Drying Technologies For Pharmaceutical Applications

REVIEW
Next Generation Drying Technologies for Pharmaceutical

Applications
ROBERT H. WALTERS,1 BAKUL BHATNAGAR,1 SERGUEI TCHESSALOV,1 KEN-ICHI IZUTSU,2
KOUHEI TSUMOTO,3 SATOSHI OHTAKE4
1
Pfizer, Pharmaceutical R&D – BioTherapeutics Pharmaceutical Sciences, Andover, Massachusetts 01810
2
National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan
3
The University of Tokyo, Medical Proteomics Laboratory, Institute of Medical Science, Minato-ku, Tokyo 108-8639, Japan
4
Pfizer, Pharmaceutical R&D – BioTherapeutics Pharmaceutical Sciences, Chesterfield, Missouri 63017
Received 10 March 2014; revised 13 April 2014; accepted 14 April 2014

Published online 10 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23998
ABSTRACT: Drying is a commonly used technique for improving the product stability of biotherapeutics. Typically, drying is accomplished
through freeze-drying, as evidenced by the availability of several lyophilized products on the market. There are, however, a number
of drawbacks to lyophilization, including the lengthy process time required for drying, low energy efficiency, high cost of purchasing
and maintaining the equipment, and sensitivity of the product to freezing and various other processing-related stresses. These limitations
have led to the search for next-generation drying methods that can be applied to biotherapeutics. Several alternative drying methods are
reviewed herein, with particular emphasis on methods that are commonly employed outside of the biopharmaceutical industry including
spray drying, convective drying, vacuum drying, microwave drying, and combinations thereof. Although some of the technologies have
already been implemented for processing biotherapeutics, others are still at an early stage of feasibility assessment. An overview of each
method is presented, detailing the comparison to lyophilization, examining the advantages and disadvantages of each technology, and
evaluating the potential of each to be utilized for drying biotherapeutic products. C 2014 Wiley Periodicals, Inc. and the American
Pharmacists Association J Pharm Sci 103:2673–2695, 2014

Keywords: drying; dehydration; freeze-drying; hybrid drying; spray drying; foam drying; processing; supercritical fluids; microwave;
proteins
INTRODUCTION of the dried product are also critical parameters assessed dur-
ing the evaluation of a novel drying technology. The different
Most biological materials contain high water content (typically
techniques introduce varying stresses, which may compromise
≥80%, w/w). Removal of water through drying provides numer-
stability. Furthermore, the techniques can produce dry materi-
ous benefits, including ease of handling and storage, reduction
als possessing significantly different characteristics.1,2
in transportation costs, and improved stability, to name a few.
Freeze-drying, or lyophilization, is the most widely used
Although all drying techniques share a common objective (i.e.,
technique for improving the stability of biopharmaceutical com-
dehydration), conceptually they are different and require mod-
pounds. In the book by Rey and May,3 a primitive form of
ification/adaptation based on the properties of the compound.
lyophilization is described as having been employed centuries
Prior to discussing the various drying technologies, the pro-
ago by the Inca to dry frozen meat through the application of
cess of drying will be described in general terms. In order to con-
heat (radiation from the sun) and low pressure (high altitude
vert a solution or suspension into a dry powder or cake, water
of the Altiplano). For a detailed description of the lyophiliza-
must be removed. Applying heat during drying through conduc-
tion process, the reader is referred to the following reviews.4–6
tion, convection, and/or radiation are the basic techniques uti-
Several commercially approved products are manufactured by
lized to vaporize water (Fig. 1). In addition, forced air or vacuum
freeze-drying.7 As such, lyophilization represents the gold stan-
may be applied to enhance the rate of dehydration. The choice
dard to which alternative drying methods must be compared.
of drying method depends on several factors including the phys-
Lyophilization, however, suffers from a number of shortcom-
ical properties of the product, application of the product, type
ings that limit its utility. Such limitations can be addressed
of energy source available, container closure system, and scala-
through modification of the process or equipment setup, as will
bility of the equipment. For high value products, as is often the
be discussed below, or through the use of alternative drying
case with pharmaceuticals, the cost of the raw ingredient may
methods.
be the primary driver that dictates the selection of the process-
The majority of pharmaceutical compounds are susceptible
ing method, as low yield or product recovery less than 100% may
to stresses that develop during freezing and drying. A combi-
not be acceptable. Energy consumption, quality, and shelf-life
nation of rational formulation design and process development
can reduce degradation during lyophilization.5,6 Even with
proper design, freeze-drying processing times can be lengthy
Correspondence to: Satoshi Ohtake (Telephone: +636-247-9685; Fax: +636-
247-6122; E-mail: satoshi.ohtake@pfizer.com) (on the order of days),5 and in the case of poorly designed for-
Journal of Pharmaceutical Sciences, Vol. 103, 2673–2695 (2014) mulations and processes, the cycle durations can be unusu-

C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association ally long (weeks). Rational formulation and cycle design, in
Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 2673

2674 REVIEW
Table 1. Summary Table of Various Drying Technologies with

Applications and References
Drying technique Applications
Foam drying Monoclonal antibodies,1 vaccines13–19

Supercritical fluid Proteins,20–24 metal composite,25 aerogel,26,27
drying polymers28
Convective drying Yeast,29 probiotics,30 proteins,31,32 antibodies,33
enzymes,34 platelets,35 fish,36 fruit37
Vacuum drying Probiotics,38–40 food,41–44 enzymes45,46
Figure 1. Illustration of a generic drying process. The energy sup- Microwave dryinga Food,47–51 enzymes,52 yeast,53
plied to the solution or suspension can come in a variety of forms (heat, pharmaceuticals,54–56 biopharmaceuticals,57
microwave, IR, etc.); other environmental conditions can also be im- polymers58
posed (i.e., convection, vacuum, lowered RH, etc.) to enhance the drying Acoustic drying Food,59–62 lumber,63 coal,64 waste treatment65
process.
Infrared drying Food,66–69 polymer film70
Osmotic drying Food71–75
Ohmic heating Food,76–78 waste treatment79
Spouted bed Food,80,81 blood plasma,82 yeast,83
place of traditionally employed empirical approaches, can be drying pharmaceutical powders,84 probiotics85
utilized to design a lyophilization process of suitable duration. Fluidized bed Yeast,86 food,87 sludge waste,88 chemicals,89
Still, freeze-drying remains a complex problem of coupled heat drying microspheres,90 pharmaceutical tablets91,92
and mass transfer. Typically, the primary drying stage is the
a
longest step of lyophilization; an analysis of the energy bal- Includes microwave drying, microwave vacuum drying, and microwave
freeze-drying (both atmospheric and vacuum).
ance for lyophilization in vials demonstrated that most of the
energy losses were associated with the primary drying step fol-
lowed by losses associated with the condenser and the vacuum encountered in developing an efficient drying process. Depend-
system.8 Ultimately, energy losses lead to reduced efficiency. ing on the energy source and the configuration of the drying
Alexeenko9 determined that the efficiency of fully loaded lab- system, the parameters to be optimized will differ, as will be
oratory and production-scale lyophilizers ranged from 1.5% to described below.
2%, for which efficiency is defined as the ratio of the prod- The focus of the current review is drying methods that
uct of the sublimation enthalpy and rate, to the power input offer an alternative to lyophilization. First, modifications to
into a lyophilization process. In addition, it should be noted a typical freeze-drying process (e.g., bulk freeze-drying and
that the fundamental design of a lyophilizer has not evolved foam drying) will be described. Next, spray drying will be re-
significantly10 even though there have been several key ad- viewed, with the theory behind the process, its application,
vancements in the development of tools to monitor the freeze- and recent developments examined in detail. Spray drying
drying process.11 The design of the drying chamber and the con- is currently used for the production of dry powder across a
figuration and geometry of the duct, which connects the drying wide range of applications in the food, chemical, and phar-
chamber to the condenser of the lyophilizer, influence the va- maceutical industries,12 and as such represents the most ma-
por flow during the drying process.10 Formulations undergoing ture alternative technology to lyophilization. Following the
freeze-drying can be sensitive to deviations in temperature and description of spray drying, supercritical fluid (SCF) drying
chamber pressure, which may be exacerbated in a lyophilizer technologies will be reviewed as these drying methods have
with poor temperature and chamber pressure control, thereby been tested with biologics. Finally, other methods of drying,
leading to additional losses in process efficiency as well as such as vacuum, osmotic, fluidized bed, ohmic, microwave, and
poor product appearance and quality attributes. Further- combinations thereof will be reviewed. These drying methods
more, the high costs of purchasing and maintaining a freeze- are common in other industries (Table 1), but currently of
drying equipment contribute to the final cost of a freeze-dried limited use with biopharmaceuticals. Advantages and disad-
product. vantages of each drying method will be presented, with em-
phasis on how the techniques compare to lyophilization and
potential barriers to their implementation in the pharmaceuti-
NEXT-GENERATION DRYING TECHNOLOGIES cal industry.
Traditional methods of commercial drying are limited either by
their high production costs (e.g., dehydration by sublimation
MODIFICATIONS TO FREEZE-DRYING
under vacuum) or high quality loss due to the long exposure
time of the product to high temperature (e.g., solar drying or There has been an increased emphasis on replacing the tradi-
drying by hot air). The temperature at which a product is dried tional trial-and-error-based approaches with rational formu-
is one of the key parameters influencing the quality of the dried lation and process design for lyophilized pharmaceuticals.4
product. Typically, higher temperatures will have a negative In addition, the technologies to control and characterize the
impact on product quality while decreasing the drying time. freeze-drying process have advanced significantly. The char-
Lower drying temperatures, on the other hand, maintain prod- acteristics of the frozen matrix (number and size of ice crys-
uct quality, but require a lengthy drying process. In addition, tals) depend on the ice nucleation temperature, or the de-
the greater the deviation of the processing temperature from gree of supercooling, an attribute which, until recently, could
ambient, the greater the energy consumption. Thus, finding not be controlled adequately due to the stochastic nature of
the optimum drying temperature is the most common problem the freezing process.93 Since ice nucleation occurs at different
Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

