Spray-Freeze-Drying: A Novel Process For The Drying of Foods and Bioproducts

Trends in Food Science & Technology xx (2014) 1e21
Review
Spray-freeze-
drying: A novel technologies to improve product quality. In addition, the ad-
vantages, limitations and future scope for research in the field
of SFD are discussed.
process for the drying
of foods and Introduction
For almost all foods and bioproducts, drying involves the
removal of water from the material via the vapour phase.
bioproducts It is one of the oldest methods of preservation and results
in shelf stable products which can be kept in a good condi-
tion for months or even years at ambient temperature. Dry-
S. Padma Ishwaryaa,b, ing techniques can be categorized based on the methods
used for heat addition and water vapour removal. Drying
C. Anandharamakrishnana,b,* can be facilitated by direct contact with hot air at atmo-
and Andrew G.F. Stapleyc spheric pressure, such as in the case of spray drying, or
the sublimation of water from the frozen material as in
a
Department of Food Engineering, CSIR e Central freeze drying (Geankoplis, 2006).
Food Technological Research Institute, Spray drying (SD) is a well-established technique for
Mysore 570 020, India producing dried powdered products, involving rapid evapo-
ration of water from an atomized liquid fed into a spray
b
AcSIR e Academy of Scientific & Innovative
chamber. Hot air flows inside the chamber in a co-current
Research, CSIR-CFTRI Campus, Mysore 570 020, India
or counter-current direction, evaporating water from the
(Department of Food Engineering, CSIR e Central
atomized particles and transforming the aqueous feed into
Food Technological Research Institute, Mysore 570
a dry powdered product. Spray drying is advantageous in
020, India. Tel.: D91 821 2513910; e-mail:
terms of producing free flowing powders with a controlled
anandhram@cftri.res.in)
c particle size range at a fast drying rate. Despite the above
Department of Chemical Engineering, Loughborough
positive aspects, the method can suffer from significant los-
University, Loughborough LE11 3TU, UK
ses of volatile materials and thermal degradation of heat
sensitive materials owing to the operation at high inlet tem-
Spray-freeze-drying (SFD) is an unconventional freeze drying peratures (Bhandari, Patel, and Chen, 2008).
technique that produces uniquely powdered products whilst Freeze drying (FD), on the other hand, directly addresses
still including the benefits of conventionally freeze dried prod- the challenge of preserving heat labile components. In the
ucts. SFD has potential applications in high value products due FD process, the material is first frozen at a low temperature,
to its edge over other drying techniques in terms of product forming ice crystals. These crystals are sublimed from the
structure, quality, and the retention of volatiles and bioactive solid state directly into the vapour phase in a vacuum cham-
compounds. In cases where other drying techniques cannot ber (Liu, Zhao, and Feng, 2008) in a process known as pri-
provide these product attributes, SFD stands out despite the mary drying. The prerequisite for sublimation is that the
costs and complexities involved. This paper outlines the prin- vapour pressure and the temperature should both be held
ciples, methods, significant process parameters, particle below that of the triple point of water (0.6 kPa and
morphology and quality aspects of SFD. Recent developments 0.01 C, Fig. 1) (Mumenthaler and Leuenberger, 1991).
in this technique are reviewed including ultrasonic spray- The sorbed water that remains in the solute matrix (the
freeze-drying, the application of computational fluid dynamics freeze concentrated non-ice phase), is then further reduced
and mathematical modelling, and the incorporation of new by desorption (secondary drying) (Liapis and Bruttini,
2009). Porous structures are formed by the sublimation of
ice crystals which leads to very good rehydration behaviour
* Corresponding author. of the powdered product. The freeze dried particles
http://dx.doi.org/10.1016/j.tifs.2014.10.008
0924-2244/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ishwarya, S. P., et al., Spray-freeze-drying: A novel process for the drying of foods and bioproducts, Trends in Food
Science & Technology (2014), http://dx.doi.org/10.1016/j.tifs.2014.10.008
2 S.P. Ishwarya et al. / Trends in Food Science & Technology xx (2014) 1e21
When Heldman and Hohner (1974) then mathematically

