these solutes
can move towards the surface of the drying bed or
2. The solution is frozen such that the nal dry
granule and be deposited there when the solvent
product is a network of solid occupying the
evaporates. Solute migration during drying can lead
same volume as the original solution. Thus the
to localized variability in the concentration of soluble
product is light and porous.
drugs and excipients within the dried product.
3. The porous form of the product gives ready
Migration associated with drying granules can be
solubility of the freeze-dried product.
of two types: intergranular migration (between gran-
4. There is no concentration of the solution prior ules) and intragranular migration (within individual
to drying. H ence, salts do not concentrate in granules).
the wet state and denature proteins, as occurs
with other drying methods.
5. Since the process takes place under high Intergranular migration
vacuum, there is little contact with air and
oxidation is minimized. Intergranular migration, where the solutes move
from granule to granule, may result in gross maldis-
tribution of active drug. It can occur during the
Dis a d va nta ge s .of.fre e ze .d rying drying of static beds of granules (e.g. tray drying)
since the solvent and accompanying solute(s) move
There are two main disadvantages of freeze drying:
from granule to granule towards the top surface of
1. The porosity, ready solubility and complete the bed where evaporation takes place. When the
dryness of the product result in one with a very granules are compressed, the tablets may have a
hygroscopic nature. Unless dried in the nal de ciency or an excess of drug. For example, experi-
container and sealed in situ, packaging requires mentation found that only 12% of tablets made
special consideration. from a tray-dried warfarin granulate were within the
2. The process is very slow and uses complicated USP limits for drug content.
plant that is very expensive. It is not a general
method of drying, therefore, but is limited to
certain types of valuable products that, because Intragranular migration
of their heat sensitivity, cannot be dried by any
other means. Drying methods based on uidization and vacuum
tumbling keep the granules separate during drying
and so prevent the intergranular migration that may
Us e s .of.fre e ze .d rying occur in xed beds. H owever, intragranular migra-
The method is used for those products which could tion, where the solutes move towards the periphery
not be dried by any other heat method. These of each granule, may take place.
include biological products; for example, some anti-
biotics, blood products, vaccines (such as BCG , Cons equences of s olute migration
yellow fever, smallpox), enzyme preparations (such
as hyaluronidase) and microbiological cultures. The Solute migration of either type can result in a
latter enables speci c microbiological species and number of problems and occasional bene ts.
501
P A R T F IVE Do s ag e Fo rm De s ig n and Manufac ture
Los s .of.a c tive .d rug and more resistant to abrasion. It has been shown
that this migration can aid the bonding process
The periphery of each granule may become enriched,
during tablet compaction as a result of binder–
with the interior suffering depletion. This will be of
binder (rather than drug–drug or drug–excipient)
no consequence unless the enriched outer layer is
contact and is therefore sometimes bene cial.
abraded and lost, as may happen during uidized-
Many other factors such as granule formulation,
bed drying when the ne drug-rich dust will be
drying method and moisture content have been
eluted in the air and carried to the lter bag or lost.
shown to affect solute migration.
The granules suffer a net loss of drug and as a result
will be below speci cation with respect to quantity
of active ingredient. In uence of formulation factors on
s olute migration
Mottling.of.c oloure d .ta b le ts
Coloured tablets can be made by adding soluble Na ture .of.s ub s tra te
colour during wet granulation. Intragranular migra- The principles governing solute migration are similar
tion of the colour may give rise to dry granules with to those of thin-layer chromatography. Thus, if the
a highly coloured outer zone and a colourless interior granule substrate has an af nity for the solute then
(Fig. 29.12). During compaction granule fracture migration will be impeded. Luckily, many of the
takes place and the colourless interior is exposed. common tablet excipients possess this af nity. The
The eye then sees the coloured fragments against presence of absorbent materials, such as starch
a colourless background and the tablets appear and microcrystalline cellulose, will minimize tablet
mottled. solute migration.