REVIEW 2675
temperatures within the vials undergoing freezing, heterogene- clude a combined valve–baffle system (instead of only a valve
ity in drying is unavoidable. In a Class 100, Good Manufac- as in a traditionally designed dryer), the vapor flow rate was
turing Practices (GMP) production environment, the degree of reported to increase by a factor of 2.2. Additional minor mod-
supercooling is higher (i.e., the ice nucleation temperatures are ifications, including the relocation of the baffle further down-
lower) in comparison to freezing conducted at laboratory scale stream into the condenser, increased the vapor flow rate by
in a typical non-GMP environment.5 Consequently, the ice crys- 54%. The work demonstrated that changes in the dryer design
tals are smaller, which leads to higher product (i.e., cake) re- could increase drying rates, decrease cycle duration, and en-
sistances during drying and a longer primary drying process hance efficiency. Furthermore, a combination of computational
during manufacturing. The inclusion of an annealing step (post fluid dynamics with system-level, non-steady-state heat and
freezing and prior to initiating drying) promotes growth of ice mass transfer model enabled the prediction of dynamic process
crystals through Ostwald ripening and could reduce intervial parameters for dryers of different configurations.10 In another
heterogeneity during primary drying.94 Unfortunately, anneal- report, Xu et al.111 investigated the ultrasound pretreatment on
ing can also facilitate the crystallization of buffer components edamame prior to freeze-drying and have reported the forma-
and phase separation in polymer solutions or protein–sugar tion of finer ice crystals and reduction of crystallization time.
systems, which can lead to instability during freeze-drying. Woo and Mujumdar112 provided a review on the application of
A suitable alternative to annealing during lyophilization is electric or magnetic field to affect the freezing characteristics of
the use of controlled ice nucleation-based approaches. Several water; application of DC and AC fields were reported to confer
methods to induce and control ice nucleation have been devel- opposite effects on inducing nucleation (enhancement and de-
oped and refined in the past decade. These include the use lay, respectively), whereas the application of magnetic field has
of agitation,95 electric current,96 ice fog,97,98 pressurization– been reported to result in the generation of smaller ice crystal
depressurization,99 ultrasound,100–102 and vacuum.103,104 Both size distribution and delayed nucleation. Although the applica-
ice fog- and pressurization–depressurization-induced freezing tion of ultrasound, electric, and magnetic fields may be useful
systems are available for use in laboratory and commercial in controlling the freezing process, their effects on the stabil-
lyophilizers, and appear to be the most promising methods in ity of labile biologicals have not yet been thoroughly examined.
comparison to the other approaches proposed for ice nucleation. Cui et al.113 reported on the application of microwave during
Key advantages of controlled ice nucleation include: formation freeze-drying process of carrot and apple crisps and demon-
of larger ice crystals during freezing that facilitate faster ice strated reduction in processing time by nearly 50% of that
sublimation, larger pores within the cake, and more homoge- required for lyophilization to produce samples of comparable
neous drying behavior. Recently, Geidobler et al.105 observed a quality and residual water content. Several combination drying
reduction in the reconstitution time from 15 to 5 min of cakes techniques with examples of their application will be reviewed
containing a highly concentrated freeze-dried monoclonal anti- below.
body (161.2 mg/mL) and trehalose (10%, w/v). They suggested
the role of improved wetting and displacement of gas from the
Bulk Freeze-Drying
larger pores in cakes, generated using controlled ice nucleation,
as the main cause. There have also been efforts to increase the Pharmaceutical freeze-drying is performed within a confined
ice sublimation rates by drying at higher temperatures, either container (cartridge, syringe, or vial), which ensures sterility
close to or above the temperature of collapse (Tc ).106,107 At tem- of the final dried product, but limits the amount of material
peratures slightly above the Tc , the pore structure may remain that can be processed. Bulk freeze-drying is typically employed
intact, but is accompanied by the appearance of small holes in when either large amounts of material are needed or the dried
the walls of the pores as a consequence of limited viscous flow material is subjected to additional processing steps following
of the formulation. In this scenario, described as micro- completion of drying; for example, the production of process
collapse, the tortuosity of the path decreases, enabling a greater intermediates that are not required to be sterile. Bulk drying
mass transport, and thus faster sublimation. Several reports can be performed in open metal trays (fabricated from stainless
document lyophilization accompanied by micro-collapse at steel, aluminum, anodized aluminum, or alloys), although this
temperatures up to 15◦ C greater than the Tg of protein does present risks of contamination of the equipment and prod-
formulations (>20 mg/mL).106,108–110 It is proposed that the uct flyoff during processing, in addition to the potential increase
freeze-concentrate of protein formulations is highly viscous and in the cleaning time post-drying.114 The LYOGUARD Freeze- R
thereby has only limited mobility, which avoids visible col- Dry tray is an alternative to drying using open metal trays. The
lapse even if drying is performed at temperatures above the tray comprises a polypropylene frame sealed at the bottom with
Tg . Such aggressive drying cycles have been effectively em- a thin, transparent, flexible polypropylene film and closed at the
ployed to reduce the drying time by a factor of two in com- top with a semipermeable GORE-TEX -expanded polytetraflu-
R
parison to the conservative drying conducted at temperatures oroethylene laminate specifically developed for lyophilization.
below the Tc .106,110 There appeared to be no significant impact The top of the tray is equipped with a fill port and a liquid-
on protein stability as long as the residual water content in tight, screw-tight cap to enable filling, sealing, and unloading
the product remained low, thus proving the usefulness of this of the tray. Although water uptake can be of concern with ma-
strategy. terials dried in open trays, the inclusion of a semipermeable
Several reports have described approaches and technologies membrane and a screw-tight cap in LYOGUARD presents a R
to improve the drying rate and production quality of freeze- barrier and holds the dried material in a confined environment.
drying. Recently, Ganguly et al.10 presented a simulation frame- Several reports describe the combination of spray freezing
work that enabled quantification of the impact of lyophilizer with dynamic bulk freeze-drying at atmospheric115 or reduced
design at the commercial scale on drying rates and product pressure.116 Droplets of the formulation to be dried are gen-
temperature. Upon modifying the design of the dryer to in- erated by spraying or atomizing the liquid, directly into a
DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

2676 REVIEW
ological. Effective formulation composition is similar to that

used in freeze-drying, including sugars, polyols, polymers, and
surfactants, as can be inferred from the references pertaining
to the following examples.
For parainfluenza virus stored at 25◦ C for 20 weeks, foam
drying outperformed spray drying and freeze-drying by demon-
strating 0.73 log/week0.5 loss in titer, whereas the other two
processes demonstrated greater than 1 log/week0.5 decrease
in titer.15 The foam dried Francisella tularensis was reported
to demonstrate less than 1 log10 decrease in titer following
12 weeks of storage at 25◦ C,16 and no loss in activity for at
least 12 weeks under refrigerated condition (2–8◦ C). In com-
parison, lyophilized F. tularensis LVS demonstrated >3 log10
decrease in titer following 12 weeks of storage under ambi-
ent condition.119 The foam dried Ty21a vaccine was reported
to demonstrate stability for longer than 4 and 42 weeks, at
37◦ C and 25◦ C, respectively.17 In comparison, VivotifTM (freeze-
dried, commercial vaccine) demonstrated stability for 12 h at
37◦ C and 2 weeks at 25◦ C.120,121 Scalability of the process is yet
Figure 2. Appearance comparison of a (a) foam dried sample to (b) to be demonstrated, but the reported stability of the foam dried
freeze-dried sample. Sample consists of Ty21a in 25% sucrose and material is remarkable.
25 mM potassium phosphate. Figure adapted from Ohtake et al.17 Benefits of foam drying include the ability to operate at near-
ambient temperature (i.e., 15–25◦ C).1,15 This reduces energy
consumption compared to the processes that require either low
or high temperature for drying, allowing for a more economical
cryogenic medium (liquid nitrogen) to freeze the droplets. process and reduced stress on the material. In addition, foam
Freezing in liquid nitrogen results in a high degree of super- drying removes water at a moderate rate, as the process is com-
cooling and formation of smaller ice crystals. The frozen pellets pleted within hours to days. Foam drying avoids the formation
are then transferred to either prechilled shelves of a lyophilizer of ice, which may lead to protein aggregation.16 Additionally,
(for drying in trays) or to a rotating vacuum lyophilizer (contin- foam dried materials typically possess lower specific surface
uous process). In the latter case, ice sublimation occurs via areas in comparison to lyophilized materials, which may lead
heat transfer through radiation and temperature-controlled to stability enhancement.16 With respect to aseptic processing,
surfaces. The rotational movement ensures uniform heat and the challenges encountered in foam drying are similar to those
mass transfer, thereby improving product homogeneity and in- in freeze-drying. Foam drying does introduce its own unique
creasing the drying rates in comparison to those achievable by set of stresses not encountered in lyophilization, namely the
conventional freeze-drying. Coupling between atomization and surface tension stress associated with cavitation. In addition,
rapid freezing significantly influences the morphology of the the rate of water desorption is expected to be slower for foam
dried product. Typically, non-hollow spherical particles with dried material compared with a similar formulation processed
high internal porosity117 and high specific surface area118 are by freeze-drying, due to the lower specific surface area of the
generated from a spray freeze-drying (SFD) process (see more former.15 Thus, a longer secondary drying process may be re-
in section Spray Freeze-Drying). quired to reduce the residual water content to similar levels as
that achieved by freeze-drying, which may potentially negate
Foam Drying
the energy and time savings associated with foam drying. Fur-
Foam drying is a desiccation process, whereby the solution is thermore, vacuum levels must be optimized so that foaming
converted to a dried foam structure in a single step. The over- is effective. Freezing of the solution or rapid boiling, which
all method involves boiling, or foaming, of the solution under may cause material to escape from the vial, must be avoided
reduced vapor pressure followed by rapid evaporation, leaving through the choice of appropriate vacuum conditions that may
a solidified foam structure (Fig. 2). The temperature is care- be challenging at scale. The potential for boil over could also
fully controlled to avoid freezing due to evaporative cooling. negatively impact container closure, leading to sterility con-
The process can be thought of as a freeze-drying method concerns. Although much research has been conducted recently
ducted under a cake collapse condition. on understanding the nature of foaming materials,122,123 sig-
Excellent vacuum control is crucial for foam drying.16,17 For nificant process development is still required to ensure a ro-
processing methods in which the system pressure is decreased bust process. Additionally, the appearance of foam dried mate-
too quickly, the solution has a greater tendency to freeze and rials is inherently more heterogeneous than that of lyophilized
will not foam effectively. Conversely, foaming will be inhibited cakes (Fig. 2), which may make product characterization and
by decreasing the pressure too slowly, as the concentration and quality control difficult, let alone acceptance by patients and
viscosity of the remaining solution will increase. By decreasing health care professionals. Hence, foam drying faces a num-
the chamber pressure stepwise, while allowing for a short equi- ber of significant barriers that may be difficult to overcome
libration period, the process-associated loss can be minimized prior to its implementation for manufacturing a drug product.
significantly.17 In addition to the processing variables, the for- Its utilization for processing and storage of drug substance in-
mulation composition has been reported to affect the foaming termediate, however, may be a possibility if scalability can be
efficiency and the subsequent storage stability of the labile bi- demonstrated.