modelled the simultaneous heat and mass transfer taking
place during the atmospheric freeze drying process, he
concluded that reducing particle size and increase in sur-
face mass transfer coefficient are effective ways to increase
the drying rate. Both freezing and freeze drying times vary
approximately with the square of the sample thickness.
Hence reducing the dimensions of the material is a means
of reducing both freezing and freeze drying times. This is
the basis of the spray-freeze-drying (SFD) technique which
is our topic of interest.
SFD is a three-step process which involves a liquid or so-
lution being atomized into droplets, solidified by contact
with a cold fluid, and sublimed at low temperature and pres-
sure (Leuenberger, 2002). SFD is thus a unique drying tech-
nique as it is a combination of both spray drying and freeze
drying (Filkova, Huang, and Mujumdar, 2007). The potential
Fig. 1. Phase diagram for water (not to scale). applications of SFD in the processing of food and pharma-
ceutical products have been the subject of study by various
different authors (Table 1). SFD also has applications in pro-
generally have a high product quality, but the long drying ducing low porosity ceramic particles, but this is not covered
times, batch nature, low temperatures, high vacuum and in this review. The applications of SFD shown in Table 1 fall
the resultant high operational cost limits the usage of the into three major categories: (i) drying of high value foods,
freeze drying technique (Lopez-Quiroga, Antelo, and (ii) drying of pharmaceutical products and (iii) encapsula-
Alonso, 2012; Malecki, Shinde, Morgan, and Farkas, tion of active compounds sensitive to the surrounding
1970; Ratti, 2008). milieu. The ability to encapsulate low water soluble drugs
Different approaches have been proposed by various re- (Leuenberger, 2002) and the unique aerodynamic qualities
searchers to reduce the costs of conventional freeze drying. of the porous particles produced (D’Addio, Chan, Kwok,
One approach is to dispense with the vacuum by operating Prud’homme, and Chan, 2012; Sweeney et al., 2005;
instead at atmospheric pressure. In this context, Merymann Wang, Kho, Cheow, and Hadinoto, 2012) has made this a
(1959) and then Lewin and Mateles (1962) demonstrated particularly attractive process for producing particles for
that freeze drying is possible at atmospheric pressure if pulmonary delivery. Tailoring the process for manufacturing
the partial pressure of water in the drying chamber is held different end products requires a thorough knowledge and
sufficiently low. This method eliminates the vacuum pump understanding of all aspects of the SFD technique.
and makes continuous freeze drying operations much easier The objective of the current paper is to summarize the
as interlock systems are not required. However, this method various methods of SFD, the mechanisms governing these
was not found to be suitable for puree or bulk liquid because SFD processes, and the application of SFD to the produc-
of the very slow drying rate. Woodward (1963) followed the tion of food and biological products. Recent innovations
investigation of Lewin and Mateles (1962) for analyzing the in the field of SFD and the scope for future research are
commercial feasibility of freeze drying without vacuum and also discussed.
concluded that the total drying time was chiefly affected by
the product dimensions and gas temperature, rather than the Classification of SFD processes
gas flow rate. Quast and Karel (1968) observed the forma- SFD involves three main process steps: (i) atomisation,
tion of an impermeable layer over the frozen liquid surface (ii) freezing and (iii) drying. Each of these steps will be ex-
which resists the mass flow rate. The authors found that me- plained initially in this section along with the significant pa-
chanical removal of the surface layer could reduce the sur- rameters associated with them. Various methods can be used
face resistance and increase sublimation rates. for each step, and these can then, in principle, be combined
Later, researchers extensively studied the different in various permutations to result in a variety of processes.
freezing mechanisms by microscopic examination of the The main basis of classification for SFD techniques is the
structural changes during freeze drying. Malecki et al. conditions under which spray freezing and freeze drying
(1970) attempted to reduce the drying time by atomizing are carried out. In the case of spray freezing, the technique
liquid foods into a cryogenic medium (liquid nitrogen) is categorized depending on the physical state of the cryogen
and the frozen particles were sublimed in a fluidized bed which is used for freezing the spray. The feed solution can
at atmospheric pressure. The reduction in droplet size be sprayed into a cold dry gas (Spray Freezing into Vapour,
greatly enhanced the sublimation rate and the drying pro- SFV), sprayed directly into a cryogenic liquid (Spray
ceeded in unrestricted manner from each frozen droplet. Freezing into Liquid, or SFL), or sprayed into a cryogenic
S.P. Ishwarya et al. / Trends in Food Science & Technology xx (2014) 1e21 3
Table 1. Applications of spray-freeze-drying.
Application Temperature Temperature of freeze Reported physical properties Reference