Migration may be reduced by using the insoluble The use of water-insoluble aluminium lakes (pig-
aluminium ‘lake’ of the colouring material (in which ments) reduces mottling compared with water-
the soluble dye is adsorbed strongly onto insoluble soluble dyes. This effect has also been seen with
alumina particles) in preference to the soluble dye lm-coat colours (Chapter 32).
itself. Studies have indicated that the production
of small granules, which do not fracture so readily, Vis c os ity.of.gra nula ting. uid
are preferable to larger ones if mottling is
troublesome. The popular granulating uids are solutions of poly-
mers whose viscosity is appreciably greater than
water alone. This viscosity impedes the movement
Migra tion.of.s olub le .b ind e rs of moisture by increasing the uid friction. Increas-
Intragranular migration may deposit a soluble binder ing the concentration and therefore the viscosity of
at the periphery of the granules and so confer a PVP solution has been shown to slow the migration
‘hoop stress’ resistance, making the granules harder of drugs in xed beds of wet granules. Solution of
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Dryin g C H AP TE R 2 9
methylcellulose with comparable viscosities gave • Prepare the smallest granules that will ow
similar migration rates showing that the effect is due easily and are generally satisfactory if mottling
to viscosity alone and not to any speci c action of is troublesome.
either of the binders. • Avoid tray drying unless there is no alternative.
• If tray drying is unavoidable, then the dry
In uence of proces s factors on granules should be remixed before compression.
This will ensure that a random mix of
s olute migration enriched and depleted granules will be fed
to the tablet machines. This remixing will be
Drying.me thod more effective if the granule size is small since
Intergranular migration in xed beds of granules will there will be a greater number of granules per
occur whenever a particular method of drying die ll.
creates a temperature gradient. This results in • If intragranular migration is likely to be
greater evaporation from the hotter zones. troublesome, consider vacuum or microwave
In slow convective drying (e.g. during static tray drying as an alternative to uidized-bed drying.
drying), the maximum concentration of migrated
solute will normally occur in the surface of the
drying bed since the process of drying is slow enough Reference
to maintain a capillary ow of solvent/ solute to the
surface over a long period of time. Wendel, S., Çelik, M. (1997) An overview of spray-drying
applications. Pharmaceutical Technology, 10, 124–144.
Drying by microwave radiation results in uniform
heating that in turn minimizes solute migration.
Drying methods which keep the granules in Bibliography
motion will abolish the problem of intergranular
migration, but intragranular migration can still occur. Banker, G .S., Rhodes, C.T. (2002) M odern Pharmaceutics,
This is marked in uidized granules. 4th edn. Marcel Dekker, NY, USA.
Broadhead, J., Rouan, S.K., H au, I., Rhodes, C.T. (1994)
The effect of process and formulation variables on the
Initia l.mois ture .c onte nt properties of spray-dried beta-galactosidase. Journal o
Pharmacy and Pharmacology, 46(6), 458–467.
The initial moisture content of the granule will also am Ende, D.J. (2010) The freeze drying process. Chap. 41
in uence the extent of migration. The greater the in: am Ende, D.J. (ed.) Chemical Engineering in the
moisture content, the greater will be the moisture Pharmaceutical Industry: R&D to M anu acture.
John Wiley & Sons (in conjunction with AIChE),
movement before the pendular state is reached, at New Jersey, USA.
which migration cannot continue as there is no Franks, F., Auffret, T. (2008) Freeze Drying o
longer a continuous layer of mobile liquid water Pharmaceuticals and Biopharmaceuticals: Principles and
within the wet solid (see Fig. 29.2). Practice. RSC Publishing, London.
Masters, K. (1991) Spray Drying H andbook, 5th edn.
Longman Scienti c and Technical, H arlow, Essex.
Some practical means of Travers, D.N. (1983) Problems with solute migration.
M anu acturing C hemist and Aerosol N ews, 53(3), 67–71.
minimizing s olute migration Troy, D.B. (ed.) (2006) Remington: The Science and Practice
o Pharmacy, 21st edn. Lippincott, Williams and Wilkins,
It may be useful to list the measures that can be Maryland.
taken to minimize migration: Tsotsas, E., Mujumbar, A.S. (2011) M odern Drying
Technology, vol. 3. Wiley-VCH , G ermany.
• Use the minimum quantity of granulating uid Wan, L.S., H eng, P.W., Chia, C.G . (1991) Preparation of
and ensure that it is well distributed. H igh- coated particles using a spray drying process with an
speed mixer/ granulators give better moisture aqueous system. International Journal o Pharmaceutics,
77, 183–191.
distribution than earlier equipment and
Zoglie, M.A., Carstensen, J.T. (1981) Drying. In:
granules prepared in this way show less Leiberman, H .A., Lachman, L. Pharmaceutical Dosage
migration. Forms: Tablets. Marcel Dekker, New York.
503