REVIEW 2677
SPRAY DRYING tribution, this process must start with the appropriate design
or selection of an atomizer nozzle.
Introduction
The impact of nozzle selection propagates into the drying
Spray drying provides control of particle properties such as environment by influencing the initial droplet size and trajec-
crystallinity, particle size, residual water content, bulk density, tory. These initial conditions set the stage for the evaporation
and morphology.124 In the pharmaceutical industry, the pro- process within the drying chamber. Therefore, atomizer design
cess was first applied as an intermediate processing step for and performance parameters should be considered during the
the production of solid dosage forms. Exubera (Nektar/Pfizer)
R
development of a spray drying process to ensure the achieve-
is the first inhaled therapeutic that has been successfully ment of target powder properties such as size and density, while
manufactured by spray drying.125 Spray drying is also being minimizing thermal exposure of the active ingredient. Atomizer
evaluated as an alternative to freeze-drying for stabilization performance, as a function of solution properties and operating
of biotherapeutics.126 Similar to freeze-drying, spray drying conditions, has been described elsewhere.12 Of the various types
involves the exposure of pharmaceutical material to various of atomizers available,12 rotary atomizers and twin-fluid noz-
stresses, which will be described in more detail below. Despite zles are the most commonly provided nozzles by commercial
these stresses, if an appropriate formulation is selected and spray drying manufacturers for pharmaceutical applications.
processing conditions are optimized, a stable pharmaceutical In rotary atomization, the liquid feed is centrifugally acceler-
powder can be produced.127,128 ated to high velocity before being discharged into the drying
chamber. The atomization energy is provided by the rotational
Theory speed of the wheel, and the droplet size decreases with increas-
ing rotational speed. Twin-fluid nozzles utilize a high speed gas
The spray drying process is conceptually simple; a solution is
stream, typically air, to blast the liquid into droplets. A variety
fed through an atomizer to create a spray, which is exposed to a
of twin-fluid designs exist with the distinction being the geom-
suitable gas stream to promote rapid evaporation. When suffi-
etry, which controls the gas and liquid interaction, and sub-
cient liquid mass has evaporated, the remaining solid material
sequent droplet size distribution. Twin-fluid nozzles produce
in the droplet forms an individual particle, which is then sep-
smaller droplets with a broader distribution in comparison to
arated from the gas stream using a filter or a cyclone. Particle
rotary atomizers, and are therefore preferred for applications
formation time is a function of the initial liquid droplet size,
targeting smaller particle size. During the selection process of
the composition of the droplet, and evaporation rate. The evap-
a nozzle from the various types of atomizers available, consid-
oration rate is dependent upon the heat and mass transfer of
eration must be given to the design that economically produces
the system. The rate of particle formation is a key parameter
the most favorable spray characteristics as well as throughput
that dictates the required residence time, and hence the scale
for a given set of operational conditions.
of equipment and processing parameters required to produce
the desired particle size at the target production rate. Particle Formation
The concept has been implemented over a range of equip-
The evaporation of volatiles (usually water) from a spray in-
ment scales from bench units to large multistory commercial
volves simultaneous heat and mass transfer, the rate of which
drying towers. Powder production rates for a typical bench
depends on temperature, humidity, and transport properties
spray dryer are on the order of grams/hour, whereas commercial
of the gas surrounding each droplet. It is also a function of
systems process tons/year. Regardless of the size of the equip-
droplet diameter and relative velocity between droplet and gas.
ment, three fundamental subprocesses occur for a spray drying
For single droplet evaporation, the evaporation rate (6) can be
operation: (1) atomization, (2) droplet drying/particle forma-
approximated as
tion, and (3) particle collection. Each of these will be described
in more detail next. ρg
6 = 8Dg (Ys (Te ) − Y) (1)
ρl
Atomization
The atomization stage produces a spray of droplets possessing where Dg is the diffusion coefficient of the gas phase, Dg and Dl
a high surface-to-mass ratio. Atomization results from an en- are the density of the gas and liquid phases, respectively, Ys is
ergy source acting on liquid bulk, and the minimum energy for the mass fraction of solvent at the surface of the droplet, which
atomization is that required to create a new liquid–air surface. is a function of Te , the equilibrium temperature of the droplet,
Resultant forces build up to a point at which liquid breakup and Y∞ is the mass fraction of solvent far from the surface. For
occurs and individual spray droplets are created. Insufficient a more detailed description of the evaporation rate, the reader
energy transfer during atomization is a problem that is common is referred to the work of Vehring.124
to all atomization techniques. A key performance parameter for The particle formation process involves the conversion of the
nozzle design is the resulting liquid droplet size distribution. atomized spray droplets into solid particles. First, the droplets
Ideally, a narrow droplet size distribution should be targeted must adjust to the temperature of the environment near the
to enable a more uniform drying event and to prevent product nozzle. The type of atomizer will have an impact on the droplet
loss to the sidewalls of the drying chamber. Droplets of a spray temperature profile, as described above. The next stage involves
evaporate quickly,129 and low droplet temperatures are main- the constant rate drying period of the carrier solvent, during
tained during the drying phase due to evaporative cooling. The which the evaporation rate will be driven by the net balance
final product particle size is controlled predominantly by the between the heat transfer to the droplet and the energy re-
initial liquid droplet size and to a lesser extent by the feed- moved due to evaporative cooling.12 During the constant rate
stock concentration and the solution-to-particle density ratio. period, the liquid droplet will experience a temperature close to
For applications requiring tight control of the final product dis- the thermodynamic wet bulb value, which will be significantly

2678 REVIEW
Figure 3. Illustration of particle formation process and impact of Peclet number (Pe). Figure adapted from Vehring.125
below the local drying gas temperature.130 The final stage of smaller, less dense particles. Therefore, this method of particle
particle formation occurs following the evaporation of a portion collection can alter the resulting particle size distribution.
of the solvent carrier. The solid content within the droplet influ- Baghouse filtration utilizes filters to collect dried particles
ences the evaporation rate of the solvent into the gas medium. while allowing the drying gas to pass through. The selection of
Typically, this reduces the mass transfer rate for the remain- an appropriate filter is critical as baghouse filtration has the
ing solvent, and thus this stage is commonly referred to as the capability to collect very fine particles that cannot be recov-
“falling rate period.”12 At this point, as the solute concentra- ered using an inertial separator. The composition of the filter
tion reaches its solubility, the droplet surface starts to solidify, must be compatible with the application and robust enough to
resulting in shell formation (Fig. 3). This creates an internal withstand the temperatures and humidity levels employed in
droplet diffusion-controlled mass transfer process, which slows spray drying.133 Although cake formation on the filter surface
the rate of solvent escape from the inner core to the surface is beneficial in many baghouse separations, it does not always
prior to evaporation.131,132 have a positive impact on spray drying applications. Should
For products in which low residual water content is critical, a problem arise during processing, moist particles could ag-
the outlet relative humidity (RH) will effectively determine the glomerate on the cake at the filter surface causing increased
powder production rate for a given dryer outlet temperature. backpressure and requiring extensive cleaning.133 Additionally,
The manner in which the spray combines with the drying gas prolonged contact with the filter surface may lead to extended
dictates the rate and extent of drying. Drying chamber and gas exposure of the product to high temperatures, which could neg-
disperser design must create a flow pattern that prevents the atively impact product quality.133
deposition of partially dried product on the wall. Retention of
product on the chamber wall is undesirable, as it affects product
quality, reduces product yield, and contributes to more frequent Application
shutdown of the dryer for cleaning.
The basic theory of spray drying is well understood and en-
ables excellent control of the critical parameters that affect
Particle Collection
product attributes. Judging by the number of publications, one
Completion of the particle formation process in the spray dryer can conclude that spray drying is a process that meets the
creates a dispersed particulate aerosol, from which the solid demand of sophisticated pharmaceutical systems through an
material needs to be separated from the process gas stream. efficient, one-step process that may enable continuous man-
One of two different methods is typically used for product cap- ufacturing. Spray drying has seen increasing utilization as a
ture in a pharmaceutical spray drying process; cyclone sepa- process to stabilize biologics, as will be described below. In ad-
ration or baghouse filtration. Each approach offers distinct addition to its ability to control powder properties (e.g., particle
vantages for efficient recovery of high-value pharmaceuticals. size, particle morphology, powder density, and surface composi-
The cyclone, or inertial separation method, is the most com- tion), the key advantages of spray drying as compared with con-
monly used industrial approach for segregating a dispersed ventional freeze-drying are: (1) shorter process cycle time (i.e.,
phase from a continuous medium. The principal of separation more batches per unit time), (2) scalability (i.e., large batch size
is based upon the density difference between particle and gas. per unit, requiring fewer production units), and (3) the ability
Cyclone separation efficiency is dependent upon the cyclone to process at atmospheric pressure. As can be inferred from
design, operating conditions, and the particle size distribution the following examples, the application of spray drying to the
of the incoming material, to name a few. The nature of inertial various aspects of pharmaceutical product development is ex-
separation-based technologies impose the limitation that larger pected to continue its growth, although there are certain areas
and more dense particles will be readily separated from the gas that still require further development. Table 2 lists areas of
phase, and thus obtain higher collection yields compared with current interest and new applications.