of spray drying ( C)
freezing ( C)
Whey protein powder 85 C 2 C 10 C Moisture content (%): 8.1 2.27 Anandharamakrishnan
Particle diameter (mm): 480 53 et al. (2010)
Whey protein powder 45 C 5 C Self regulated by Moisture content (%): 4.11 Al-Hakim and
sublimative cooling. Absolute density (g/cm3): 0.41 Stapley (2004)
Bulk density (g/cm3): 0.22
Insoluble matter (%): Not detected
Coffee powder 60 C 5 C <60 C Moisture content (%): 15.0 Khwanpruk et al. (2008)
Maltodextrin powder -do- -do- Moisture content (%): 10.5
Skimmed 8 C to 25 C -NM- Mean particle diameter (mm): 415 Rogers et al. (2008)
and whole milk powders Mean wetting time (s): 2.31
Drying of Apple juice Frozen by liquid 34 C Size of frozen droplet: 250e600 mm; Malecki et al. (1970)
Drying of Egg albumin nitrogen (196 Ca) 20 C Moisture loss: 0.6% per hour.
-do- Size of frozen droplet (mm): 250e600
Moisture loss (% per hour): 6.5.
Particles of Kanamycin Frozen by liquid 25 C (primary drying) Particle diameter (mm): 13.5e21.8 Her, Song, Lee,
nitrogen (196 Ca) 20 C (secondary drying). and Lee (2010)
Particles of Anti IgE Frozen by liquid 50 C for 1 h followed Particle size (mm): 7.7 Maa et al. (1999)
antibody nitrogen (196 Ca) by 25 C for 42 h. Surface area (m2/g): 127.7
Powder of inactivated Frozen by liquid 55 C Moisture content (%): 5.39 Garmise, Staats,
heat stable influenza nitrogen (196 Ca) Volume median diameter (mm): 24.9 and Hickey (2007)
vaccine for nasal delivery. Bulk density (g/mL): 0.17
Tapped density (g/mL): 0.26
Specific surface area (m2/g): 1.25
Nanosuspensions Frozen by liquid 20 C for 48 h followed Bulk density (g/cm3): 3.45 103 Schiffter, Condliffe,
containing insulin and nitrogen (196 Ca) by 20 C for 12 h. Tapped density (g/cm3): 4.63 103 and Vonhoff (2010)
trehalose (1:1) Porosity (%): 99.7
Encapsulation of Frozen by liquid 70 C for 1 h followed Median volume diameter (mm): 5.2 Nguyen, Herberger,
Darbepoetin alfa nitrogen (196 Ca) by 35 C over 2 h and Specific surface area (m2/g): 29 and Burke (2004)
(sialoglycoprotein) held for 40 h. Moisture content: 13%
Microparticles of Salmeterol Frozen by liquid Initially, 70 C, followed With different combinations of the Rahmati et al. (2013)
xinafoate with lactose, nitrogen (196 Ca) by an increase to 20 C active ingredient and carrier agents,
mannitol, trehalose for 6 h. the median particle diameter ranged
and b-cyclodextrin. between 10.9 and 34.9 mm.
Microencapsulation of Frozen by liquid 24 C Moisture content (%): 3.667 0.014 Karthik and
docosahexaenoic acid nitrogen (196 Ca) Oil content (%): 71 Anandharamakrishnan
with whey protein isolate (2013)
as carrier material
a
Boiling point of liquid nitrogen.
liquid but with atomisation occurring in a gaseous headspace which can be a solution, a suspension or a fluid with a com-
region above the liquid (Spray Freezing into Vapour over plex rheology. This is done by using a variety of nozzles
Liquid, or SFV/L). Likewise, the freeze drying step can be such as one fluid (hydraulic), two fluid (pneumatic), or ul-
carried out under different conditions: under vacuum as in trasonic nozzles. One key difference with spray drying is
conventional freeze drying; at atmospheric pressure (Atmo- that freezing within the nozzle may occur due to the low
spheric spray-freeze-drying; ASFD); at sub-atmospheric temperatures used in spray freezing and so steps to counter
pressure (Sub Atmospheric spray-freeze-drying; SASFD); this need to be put in place. Common strategies are to use
or in a fluidized bed under either atmospheric (AFBSFD) nozzle heaters or plastic nozzles. Two fluid nozzles gener-
or sub atmospheric (SAFBSFD) pressure. The principles ally produce a finer spray but do introduce warm gas into
of operation of each of the above will be explained in detail the system which will affect cooling rates.
in the following sections. The atomisation method directly affects the drop size dis-
tribution of the spray. As the processes of freezing and freeze
Methods of atomisation drying do not significantly change the size of the droplet as it
Atomisation is a process, where the bulk liquid breaks is transformed into a dry particle (unlike spray drying for
up into a large number of small droplets. As in spray dry- example), the droplet size distribution is closely mirrored
ing, the process involves spraying or atomizing a feedstock, in the particle size distribution of the final product.
Table 2. Summary of findings from different SFD methods.
Process Product Focus & findings Researchers

SFV þ AFD Mouse kidney tissue Proposed the concept of freeze drying at Merymann (1959)
atmospheric pressure.
SFV þ AFD Low water soluble drugs Obtained free flowing powder, porous structure Leuenberger (2002)
with high surface area and improved bio
availability of extremely low water soluble drugs.
SFV þ AFD BSA Combined the spray-freezing step and fluidization Wang et al. (2006)
conveying of frozen powder using co-current flow
to convey the frozen powder to the exit filter.
SFV þ AFBFD Mannitol Equipment development for SFV process. Mumenthaler and
Leuenberger (1991)
SFV þ SAFBFD Whey Protein Equipment development and drying of proteins. Anandharamakrishnan et al.
A pilot scale SFV combined with SAFBFD was (2010)
developed for whey proteins at 30 C and
0.1 bara.
SFV þ SAFBFD Whey proteins Demonstrates fluidized bed SFD at sub- Anandharamakrishnan et al.
atmospheric pressure (0.1 bar). (2010)
The method allowed rapid freeze drying but using
much less gas than ASFD with little loss of
solubility of principal proteins of the isolate.
SFV þ conventional FD Whey protein Compared the morphology of the spray dried and Al-Hakim and Stapley
spray freeze dried powder using scanning electron (2004)
microscope.
SFV/L þ conventional FD Docosahexaenoic acid Microencapsulation of DHA to prevent oxidation Karthik and
(DHA) and comparison of results with that encapsulated Anandharamakrishnan
using SD and FD. (2013)
Microencapsulated DHA with SFD was found to
show better protection from oxidation and storage
stability but comparatively lesser encapsulation
efficiency.
SFV/L þ conventional FD Trypsinogen Compared protein aggregation and inactivation Sonner et al. (2002)
stability, and particle morphology for SFD and
freeze drying.
SFV/L þ Darbepoetin Alfa Compared the spray dried and spray freeze dried Nguyen et al. (2004)
conventional FD microencapsulated powder.
SFD technique was not found to be suitable for
encapsulation because of aggregate formation.
SFV/L þ conventional FD Ciprofloxacin, liposomes Aerosol properties of liposome encapsulated spray Sweeney et al. (2005)
freeze dried Ciprofloxacin.
SFD process improved the mass median
aerodynamic diameter.
SFV/L þ conventional FD D9-Tetrahydrocannabinol SFD produced highly porous particles with large VanDrooge et al. (2005)
surface area, suitable for inhalation.
SFV/L þ conventional FD Drug (phenytoin) Modified and enhanced dissolution profiles of Niwa et al. (2009)
poorly water-soluble phenytoin.
4fluid nozzle SFD method gave smaller particles
with single micron diameter and 3e4 times larger
specific surface area.
SFV/L þ conventional FD Mannitol, lysozyme, and Established functional relationship between fine D’Addio et al. (2012)
bovine serum albumin particle fraction and formulation concentration.
Rapid freezing produced particles of uniform size
and it is determined by the atomized feed droplet
size.
However, the average particle density is governed
independently by the solute concentration.
SFV/L þ conventional FD Thermally sensitive drugs Examined the effects of feed concentration and its Cheow, Ng, Kho, and
adjuvant content on the particle morphology, Hadinoto (2011)
aerodynamic diameter, aqueous redispersibility,
flowability, and production yield.
Thermally sensitive nanoparticle aggregates ex-
hibited significantly higher aqueous redispersibil-
ity than those produced by spray drying.
(continued on next page)
Table 2 (continued )
SFV/L þ conventional FD Salbutamol sulphate Used thermal ink-jet nozzle for atomisation. Mueannoom, Srisongphan,
Produced inhalable porous particles of <5 mm. Taylor, and Hauschild
(2012)
SFV/L þ conventional FD Inhaler formulation of drug- Compared spray drying and spray freeze drying for Wang et al. (2012)
loaded lipidepolymer dry powder inhaler formulation.
hybrid nanoparticles Nano-aggregates produced by SFD had superior
aerosolization efficiency and fine particle fraction
with lower mass median aerodynamic diameter.
SFV/L þ conventional FD Thermally-sensitive Production of dry-powder aggregates of thermally- Kho and Hadinoto (2011)
polymeric substances sensitive polymeric nanoparticles.
Examined morphology, production yield, flow-
ability, and aqueous reconstitution of SFD
particles with the effect of atomisation rate, feed
concentration, and feed rate.
SFV/L þ conventional FD Protein A systematic characterization of the SFD trehalose/ Rochelle and Lee (2007)
mannitol/dextran particulate composition.
Produced microencapsulated protein particles
using SFD technique for sustained release.
SFV/L þ conventional FD Active pharmaceutical Showed that processing of salmeterol xinafoate Rahmati et al. (2013)
ingredient (SX) by SFD technique could be a constructive
approach to the production of various forms of
drug.
Drastic changes in the physical characteristics of
microparticles could be achieved by changing the
composition of bulking agent (trehalose, and
cyclodextrin).