REVIEW 2679
Table 2. Various Applications of the Spray Drying Process in the adsorption of components on the droplet surface, causing a dif-
Pharmaceutical Industry fusional flux toward the surface. On the other hand, as the
Application Reference evaporating droplet shrinks, its receding droplet surface leads
to increasing solute concentrations at the surface. This causes
128,134–141
Vaccines a diffusional flux away from the surface. Slowly diffusing com-
Antibodies 142–147
ponents can become enriched at the particle surface if recession
Inhalation therapeutics 125,148–153
of the air–liquid interface of the droplet is faster than the diffu-
Spray freeze-drying 154–162
sion of the component from the surface. The Peclet number, Pe,
Particle engineering 163–168
169–176
provides a measure of the evaporation rate relative to diffusive
Coating and encapsulation
motion. It is defined as
6
Particle Engineering Pe = (2)
8D
Many particle parameters affect powder dispersibility; fre-
quently mentioned are size distribution, density, morphology, where D is the diffusion coefficient of the solute. As each solute
surface roughness, and surface hydrophobicity. The traditional component has a distinct diffusion coefficient, each component
approach to improving the dispersibility of cohesive powders has a distinct Peclet number for a given evaporation rate. Large
is to blend them with carrier particles that modify the inter- values of Pe indicate the component diffuses slower than the
particle forces. Various amino acids and chitosan have been recession of droplet surface, whereas small values of Pe indicate
suggested for this purpose.177,178 For example, spray dried the component diffuses faster than the recession of the droplet
leucine and tri-leucine have been reported to form hollow, low surface (Fig. 3).
density particles163,164 (Fig. 4a). In fact, this particle design Quite often, the shell is likely to be deformed by stress due
concept has been utilized to improve the dispersibility of, or to the pressure differential and changes in material properties
encapsulate a variety of, active pharmaceutical ingredients caused by desiccation and/or phase transformations.179 This pe-
and vaccines, including disodium cromoglycate165 and bacillus riod of the particle formation process determines whether a dry
Calmette-Guerin vaccine.134 particle remains a hollow sphere, forms dimples, or folds on it-
Shell formation will occur if one of the formulation com- self, and is a critical area of focus in particle engineering (Fig. 3).
ponents reaches its solubility and precipitates (Fig. 3). Low The key to successful particle engineering is the control of
aqueous solubility components have the tendency to precipitate mechanisms that determine the radial distribution of compo-
early in the drying process as their solubility is reached quickly, nents during the drying process. Early shell formation can be
resulting in the formation of corrugated particles. In contrast, intentionally forced by selecting high initial saturation, high
highly water-soluble components remain in solution as the liq- Peclet number, or a combination of both for the shell forming
uid droplet dries, resulting in the formation of smooth, spherical component (Fig. 4b). Which shell former dominates the parti-
particles. In addition, surface activity may lead to preferential cle formation process depends on their characteristic times to
Figure 4. SEM images of various types of particles formed by spray drying. (a) Gentamicin without (left panel) and with 15% trileucine (right
panel),164 (b) glycoprotein particles produced at Pe numbers of 2.7, 5.6, and 16.8 (left to right panel).125 Figures adapted from the references
provided.

2680 REVIEW
reach a critical surface concentration and their interactions. tion of air–liquid interface.189 For this purpose, surfactants are
For a detailed consideration of Peclet number in particle engi- typically included to stabilize and prevent the formation of in-
neering, the reader is referred to the work by Vehring.179 soluble aggregates. The type and amount of surfactant must be
carefully selected, as it may unintentionally produce a coat on
Spray Dried Powders for Inhalation the particle surface with low glass transition temperature. Such
a coat can cause unacceptably high cohesive forces between the
Systemic drug delivery using the pulmonary approach must
particles.1
target the deep lung region, which requires the use of very
The surface activity of the protein is an important deter-
small particles ranging in aerodynamic size from 1 to 3 :m.
minant for stability at the air–liquid interface. Proteins may
If the particles are too large, they will deposit in the upper
enrich the particle surface as a result of slow diffusivity if
airway at which absorption is poor. If they are too small, they
the other formulation components are low-molecular-weight
will stay suspended in air and be exhaled. Therefore, control of
(LMW) compounds with high solubility in water. Alternatively,
the particle size distribution is critical to achieve an efficient
LMW excipients with low aqueous solubility (e.g., leucine,
and reproducible pulmonary deposition.180
trileucine, etc.), or larger molecular-weight excipients, can be
The first pharmaceutical product targeting systemic treat-
used to control the surface composition/enrichment. Using this
ment through the pulmonary route was inhaled insulin,
concept, spray drying has been employed to engineer parti-
Exubera .125 It contains 60% recombinant human insulin for-
R
cles possessing variable radial composition to effectively “coat”

mulated with sodium citrate, glycine, and mannitol.181 This dry
protein particles and to reduce or prevent surface-induced con-
powder-based delivery system utilized spray drying to create
formational changes of the protein during spray drying.164,171
homogeneous particles that were engineered to disperse using
Several examples of spray drying applications for mAbs are re-
a handheld delivery device. Numerous physicochemical at-
ported in the literature. Costantino et al.142 have produced a
tributes were optimized to manufacture the powder for inhala-
stable, dry powder recombinant human anti-IgE mAb (rhuM-
tion, including particle size, stability (both physical and chem-
AbE25) formulated using mannitol and various levels of sodium
ical), and aerosol dispersibility. In pharmaceutical dry powder
phosphate. Kaye et al.143,144 have demonstrated the feasibility
applications, the ability to disperse the powder into individual
of spray drying a model antibody intended for nasal and pul-
particles is critical. In general, as particle size is reduced, dis-
monary delivery. In one case,144 the antibody was formulated
persion becomes difficult as a result of shift in balance between
using lactose, poly(lactic-co-glycolic acid) (PLGA), and Dipalmi-
interparticle cohesive forces and drag forces.182 Residual wa-
toylphosphatidylcholine (DPPC), and then spray dried, result-
ter content can also affect powder dispersion and powder flow
ing in nanoparticles that exhibited continuous release of the
characteristics,183 highlighting the importance of achieving the
encapsulated antibody over a 35-day period. The released anti-
targeted residual water content as well as the use of an effective
body was demonstrated to be stable and active.
container closure system to eliminate water uptake.
Spray drying can also be used to prepare a high-dose mAb
formulation by reconstitution using low diluent volume. Dani
Stabilization of Biologics
et al.145 demonstrated the use of spray drying in preparing a
Similar to lyophilization, protein denaturation has been high-dose human IgG formulation intended for subcutaneous
observed during spray drying due to the dehydration- injection. Analyses demonstrated maintenance of the mAb’s
associated stress, often necessitating the use of excipients for secondary structure post-processing, and the dry powder mAb
stabilization.184,185 Even though the drying gas temperature was successfully reconstituted at 200 mg/mL without loss of
may exceed 100◦ C in normal spray drying conditions, thermal protein monomer content. The powders were reported to recon-
denaturation of proteins is typically not observed, mainly be- stitute within a few minutes.
cause the temperature of the droplet barely exceeds the wet The majority of commercially available vaccines are stored
bulb temperature of water (∼40◦ C). Additionally, the protein under refrigerated conditions, if not frozen. Although signifi-
denaturation temperature is a function of water content, in- cant focus and progress have been made to develop new vac-
creasing sharply with decreasing water content. Although one cines demonstrating improved safety and efficacy, progress
must keep in mind the risk of prolonged particle exposure to toward the development of thermally stable vaccines appears
drying gas in the collector vessel,186 dry proteins are relatively incremental. In contrast, a review of recent publications reveals
stable, demonstrating denaturation temperatures typically ex- a number of promising approaches. Spray drying has been uti-
ceeding 100◦ C.187 The components in a particle may separate, lized to successfully prepare a number of dry vaccines, includ-
due to the differences in diffusion rates and solubilities, and ing measles vaccine,128 tuberculosis vaccine,135 live Newcastle
lead to heterogeneous distribution within the particle. Rapid disease vaccine,136 and hepatitis B antigen,137 to name a few.
droplet evaporation tends to produce dry particles in which the The dry powder vaccines can be utilized directly for pulmonary
composition is a function of the radius. Hence, the glass tran- delivery or for mass production to allow for bulk storage. The
sition temperature is also expected to be different for the core complexity of vaccines range from proteins, or their fragments,
and the shell of a layered particle.188 Denaturation may occur to live attenuated viruses. Further exploration of spray drying
if the stabilizers separate from the molecule they are designed methods to prepare stable vaccines is expected.
to stabilize.
Besides the stress caused by thermal dehydration, the pro-
Spray Freeze-Drying
tein is subjected to shear stress and exposed to increased air–
liquid interface during atomization. Although proteins have Spray freeze-drying (SFD) is a drying process that involves el-
been reported to withstand shear rates on the order of mag- ements of spray drying and freeze-drying. The process steps
nitude encountered during atomization, significant instability involved in SFD include atomization, rapid freezing, primary
can result if shear stress is combined with the rapid forma- drying, and secondary drying. As in spray drying, atomization