SFL þ AFBFD Apple juice, Feasibility of AFD of frozen juice in droplet form Malecki et al. (1970)
Egg albumin was studied.
Sticky nature of the product influenced drying rate.
SFL þ conventional FD Protein (Bovine Serum Investigated the effect of atomisation conditions Costantino et al. (2000 and
Albumin, BSA) and formulation variables on particle size and 2002)
stability of excipient free and zinc complexed
Bovine Serum Albumin (BSA).
Significant atomisation parameter was mass flow
ratio (mass of atomisation N2 relative to that of
liquid feed).
Protein with excipients showed greater stability.
SFL þ conventional FD Bovine Serum Albumin Compared microparticles produced by SFV/L and Yu et al. (2004)
SFL process.
Intense atomisation and ultra-rapid freezing
reduced the degree of denaturation and
aggregation of nanostructured protein.
SFL þ conventional FD Carbamazepine and SFL process enhanced the dissolution rates of Rogers et al. (2002)
danazol. poorly water-soluble compounds.
SFL þ conventional FD Danazol, Hydroxypropyl Produced microencapsulated free flowing powder Rogers, Hu, et al. (2002)
-b-cyclodextrin consisting of API.
Exhibited better dissolution than conventional
freeze dried powder.
SFL þ conventional FD Danazol and Produced nanostructured porous microparticles Hu et al. (2002)
carbamazepine with enhanced wetting and dissolution rates.
SFL þ conventional FD Carbamazepine (CBZ) Enhanced the SFL technique for the preparation of Hu, Johnston, and Williams
nanoparticles of CBZ, by using acetonitrile system. (2003)
SFL (CO2) þ conventional Trypsinogen Developed the model of dispersion and solidifi- Henczka and Ba1dyga,
FD cation of aqueous droplets in turbulent flow field. (2006)
Developed model enables estimation of tempera-
ture profile of the continuous and dispersed
aqueous phases as well as final size of the frozen
droplets.
SFL þ conventional FD Albuterol sulphate Investigated processing parameters to prepare Barron et al. (2003)
polyethylene glycol micro-particles for drug
delivery.
(continued on next page)
SFL þ conventional FD Inhaled drug- Physical and antibiotic properties of kanamycin Her et al. (2010)
Kanamycin powders obtained by spray freeze drying (SFD)
were compared with those of raw kanamycin.
SFD procedure was optimized for use of
Kanamycin drug.
SFL þ conventional FD Microencapsulated Produced micro-capsules of Lactobacillus Semyonov et al. (2010)
Lactobacillus paracasei paracasei with high viability.
High viability was obtained (>60%).
SFL þ conventional FD Protein Produced uniform encapsulation of stable protein Leach et al. (2005)
nanoparticles.
High loadings (10e15%) of proteins in micro-
spheres with low burst release and low protein
aggregation. All three of these goals were met in
this study.
SFL þ conventional FD, Lysozyme Studied the influence of protein aggregation and Yu, Johnston, and Williams
SFV/L þ conventional FD biological activity of enzyme. (2006)
Reduced protein aggregation, less loss of enzyme
activity and increased particle surface area was
achieved for SFL process.
SFL þ conventional FD, Lysozyme Increased cooling rate produced high specific Engstrom, Simpson, Lai,
SFV/L þ conventional FD surface area of the spray freeze dried powder. et al. (2007)
& Cryogens: LN2 and Among the two cryogens, cooling rate for SFL into
isopentane liquid nitrogen was three times slower than
isopentane (i-C5) due to the Leidenfrost effect.
ASFD Biologically active Development of apparatus and technique for spray Mumenthaler and
substances and commercial freezing and subsequent dehydration. Leuenberger (1991)
liquid foods (milk, orange Investigated the influence of process conditions
juice and coffee extract) and product characteristics on drying kinetics.
Fine free flowing powder, <1.5% residual
moisture content, reduction in drying time.
AFBSFD &FB sub AFBSFD Proteins Equipment developed for spray freeze drying in a Leuenberger et al. (2006)
fluidized bed at normal and low pressure.
Short drying time, good control of drying
parameters was achieved.
The choice of atomiser is most important in achieving specific surface area. The results demonstrated that the
economic production of high quality products (Fellows, SFD technique using four fluid nozzles has potential to
1998). Most experimental work on SFD has either involved develop novel solubilized formulations for poorly water-
conventional one fluid or two fluid nozzles (Al-Hakim, soluble active pharmaceutical ingredients. For drugs with
Wigley, and Stapley, 2006). However, these produce a very low water solubility the technique was also demon-
wide range of droplet sizes which in turn affect freezing strated with organic solvents (Niwa, Shimabara, and
rates. To tackle this issue, Rogers, Wu, Saunders, and Danjo, 2010) although the porosity and specific surface
Chen (2008) explored the use of a monodisperse droplet area of these particles was lower than when an aqueous sol-
generator. This nozzle has the ability to produce droplets vent was used.
with a predefined trajectory and a narrow size distribution. D’Addio et al. (2012) studied the ability of ultrasonic
The droplet formation is regulated by shearing with a sec- nozzles to control the particle size and aerodynamic prop-
ond fluid, with electrostatic repulsive force, or by directly erties of SFD particles for pulmonary delivery. Mannitol,
applying pressure to the liquid. lysozyme and BSA protein were chosen for this study.
More recent experiments with SFD have made use of The study established that ultrasonic nozzle atomizers can
four fluid nozzles and ultrasonic nozzles. Niwa, be used to prepare large, porous particles from a range of
Shimabara, Kondo, and Danjo (2009) developed the SFD water soluble materials. The key parameter controlling
process for pharmaceutical applications with a four fluid the geometric size of particles was the ultrasonic nozzle fre-
nozzle instead of a conventional two fluid nozzle. Two quency, which controlled the size of liquid droplets. The
separate liquid feeds were supplied which were atomized particle size was determined by the atomized feed droplet
by separate air streams, and the droplets collided with size, while the average particle density was determined
each other at the nozzle tip. These were then passed into by the solute concentration. Ultrasonic methods can there-
liquid nitrogen 20 cm below the nozzle. It was found that fore provide a high degree of control over particle size by
the particles had a fine porous structure producing a vast varying the frequency of the ultrasonic atomiser. Table 3
provides details on the particle sizes obtained with different of feed flow rate used in the study was 1e20 mL/min. In
types of atomiser and under various conditions of addition, the influence of viscosity on droplet size was stud-
atomisation. ied. They observed that at high viscosity (11.16 cP) of the
polymer solution, a low flow rate range of 1e5 mL/min was
Influence of atomisation conditions not enough to atomize and was unable to produce particles
The effects of feed properties, atomisation conditions smaller than 100 mm. Whereas at low viscosities
and nozzle geometries on sprays have been extensively (1.65e3.85 cP), atomisation led to particles of less than
studied in fields as diverse as internal combustion engine 100 mm in diameter indicating that an increase in flow
sprays, paint sprays and spray drying. It is well established rate produced a slight decrease in particle size, reflecting
that particle sizes vary with changes in atomisation param- intense atomisation. Viscosity inhibits instability in the
eters. The major atomisation parameters include atomisa- emerging jet and delays the onset of disintegration causing
tion energy (i.e. pressures), feed viscosity, surface tension atomisation to occur in the regions of lower velocity.
and flow rate. For the same type of nozzle and feed mate- Hence, droplet size increased with increasing liquid
rial, the droplet size decreases as the atomisation pressure viscosity.
is increased (Masters, 1991). At constant atomisation pres-
sure, increasing the liquid flow rate increases the droplet Freezing
size since there is more liquid to be atomized. As the After atomisation, the fine droplets are quickly frozen
feed viscosity increases, the atomisation energy supplied upon contact with a cryogen to form icy particles. The rapid
to the nozzle must overcome larger viscous forces to freezing phenomena during this step have been studied by
achieve smaller droplet sizes. Higher viscous forces require Hindmarsh, Russell, and Chen (2003) and Hindmarsh,
more energy for breaking the droplets, thus resulting in Russell, and Chen (2007) and follows the general pattern out-
larger droplets. The surface tension of the liquid also plays lined by Fellows (1998) and MacLeod et al. (2006) as fol-
an important role in the extent of atomisation, as to achieve lows. The freezing process comprises of a number of stages
atomisation the atomiser has to overcome the surface ten- (Fig. 2): (a) initial cooling to a super cooled temperature
sion of the feed liquid in order to create more surface below the normal freezing temperature, (b) nucleation fol-
area. Hence a liquid having a high surface tension is diffi- lowed by growth of ice crystals and the subsequent rapid evo-
cult to atomize. In such cases the addition of an emulsifier lution of latent heat associated with fast crystal growth,
followed by a homogenization step can be used to aid the termed recalescence, (c) further, slower crystal growth which
atomisation process. is limited by heat transfer from the cryogenic fluid, during
SFD studies which have assessed the effect of atomisa- which some freezing point depression may occur and (5)
tion conditions include that of Costantino et al. (2000) who once freezing is complete, cooling of the frozen particle