REVIEW 2681
involves spraying of a feedstock. Instead of atomizing into a Hu et al.198 observed enhancement in wetting (from contact
heated gaseous medium, the liquid feed is atomized directly angle measurements) and dissolution rates of spray freeze-
into a cryogenic medium, in which rapid freezing of droplets dried danazol–poloxamer 407 and carbamazepine–sodium lau-
takes place to form ice particles. The suspended frozen droplets ryl sulfate particles in comparison to the lyophilized samples
are collected by sieves, or are collected after the cryogen has or their physical mixtures. Spray freeze-dried skim milk pow-
boiled off. The frozen particles are then transferred to prechilled ders were reported to be highly porous and wetted three times
shelves (typically −40◦ C) of a lyophilizer for subsequent dry- faster than their spray dried counterparts.199 Time-lapse pho-
ing. The principle of drying by ice sublimation for this phase of tography demonstrated that the dissolution of the spray freeze-
the drying process is identical to primary drying in a conven- dried particles was accompanied by rapid distintegration into
tional freeze-drying process. One advantage of SFD is that sub- smaller particles upon the entry of water into the pores. In con-
limation and secondary drying of the frozen particles are more trast, Webb et al.200 observed a 55-fold increase in the dissolu-
rapid than those encountered in conventional freeze-drying tion rates of lyophilized and unannealed rhIFN-(, sucrose, and
due to the increased surface area of the frozen starting mate- hydroxethyl starch cakes in comparison to the spray freeze-
rial. Key areas of application of spray freeze-dried materials in dried and unannealed particles. The impact of annealing on
biopharmaceuticals include microencapsulation in biodegrad- the reconsititution behavior was also investigated. While the
able polymers, pulmonary delivery, and delivery to the skin annealed lyophilized cakes exhibited slower dissolution com-
via epidermal powder immunization.190 In addition, SFD has pared to the unannealed cakes, the annealed spray freeze-dried
been utilized to produce several vaccines, including anthrax samples exhibited a 1.7-fold increase in dissolution rate com-
vaccine156 and influenza whole inactivated virus vaccine,158 pared to the corresponding unannealed material. The authors
microspheres,155 solid dispersions,157 and nanoparticles.159 One proposed a mechanism operating via a reduction in the surface
particular area in which SFD has demonstrated superiority area of the annealed lyophilized cakes to explain the 18-fold
over spray drying and freeze-drying is in the preparation of dry decrease in the dissolution rate in comparison with the unan-
Alum-containing vaccines.160 nealed material. In the case of the spray freeze-dried samples,
Maa et al.118 observed the formation of larger, porous parti- the authors proposed that an annealing-induced decrease in
cles using SFD in comparison to the smaller and denser parti- the internal surface area of the porous particles led to an in-
cles produced by spray drying. Costantino et al.191 investigated crease in their density, thus accelerating powder submersion
the effect of atomization variables on the size and stability of and dissolution. In addition, the authors suggested that dif-
spray freeze-dried bovine serum albumin particles. An increase ferent mechanisms may be governing the reconstitution of an-
in the mass flow ratio (i.e., ratio of the mass of atomization ni- nealed and unannealed lyophilized cakes in comparison to the
trogen gas to the mass of liquid feed) resulted in the formation spray lyophilized particles.
of more friable (e.g., easy to disintegrate) particles. In addition Due to the requirement of freezing the material, protein
to the usual stresses experienced during freezing and drying, degradation caused by exposure to ice surfaces is a possibil-
SFD presents additional stresses to protein-containing formu- ity during SFD. Significant amounts of liquid nitrogen may be
lations. These stresses result from the shear forces experienced required for the process if it is used to freeze the samples. Ad-
during atomization and from the exposure to the air–water ditionally, aseptic processing of material can be challenging.
interface at which potential adsorption, unfolding, and aggre- Overall, SFD offers some advantages over lyophilization in-
gation of proteins may occur.190 The inclusion of surfactants cluding faster drying times, lower energy consumption during
and lyoprotectants has been demonstrated to reduce the im- drying, and flexibility during scaling. However, some of these
pact of processing-induced stresses on the stability of several advantages appear to be offset by energy consumption during
therapeutic spray freeze-dried proteins similar to conventional freezing and difficulties inherent to spray-based processes.
freeze-drying. Although the inclusion of trehalose (at a pro-
tein:sugar ratio of 60:40) has been reported to decrease aggre-
Spray Drying Summary
gation during freeze-drying and SFD of rhDNase and rhMAb,
the inclusion of polysorbate 20 conferred additional stabiliza- Spray drying represents the most mature alternative drying
tion in comparison with the surfactant-free powders.192,193 Fur- technology to lyophilization. The process provides an opportu-
ther, annealing of spray frozen particles at −15◦ C for 1 h prior nity to engineer particle size and shape (including morphol-
to the initiation of drying was reported to decrease the spe- ogy, surface area, and surface composition), which can enable
cific surface area and the extent of protein aggregation.192 An delivery methods that are infeasible using other drying tech-
increase in the annealing temperature from −15◦ C to −5◦ C niques. Spray drying can also be accomplished more quickly
was also reported to minimize surface area and reduce pro- than lyophilization in most cases. It allows for the process-
tein aggregation. Webb et al.194 determined the excess protein ing of material under atmospheric pressure, offering energy
molecules on the surface of spray freeze-dried recombinant hu- savings. Spray drying does come with some unique caveats
man interferon-gamma (rhIFN-() and trehalose powders us- as well. Aseptic processing for spray drying is more challeng-
ing X-ray photoelectron spectroscopy. The inclusion of 0.12% ing than it is for lyophilization. Material is exposed to signifi-
polysorbate 20 was reported to reduce the amount of excess cant shear stress during atomization, and the large surface to
protein molecules on the surface to 3.4%, in comparison with mass ratio in droplets results in significant air–water interfaces
34% excess observed in the absence of surfactant. at which proteins can denature. Although the temperature in
As the use of SFD results in the formation of powders the evaporating droplet barely exceeds the wet bulb tempera-
prossessing high specific surface area, the technology has also ture, dried material can be exposed to high temperatures for
been utilized to promote rapid wetting and faster dissolution prolonged periods of time in the collection vessel. Addition-
of poorly water soluble drugs formulated with polyvinyl alco- ally, a secondary drying method may be required if very low
hol, polyvinylpyrrolidone, poloxamer, and other polymers.195–197 residual water content is needed in the final product, which

2682 REVIEW
may reduce the time and energy savings for spray drying as the material to extreme temperatures. Additionally, steriliza-
compared to lyophilization. Furthermore, there may be diffi- tion of microorganisms and viral inactivation can be achieved
culties associated with handling of hygroscopic and/or electro- during the SCF drying process,209 alleviating some concerns
statically charged powders. The fact that material recovery is about aseptic processing. As the atomization process is simi-
<100% is also an issue when considering its implementation lar to spray drying, particle engineering efforts for alternative
for high-cost therapeutics. Still, proper process design can over- delivery methods are also achievable.210 However, only a lim-
come many of these limitations, highlighting the great poten- ited number of studies have addressed the effect of SCF drying
tial of spray drying as an alternative to lyophilization that may on protein structure and stability. In addition to the unique
enable continuous manufacturing.146 stresses of SCF drying, other stresses common to freeze-drying
and spray drying also exist (e.g., adsorption and denaturation
at the fluid–fluid interface). The high pressure requirement for
SUPERCRITICAL DRYING
SCF may impact protein structure/stability and the dissolution
Supercritical fluid (SCF) technology has been investigated with of CO2 may result in pH decrease if the solution is not buffered
focus on the production of high purity, micron-sized particles appropriately. Furthermore, the use of organic solvents in pro-
with controlled morphology and tailored properties. Supercrit- tein solution (to enhance protein solubility in SCF) may result
ical CO2 is the most widely used SCF in pharmaceutical pro- in aggregation211 and instability caused by residual solvent or
cessing due to its low critical temperature (Tc = 31.1◦ C) and impurities introduced by the parent solvent. Process scale-up
environmental friendliness. may be an issue with several of the above described SCF pro-
Several techniques employing SCF have been investigated. cesses; specialized and expensive equipment, able to withstand
In SCF-assisted nebulization drying, protein formulation is elevated pressures, is required and compression costs can be
sprayed into SCF.24 The setup is similar to that employed for significant.212 For a thorough review on SCF-based technolo-
a typical spray drying process, with SCF being used in place gies, the reader is referred to the work by Sheth et al.213 Over-
of a drying gas. Desiccation is driven by the precipitation of all, SCF-based drying methods offer a number of advantages
solute in the droplet, which subsequently loses solvent power. over other drying methods; however, the technology is less ma-
The supersaturated protein solution precipitates as the water ture than spray drying and requires the use of high pressure
is extracted to the SCF and the protein is then vitrified in an that may impact protein stability, potentially hindering its use
amorphous matrix. for the production of biotherapeutics.
In another process, supercritical antisolvent (SAS) process,
the protein solution is mixed with the SCF prior to atomization
CONVECTIVE DRYING
and then sprayed under atmospheric condition.201 Here, SCF
is used as an antisolvent that causes precipitation of the pro- Convective drying is perhaps the simplest of all drying tech-
tein. Several examples of nano- and micro-particles have been niques. The solution/suspension is dried upon exposure to air
reported, including insulin20 and "-chymotrypsin,21 although (which can be heated or at ambient temperature), while con-
varying degrees of stability have been reported. SAS processes trolling the RH of the environment. A wide range of bio-
have also been considered for the production of protein-loaded logicals has been processed by convective drying, including
microparticles by co-precipitation of the biodegradable polymer yeast,29 probiotics,30 human platelets,35 antibodies,33 restric-
and the protein from an organic cosolvent.22 In this study, the tion enzymes,34 and fish.36 Of the various processing parame-
reported protein loading was rather low. ters that can be controlled, the rate of drying has been reported
In CO2 -assisted nebulization, the process involves the mix- to significantly impact recovery.214
ing and dissolution of CO2 within the aqueous protein solu- Lemetais et al.215 investigated the stability of baker’s yeast,
tion under supercritical pressure and temperature (typically Saccharomyces cerevisiae, to air drying stress and reported a
8–10 MPa and 20–50◦ C).202,203 The solution is then sprayed and survival rate of 40%. The loss in viability was attributed to
expanded through a flow restrictor to atmospheric pressure, re- plasma membrane (PM) reorganization, which was confirmed
sulting in the generation of dense aerosols. When CO2 expands by the lower survival rate of a mutant strain with an osmoti-
during spraying, drops are broken down to finer droplets, which cally fragile PM. Brinkhous and Read35 reported the success-
are then dried rapidly by gas flow to yield micron-size particles. ful drying of human platelets by exposing the samples to a
In this process, CO2 is not used as an antisolvent to precipi- stream of air at 23–25◦ C; integrity of the platelet aggregat-
tate the protein, but rather as an aerosolization aid (dispersing ing factor/von Willebrand factor (PAF/vWF) platelet receptor
agent) that permits droplet drying at a lower temperature than was maintained following drying. In addition, the aggrega-
that used in conventional spray drying. Thus, this technique tion rate with PAF/vWF was reported to be rapid and essen-
may be useful for processing thermally unstable materials.204 tially unchanged from that observed with the control platelet
Other processes, leveraging the unique properties of SCF, in- preparation. These results were comparable to those reported
clude solution-enhanced dispersion supercritical fluid,205 rapid for platelets preserved by freezing or freeze-drying. Fellowes33
expansion of supercritical solutions,206 particle from gas satu- compared the storage stability of the virus-neutralizing anti-
rated solutions,207 and coating.208 These processes will not be body of foot-and-mouth disease that had been air dried on paper
described here, thus the interested reader is referred to the or freeze-dried in bottles. Air drying was accomplished by ex-
references provided. posing the antiserum to 23◦ C and 30% RH for 18 h. Remarkably,
Supercritical fluid drying offers many advantages, includ- the antiserum remained stable for up to 28 weeks upon storage
ing safety and low cost of materials. Using CO2 in SCF dry- at 37◦ C, and was found to be more stable than the freeze-dried
ing allows operation at moderate temperatures and leaves no preparation.
toxic residues as it reverts to gas phase upon exposure to am- Champagne et al.30 examined the stability of vari-
bient condition. Ice formation is avoided, as is exposure of ous probiotic cultures, including Lactobacillus rhamnosus