investigated the effect of atomisation conditions on particle down to the cryogen temperature. However, substances other
size and stability of spray freeze dried Bovine Serum Albu- than pure water will not solidify completely owing to the
min (BSA) with and without a zinc excipient, using a two freeze concentration of solution in the interstices between
fluid nozzle. The atomisation variables that influenced par- ice crystals. Fig. 2 shows the typical timeetemperature pro-
ticle size and protein stability were explored. The effects of file obtained during the spray freezing of coffee solution.
atomisation gas pressure and its flow rate, liquid feed pres-
sure and its flow rate and mass flow ratio (ratio of atomisa- Methods of spray freezing
tion gas to liquid feed) were determined using different A number of different methods for spray freezing are in
combinations of the above listed variables. The conditions existence. These are categorised as follows. Literature
were focused on those for promoting smaller droplet (and studies using these techniques are also summarized in
hence particle) sizes, since these lead to greater accessi- Table 2.
bility to the particle surfaces for encapsulated drugs. A sta-
tistical analysis of the data indicated that final particle size Spray freezing into vapour (SFV)
decreased with decreasing liquid flow rate (or liquid feed SFV involves the atomisation of a liquid and contacting
pressure) and fluid cap inner diameter, and decreased the resulting spray with cold desiccated gas to freeze the
with increasing atomisation nitrogen flow rate (or atomisa- droplets. SFV is a complex process which involves a number
tion nitrogen pressure). The mass flow ratio in itself was a of mechanisms: (i) the formation and motion of individual
good predictor of particle size, and increasing this ratio droplets with respect to each other and the gas, which is
decreased the size. Neither the use of zinc as a complexing determined by the fluid mechanics of the spray, (ii) heat
agent nor changing the freezing conditions had any effect transfer between the gas and the droplets, that depends on
on the particle size. the local conditions, e.g. gas temperature, droplet tempera-
A similar relationship was observed between feed flow ture and droplet-gas slip velocity and (iii) freezing and ice
rate and droplet size in a hydraulic (single fluid) nozzle crystallization within the drops (Anandharamakrishnan,
by Barron, Young, Johnston, and Williams (2003) in the Gimbun, Stapley, and Rielly, 2008). During spray freezing,
SFD of polymeric polyethylene glycol particles. The range the freezing rate (cooling rate) and subsequently the
8
Table 3. Atomisation parameters and resultant particle size.
Product Cryogen Nozzle type Feed rate Air flow rate/ Particle size Surface area Reference
air pressure
Whey protein Nitrogen gas at Hydraulic nozzle 0.0125 kg s1 8 bar NA Anandharamakrishnan
(i) 10 C (i) 480 53 mm et al. (2010)
(ii) 15 C (ii) 393 75 mm
(iii) 30 C (iii) 412 4 mm
Insulin LN2 PEEKa NA 5000 psi 3 mm NA Rogers et al. (2002)
(i) 63.5 mm I.D, (34.5 MPa)
10 cm in length
(ii) 127 mm I.D,
S.P. Ishwarya et al. / Trends in Food Science & Technology xx (2014) 1e21
15 cm in length
Inulin stabilized influenza LN2 Two fluid nozzle NA Air flow: 10e11 mm NA Amorij et al. (2007)
subunit vaccine 700 ln/h
Darbepoetin Alfa Frozen ethanol Ultrasonic 0.5 mL/min NA 29 1 mm NA Burke et al. (2004)
with a LN2 overlay Atomisation probe
(6 mm diameter;
20 kHz)
Polymeric nanoparticle LN2 Two fluid nozzle 0.24 L/h 240 L/h 1500e2500 nm NA Cheow et al. (2011)
aggregates
Kanamycin LN2 Two-fluid nozzle 25 mL/min 100 kPa 15.1 mm,13.5 mm, NA Her et al. (2010)
2%, 10%, 15% 14.9 mm
Bovine Serum Albumin (BSA), LN2 Ultrasonic 0.5 mL/min NA 30.2 mm (BSA) NA D’Addio et al. (2012)
Mannitol, Lysozyme at feed Atomisation probe 17.2 3.6 mm
concentration: 40 mg/cm3 (40 kHz) (Mannitol)
34.8 mm (Lysozyme)
BSA (5 mg/mL) LN2 PEEKa nozzle 10 mL/min 17.2 MPa 0.05e1 mm 134 m2/g Engstrom, Simpson,
Lysozyme (5 mg/mL) 0.05e1 mm 114 11 m2/g Lai, et al. (2007)
Lysozyme (50 mg/mL) 4.0e12 mm 34 2 m2/g
Lysozyme (50 mg/mL) Isopentane PEEK nozzle 10 mL/min 17.2 MPa 0.05e1 mm 124 15 m2/g Engstrom et al. (2007)
(i) Excipient free anti IgE LN2 Two-fluid nozzle 15 mL/min 1050 L/hr 7.0 mm 121.2 m2/g Maa et al. (1999)
antibody LN2 Ultrasonic nozzle 5 mL/min NA 32 mm 44.1 m2/g
(ii) Anti-IgE antibody: Two fluid nozzle 15 mL/min 600 L/hr 19 mm 49.7 m2/g
Trehalose 60:40 -do- 15 mL/min 1050 L/hr 5.9 mm 72.9 m2/g
Trehalose LN2 Ultrasonic nozzle 3 mL/min NA 20-90 mm NA Sonner et al. (2002)
(120 kHz)
Darbepoetin Alfa LN2 Ultrasonic nozzle 0.5 mL/min NA 29 1 mm NA Nguyen et al. (2004)
(20 kHz)
Liposomal Ciprofloxacin, LN2 Two fluid nozzle e e 2.8 mm NA Sweeney et al. (2005)
Influenza subunit vaccine LN2 Two-fluid nozzle, 5 mL/min 700 L/h 23% of SFD powder 76.33 m2/g Saluja et al. (2010)
powder 0.5 mm orifice particles between
1 and 5 mm
(continued)
Semyonov et al. (2010)