REVIEW 2683
(L. rhamnosus) and Lactobacillus plantarum (L. plantarum) low solids content. Food materials and cells are able to be vac-
upon air drying. Samples were exposed to dehumidified air uum dried as the high solids content (and the presence of mem-
(<5% RH) at 90 L/h and dried for 24 h at room temperature in brane) provides structure to the product. On the other hand,
the presence of supersaturated solution of lithium chloride to vacuum drying of biotherapeutics, containing high water con-
control water activity. Optimum survival of L. plantarum and tent, is expected to transition into foam drying at the pres-
L. rhamnosus was reported to be 78% and 70%, respectively, sures utilized for processing. Thus, it may be more appropri-
which are both within the range of survival levels observed ate to consider foam drying, discussed earlier, for processing of
with freeze-drying.216 biotherapeutics.
The main benefit of convective drying is its simplicity, es-
pecially compared with freeze-drying. However, a number of
issues make its use difficult for the drying of biologics. Convec-
MICROWAVE DRYING
tive drying requires excessively long drying times at ambient
temperature or exposure of material to elevated temperatures, Drying with microwaves is different from conventional drying.
which may degrade product quality. Additionally, scalability of When using conventional dryers with hot air or vacuum, the
the process is poor, as convective drying requires small vol- speed of drying is limited by the rate at which water or sol-
umes spread over large surface areas. Paucity of data in regard vent diffuses from the interior of the material to its surface, at
to the final residual water content achievable is also a concern. which evaporation occurs. The rate of drying is enhanced by
Given the high initial water content in many biologics, convec- raising the temperature (or applying vacuum), which increases
tive drying alone may not be a viable or economical option for the evaporation rate of water from the surface. Still, drying
processing of biotherapeutics products. may be limited by the rate at which the interior water dif-
fuses to the surface. For example, fast drying may result in the
overdyring of surface, thus hindering the transport of water to
and away from the surface. Also, as drying progresses, the path
VACUUM DRYING
for diffusion of interior water becomes longer and more diffi-
Vacuum drying utilizes the application of low pressure to en- cult, resulting in the reduction of drying rate (as is observed for
hance the rate of dehydration. Vacuum drying differs from foam lyophilization).
drying as the latter relies on the intentional creation of a foam Microwaves themselves do not generate heat, but rather the
structure while vacuum drying does not. Presently, vacuum absorbed energy is converted to heat inside the product; heat-
drying has been applied to various food materials as an alter- ing by microwave energy is accomplished by the absorption of
native to freeze-drying, with the aim of lowering the manufac- microwave energy by dipolar water molecules and ionic compo-
turing cost.38,41,42 Foerst et al.39 examined the storage stability nents, if present. The carrier, or substrate, is heated primar-
of dried probiotic, Lactobacillus paracasei (L. paracasei) F19, ily and slowly by conduction. Microwaves are part of the elec-
produced by vacuum drying. The drying was conducted for 22 tromagnetic spectrum, and are located between 300 MHz and
h at 15◦ C and 15 mbar chamber pressure. Vacuum dried L. 300 GHz. The preferred frequency for drying processes is re-
paracasei was reported to be highly stable during storage at ported to be 2.45 GHz. At this level, microwaves cause the
4◦ C, and no significant inactivation was reported following 3 molecules of suitable materials/size to vibrate, and this vibra-
months of storage. This result is in accordance with studies on tion creates intermolecular heat that results in evaporation.
storage of freeze-dried lactic acid bacteria.217,218 Comparatively, Examples of industrial microwave dryers include: Linn High
the inactivation rate constants of cells dried by vacuum drying Therm GmbH,220 Thermex Thermatron,221 EnWave,222 and In-
were lower than those of the same strain dried by freeze-drying. dustrial Microwave Systems.223 Products that are processed
Conrad et al.219 examined the effect of vacuum drying on the using various microwave-assisted drying technologies include
stability of Lactobacillus acidophilus (L. acidophilus). Drying pasta, dried milk, grains, fruit, coffee, and shrimp.224 Promis-
was carried out at room temperature at 85 mTorr for 4 days. ing results have been reported for drying chicken pieces48 and
L. acidophilus on its own demonstrated 19% recovery, whereas potato slices47 by a combination of cool air and low-power
the addition of trehalose improved the recovery to 38%. Rossi microwave; quality and ability to reconstitute have been re-
et al.45 reported the stabilization of a restriction enzyme, EcoRI, ported to be comparable to those for freeze-dried foods. In ad-
by vacuum drying in various formulations. In trehalose, no loss dition, microwave drying has been used to process yeast,53
was observed upon storage at 6◦ C for up to 35 days, and up to 12 enzymes,52 small molecule pharmaceuticals,55,225 and various
days at 45◦ C. Similarly, Uritani et al.46 reported the ability to biopharmaceuticals.57
stabilize restriction endonucleases, including HindIII, EcoRI, The main advantage of microwave drying is the shorten-
and BamHI, using vacuum drying in the presence of trehalose. ing of drying time. It is possible to accomplish in seconds-to-
Vacuum drying possesses distinct characteristics, including minutes what could take minutes-to-hours using conventional
high drying rate and low drying temperature, which may lead heating methods (Fig. 5). It is not, however, economical to use
to improved quality of dried products. The reduction in pres- microwave heating for the complete drying of highly hydrated
sure (50–100 mbar) causes the expansion of water molecules foods. Rather, it should be used as a complement to conven-
to vapor phase. Low temperature can be used under vacuum, tional heating to enhance the drying at the later stages of
making it ideal for heat-sensitive material. Additionally, the the process (see Hybrid Drying section below). The on–off na-
lack of ice formation in vacuum drying eliminates the poten- ture of microwave application and the ability to change the
tial for protein denaturation that can occur at the ice–water degree of heating (by controlling the output power of the gener-
interface. Temperature control/monitoring is required to avoid ator) enables fast, efficient, and accurate control of the process.
freezing caused by evaporative cooling, and pressure needs to Although uniform heating can be realized in theory, the key
be carefully adjusted to prevent boiling over for material with problem lies in the inherent nonuniform distribution of the

2684 REVIEW
Figure 6. Drying curves of granulated kaolin (initial water content

of 0.4 kg/kgdry basis ) processed by (1) convective drying, (2) convective
drying enhanced with microwave (MW), (3) convective drying enhanced
with infrared radiation (IR) in the constant drying rate period, and (4)
convective drying enhanced with MW and IR through the first 70 min
of drying. Drying was completed upon reaching the final residual water
content (0.06 kg/kg). Figure adapted from Kowalski and Rajewska.227
gies available, thus a large number of possible combinations.

Suitable application (or compatibility) of the individual drying
methods and reasonable partitioning of the energy sources are
necessary.
For example, convective, microwave, and infrared drying dif-
fer from each other in energy supply and area of impact. In
convective drying, energy is supplied through the surface of
material using air. In microwave drying, heat is supplied volu-
metrically by high frequency polarization of dipole molecules.
In infrared drying, energy is supplied to the body through sur-
Figure 5. Comparison of (a) drying time and (b) sample tempera- face radiation, which can be absorbed, reflected, or permeated
ture for convective drying (air drying) with microwave drying. Figure through the body. Figure 6 compares the drying time of var-
adapted from Li and Ramaswamy.224 ious combinations of these drying techniques on granulated
kaolin.227 The greatest reduction in drying time was achieved
through the use of convective drying enhanced with microwave
microwave field, which can lead to uneven temperature dis-
and infrared radiation. In comparison, similar residual water
tribution within the drying material.226 The use of certain ex-
content (0.06 kg/kgdry basis , or 6%) was achieved in 5 h using
cipients may also be precluded due to their polar/ionic nature,
pure convective drying (3.8-times longer). The advantage of
which could cause the temperature of the solution to increase
applying microwave heating in the early stage of drying is
excessively without careful control of the microwave condition.
that a significant amount of water is pushed out to the sur-
This will be an issue if reformulation is not an option, although
face of the material rapidly through increase in pore pressure,
this challenge may be circumvented with further advancement
thermo-diffusion, reduction of liquid viscosity at higher temper-
in microwave technology. In addition, a thorough analysis of the
ature, etc. In other examples, Garcia and Bueno228 examined
effect of microwave application on protein mobility, structure,
the efficiency of combined convective-microwave drying on agar
and stability is yet to be reported. Thus, the usefulness of mi-
gel and Gelidium seaweeds under several operating conditions.
crowave drying may be restricted for biotherapeutics; however,
Goluannec et al.229 and Salagnac et al.230 presented the kinet-
its coupling to another drying technology may be a possibility,
ics of drying, achieved by the combination of convection with
as will be described below.
infrared and microwave radiation. Several successful cases of
hybrid drying technologies will be described below.
HYBRID DRYING
Microwave-Assisted Vacuum Drying
Introduction
In recent years, microwave vacuum drying (MVD) has been in-
Hybrid drying techniques are becoming more common as they vestigated to obtain products of acceptable quality, including
receive a combination of the benefits of individual processes.227 foods and pharmaceutical products.54,231 Microwave-assisted
As mentioned in Introduction, there are many drying technolo- vacuum drying is a technology that not only possesses the

REVIEW 2685
to materials dried using other methods.233 Tight control over

vacuum levels is still necessary to prevent unwanted freezing
of the product. Additionally, MVD has been reported to cause
color changes in some products, such as Saskatoon berries241
and fingerroot,233 with the degree of color change dependent
upon vacuum level, microwave power, and the composition of
the material being dried. As noted earlier, vacuum drying of
biologics at the pressure levels to be employed is expected to
transition into the realm of foam drying. Application of MVD to
such a process for high value biologics would require extensive
optimization of process variables through a rationally designed
experiment to eliminate, or at least reduce, the impact of mi-
crowave radiation on product quality.
Microwave-Assisted Freeze-Drying
In microwave freeze-drying (MFD), the microwave field is used
as the heat source to enable sublimation in the freeze-drying
Figure 7. Drying curves of freeze-dried (FD), air dried (AD), mi- process.242 MFD requires much less drying time and energy
crowave vacuum dried (MVD), and combined air and microwave vac- consumption compared to a conventional freeze-drying method.
uum dried (AD + MVD) edamame. Figure adapted from Zhang et al.238 MFD has been applied to a variety of products, including fruits,
vegetables, and solid soup.50,243,244 Temperature-sensitive ma-
terial should only be exposed to microwave radiation for a lim-
advantages of microwave heating (i.e., rapid heating, high ef- ited duration. Duan et al.245 demonstrated that the process
ficiency, good control, etc.) but also improves the energy effi- time for freeze-drying of cabbage can be halved through the
ciency of the process by lowering the boiling point of water application of microwave without affecting the product qual-
through application of vacuum.232 For example, MVD of fin- ity significantly. In another example, Duan et al.244 examined
gerroot (Boesenbergia pandurata) was compared with hot air MFD of sea cucumber and reported a reduction in drying time
drying at 60–70◦ C, and a 90% reduction in drying time was by about half of that required for conventional freeze-drying,
reported.233 MVD has been utilized in the processing of various while providing similar product quality. Wang et al.246 studied
foods, including banana slices231 and potato slices.234 Studies the effects of MFD on the microstructure and quality of potato
have demonstrated that drying under a pulsed microwave vac- slices and reported methods to avoid changes in shape during
uum is suitable for the drying of temperature-sensitive prod- processing. Additionally, sterilization effect through the use of
ucts, such as enzymes and proteins.235,236 microwave has been reported.247
In another example, drying of edamame using various tech- Microwave can be applied to convective drying,248 thus its
niques was compared.237 Figure 7 illustrates the residual water application to atmospheric freeze-drying (AFD) seems logical.
content-versus-time curves of edamame dried by: (1) freeze- AFD is based on the sublimation of ice driven by the pressure
drying, (2) air drying, (3) MVD, and (4) combined air and gradient (convective drying).249 The most important application
MVD.238 MVD was more efficient in reducing the water content of AFD is convective drying performed at temperatures below
than air drying or freeze-drying at any point. Although MVD the freezing point of the product. Compared with freeze-drying,
required 40 min to reach the target water content (∼3%), air the temperature is higher, typically in the range of −3◦ C to
drying required 9 h. Drying time for freeze-drying was 18 h, far −10◦ C. This is due to the physical properties of humid air, as
longer than the other methods examined. MVD was also used in lower air temperature reduces the ability to remove moisture.
the drying of "-amylase bacterial enzyme.52 For all of the condi- Drying at temperatures around −10◦ C has proven to be a vi-
tions examined, 200 s was necessary to reduce the residual wa- able trade-off between quality and costs when a fast process is
ter content to near-zero value, except at high power, for which required. AFD is controlled by internal resistance to heat and
drying was completed within 120 s. Applying a higher pres- mass transfer (due to lower vapor diffusivity at atmospheric
sure gradient helped lower the evaporating temperature and pressure), which unfortunately increases drying time. Because
enhance the drying process. The best results were obtained for the process is slow in general, microwave radiation can be ap-
processes using lower powers (200 and 300 W). Although high plied in order to increase sublimation in both fluid and fixed
vacuum normally yields improved quality, the equipment and bed conditions. For example, with the application of microwave,
operating costs increase and this may be prohibitive for low the drying time of green peas was reduced by approximately
profit margin products.239 50%.49 The first industrial AFD system for vegetables, based
Microwave vacuum drying processes retain the benefits of on a heat pump to condition and circulate the drying air, was
vacuum drying while further decreasing drying time and in- built in Hungary in 2005.250 Several industrial MFD units are
creasing energy efficiency by using microwaves as an additional currently available for processing various products.222,251
energy source. Employment of microwaves for drying processes The advantages of MFD processes include shorter drying
results in the transfer of energy throughout the drying volume, time compared with lyophilization, energy savings, improved
but within the penetration depth of the microwaves.240 This product quality, and flexibility in producing a wide array of
results in the formation of porous structures which can keep dried products.240 Sublimation can occur throughout the vol-
resistance low during the drying process and allow for quick re- ume of the drying material which is within the penetration
hydration of microwave vacuum-dried materials in comparison depth of microwaves, and penetration depths are increased if

2686 REVIEW
Table 3. Heat Transfer Coefficients for Convective Drying (h) and Acoustic-Assisted Convective Drying (hac ) of Carrots at Various Slice
Thickness and Air Velocity
Air Velocity (2.2 m/s) Air Velocity (2.8 m/s)
d = 0.5 cm d = 1.0 cm d = 1.5 cm d = 0.5 cm d = 1.0 cm d = 1.5 cm
h (J/s m2 K) 73.3 57.2 50.2 95.1 85.3 62.5

hac (J/s m2 K) 95.7 64.0 59.5 135.5 108.7 89.8
Table adapted from Aversa et al.61 .
water is frozen below −5◦ C,252 further increasing the efficiency thermore, Moy and DiMarco257,258 tested ultrasonic application
of MFD processes. Material dried by MFD may be susceptible in both vacuum and non-vacuum freeze-drying.
to degradation and color change as noted for material dried When ultrasound was used to dry carrots, the heat transfer
by MVD. Color changes can occur due to the development of coefficient and the corresponding mass transfer coefficient were
hot spots caused by localized melting of ice crystals,253 or in higher than those for convective drying (Table 3).61 Data shown
more extreme cases due to the formation of plasma in the dry- in Table 3 confirm the correlation between air velocity, sample
ing chamber.254 The degree to which energy efficiency can be diameter, and heat transfer, as predicted by the semi-empirical
enhanced through the application of microwave to a lyophiliza- correlations available in the literature.259 Drying enhancement
tion cycle is yet to be determined, as is the effect of modified mainly occurred at the beginning of the process, that is, when
drying kinetics on the stability of biopharmaceuticals. In addi- external transfer was the controlling step, which indicates that
tion, scalability is unknown. Residual water content is expected ultrasound is responsible for a significant increase in exter-
to be as low or lower than that achievable by lyophilization, nal heat and mass transfer coefficients. As hypothesized by
given the ability to apply secondary drying to MFD-processed Garcia-Perez et al.,260 this effect is ascribed to the reduction,
material. Ultimately, MFD may be suitable for the produc- as promoted by sound waves, of the boundary layer thickness
tion of biotherapeutics if it can be demonstrated that the at the material–air interface. In another example, the effect
application of microwave does not negatively impact product of ultrasound application was found to be similar for low- (car-
quality. rot), medium- (apple), and high- (eggplant) porosity products,261
with the drying time on average being shortened by 65–70%.62
Acoustic Energy-Assisted Drying Benefits of applying ultrasound in drying processes include
The utilization of acoustic waves in the food industry is becom- reduced drying times and energy consumption. Ultrasound may
ing increasingly widespread.59 The first attempt at using sound allow the use of lower temperatures in drying processes, de-
waves to intensify drying process at low temperature dates back creasing the risk of product degradation. Drawbacks to the
to the 1970s. The expression “acoustic drying” typically denotes use of ultrasound to improve drying processes include the re-
the removal of water from material under the combined influ- quirement to purchase specialized equipment and the potential
ence of hot air and high-intensity ultrasonic waves propagating for cavitation stress. Sonication of proteins has been reported
in air.59 Patist and Bates60 reported improved performance of to produce amyloid-like aggregates,262 or rather to induce
acoustic drying compared with convective process in removing aggregation,263 so the impact of high powered ultrasound on
water from various food products. For example, ultrasound was protein structure and stability would need to be assessed fur-
reported to enhance the drying rate of cylindrical carrot sam- ther. The lowest residual water content achievable, energy effi-
ples, in comparison to that dried using a traditional convec- ciency, and scalability are also unknown. At this moment, the
tive process.61 In addition, acoustic drying makes use of lower use of ultrasound is not expected to be of benefit for drying sam-
temperatures than that employed in typical convective drying ples containing high water content. It could, however, be em-
processes. Acoustic drying has also been used for processing ployed as a complement to secondary drying during lyophiliza-
lumber,63 coal,64 and in waste treatment.65 tion once a solid structure has been formed.
The mechanism of acoustic-assisted convective drying has
Additional Technologies
not yet been thoroughly explained; it is somewhat ascribed to
a combination of different effects impacting both internal and In addition to those described above, there are several other
external transport phenomena. Several authors reported that drying techniques being utilized in various industries out-
acoustic stirring reduced the resistance to mass and heat trans- side of the pharmaceutical industry. These include osmotic
fer developing in air, close to the surface of wet material.59,255 drying,71–75 infrared drying,66–68,70 ohmic heating,76–79 spouted
Moreover, the sonic waves were hypothesized to produce a se- bed drying,80–85,116 fluidized bed drying,86–89,91,116 centrifugal
ries of rapid compressions and expansions of the material. Fi- drying,264 and impingement jet drying,265 to name a few
nally, the better performance of acoustic-assisted drying was (Table 1). In the case of impingement jet drying, stable pro-
attributed to cavitation, which promotes the growth of small biotic bacteria (L. acidophilus) have been produced266 ; residual
bubbles.59 The application of an efficient power ultrasound has water content of 10% was obtained following 3 h of operation,
been reported to produce mechanical effects on both the gas- in comparison with 13% after 19 h of freeze-drying. Lin et al.267
solid interface and the material being dried; ultrasound may examined the effect of far-infrared radiation on freeze-drying
intensify water removal without introducing a high amount of of sweet potato. As far-infrared radiation creates internal heat-
thermal energy during drying.256 Thus, the use of ultrasound ing, it was selected as a complementary technology to shorten
either to dry heat-sensitive materials or for application in low- the processing time of freeze-drying. For a sweet potato cube
temperature drying appears to possess great potential. Fur- with 10 mm length, the drying time was reduced from >12 to

Table 4. Summary of Challenges Encountered by Drying Technologies as an Alternative to Lyophilization. Examples of Equipment Manufacturers at Laboratory- and
Commercial-Scale are Provided.
DOI 10.1002/jps.23998
Drying Challenges Encountered from Equipment Design, Processing, Examples of Laboratory-Scale Examples of Commercial-Scale
Technique and Product Quality Perspectives Equipment Manufacturer Equipment Manufacturer
Freeze-drying (i) Heterogeneity in drying GEA Lyophil, IMA Life, Millrock GEA Lyophil, IMA Life, OPTIMA
(ii) Use of conservative cycles resulting in long processing Technologies, SP Scientific Pharma Klee Klee Optima Group,
times KYOWAC, SP Scientific
(iii) Low process efficiencya
(iv) Lack of evolution in equipment design, leading to limited heat and
mass transfer
Foam drying (i) Rapid boiling/boil over, freezing during foaming Currently laboratory-scale freeze-dryers are employed for feasibility assessment
(ii) Inability to control higher chamber pressures during foam
formation
(iii) Heterogeneity in product appearance
(iv) Long duration of drying to reduce water content
Spray drying (i) Significant shear stress during atomization BUCHI, GEA Niro, Ohkawara GEA Niro, Ohkawara Kakohki
(ii) Aseptic processing may be challenging Kakohki Company, Ltd., SPX Company, Ltd., SPX Anhydro
(iii) Exposure of dried material to high temperatures in the collection Anhydro
vessel
(iv) Material recovery is <100%; could be increased by modification in
equipment design
(v) Higher water contents in comparison to freeze-drying
Spray freeze-drying (i) Significant shear stress during atomization and freezing Meridion Technologies GmbH, Meridion Technologies GmbH (in
(ii) Aseptic processing PowderPro AB development), PowderPro AB
(iii) Material recovery can be <100%
Supercritical fluid (i) Impact of shear, CO2 pressure, and organic cosolvents (during Separex, Apeks Supercritical, Separex, NATEX
drying processing and residual levels post processing) on protein stability; NATEX
impact of CO2 dissolution on pH
(ii) Aseptic processing
(iii) Material recovery can be <100%
(iv) Equipment costs
(v) Scalability
Convective drying (i) Long drying times at ambient temperatures Binder, G.U.N.T. Gerätebau GmbH Ingetecsa
(ii) Potential for product instability at higher processing temperatures
(iii) Poor process scalability
(iv) Very limited data exist on the achievable water content in dried
materials
a
Efficiency is defined as the ratio of the product of the sublimation enthalpy and rate, to the power input into a lyophilization process (Ref. 8).
REVIEW
Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

2687
2688
REVIEW
Table 4. Continued
Drying Challenges Encountered from Equipment Design, Processing, Examples of Laboratory-Scale Examples of Commercial-Scale
Technique and Product Quality Perspectives Equipment Manufacturer Equipment Manufacturer
Vacuum drying (i) Risk of freezing during evaporative cooling Binder, Memmert, Hosokawa Hosokawa Micron B.V., Paul O. Abbe
(ii) Risk of boiling and transition into foam drying Micron B.V., Paul O. Abbe
(iii) Long duration of drying
(iv) Scalability
Microwave drying (i) Uneconomical for complete drying of highly hydrated materials EnWave, Püschner, Sairem EnWave, Industrial microwave
(ii) Nonuniform temperature distribution within material Systems, Linn High Therm GmbH,
(iii) Unsuitable for materials with low water content or polar/ionic Püschner, Sairem, Thermex
excipients Thermatron
(iv) Effect on pharmaceutical stability is unknown
Microwave-assisted (i) Control of chamber pressure to prevent freezing EnWave, Püschner, Sairem EnWave, Püschner, Sairem
Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

vacuum drying (ii) Alterations in the physical appearance (color) of materials during
drying
(iii) Effect of processing variable (microwave power, exposure time,
chamber pressure, etc.) on product quality (stability)
Microwave-assisted (i) Heterogeneity in temperature can lead to generation of “hot spots” EnWave, Püschner EnWave, Püschner
freeze-drying as a consequence of ice melting or plasma formation, leading to
changes in physical appearance (color)
(ii) Potential for degradation during processing
(iii) Alterations in the physical appearance (color) of materials
(iv) Effect of processing variable (microwave power, exposure time,
chamber pressure, etc.) on product quality (stability)
(v) Scalability
Acoustic energy- (i) Impact of cavitation resulting from sonication and other processing Pusonics, Heat Technologies, Inc. None
assisted drying variables on stability (aggregation) and other product quality
attributes (appearance and water content)
(ii) Need for specialized equipment
(iii) Scalability
DOI 10.1002/jps.23998
REVIEW 2689
5 h, upon the application of 200 W power with a wavelength unexplored areas for further research, which if addressed ap-
in the range of 4–50 :m. In another example, Pham268 ex- propriately, may dictate the focus and investment strategy for
amined the use of a spouted-bed dryer for the production of the next-generation drying technology suitable for the pharma-
dried bovine blood, whereas Feng and Tang81 examined the ceutical industry.
application of microwave heating during spouted bed drying
of diced apples. Electrohydrodynamic drying (EHD) was used
by Hashinaga et al.269 to dry apple slices for which 4.5-fold ACKNOWLEDGMENTS
enhancement in drying rate to that achieved by ambient air The authors would like to thank Nick Warne and Kevin King for
drying was reported. This technique utilizes an electric wind the insightful discussion and the reviewers for their valuable
(corona wind) to enhance the mass transfer between the ma- comments.
terial and ambient air. EHD was first reported by Asakawa,270
who demonstrated an enhancement of water vaporization rate
by up to 40–50 times at 12◦ C. REFERENCES
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Drying Technologies For Pharmaceutical Applications

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What drying techniques are commonly used for biotherapeutics?

What drying techniques are commonly used for biotherapeutics?

What are some drawbacks of lyophilization?

What are some drawbacks of lyophilization?

REVIEW

Next Generation Drying Technologies for Pharmaceutical

Received 10 March 2014; revised 13 April 2014; accepted 14 April 2014

Pharmacists Association J Pharm Sci 103:2673–2695, 2014

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 2673

Table 1. Summary Table of Various Drying Technologies with

Drying technique Applications

Foam drying Monoclonal antibodies,1 vaccines13–19

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

ological. Effective formulation composition is similar to that

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

cles possessing variable radial composition to effectively “coat”

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

Figure 6. Drying curves of granulated kaolin (initial water content

gies available, thus a large number of possible combinations.

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

to materials dried using other methods.233 Tight control over

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

Air Velocity (2.2 m/s) Air Velocity (2.8 m/s)

d = 0.5 cm d = 1.0 cm d = 1.5 cm d = 0.5 cm d = 1.0 cm d = 1.5 cm

h (J/s m2 K) 73.3 57.2 50.2 95.1 85.3 62.5

Table adapted from Aversa et al.61 .

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014 DOI 10.1002/jps.23998

DOI 10.1002/jps.23998 Walters et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2673–2695, 2014

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