Yeom and Song (2010)
Hu et al. (2002)
Yu et al. (2004)
Reference
19.2 to 97.7 m2/g

Surface area
11.04 m2/g
12.81 m2/g
NA
NA
Fig. 2. Time - Temperature data during spray freezing of a droplet of

400e1800 mm
coffee solution (MacLeod et al., 2006).

Particle size
<500 nm
7.11 mm
11.8 mm
nucleation rate are the two important factors that influence

7.1 mm
the microstructure of the frozen droplets. This then carries

forward to determine the microstructure of the freeze dried
particles once moisture is removed. The effect of freezing
Air flow rate/
parameters on particle microstructure is discussed in a later

air pressure
air pressure
of 100 kPa
4000 PSI
5000 PSI
section on morphology. Different studies performed using

L/min
SFV and their outcomes are summarized in Table 2.

2.12
3.08
4.52
Spray freezing into vapour over liquid (SFV/L)

In the SFV/L process, the feed solution is atomized
11 mL/min
12 mL/min
25 mL/min
through a nozzle positioned a small distance above a

Feed rate
(a) 0.15
mL/min
boiling cryogenic liquid (Fig. 3). The droplets may begin

(b) 0.3
(c) 0.8
to solidify while passing through the vapour gap and then

freeze completely as contact is made with the liquid
(Adams, Beck, and Menson, 1982; Briggs and Maxwell,
Pneumatic nozzle
Two-fluid nozzle
1976; Buxton and Peach, 1984; Dunn, Masavage, and

PEEKa nozzle,
PEEKa nozzle,
63.5 mm I.D,
63.5 mm I.D
Nozzle type
Sauer, 1972; Sauer, 1969). A variation on the method was

performed by Costantino et al. (2000 and 2002) who con-
Polyether e Ether e Ether Ketone; NA e Data Not available.
tacted the spray with a liquid nitrogen spray which was

directed from four nozzles. The suspended frozen particles
were then separated from the liquid nitrogen. This has been
usually followed by a conventional lyophilization process
to remove the solvent (Rogers et al., 2003).
Cryogen
LN2
LN2
LN2
LN2
Ovalbumin (white albumin
Lactobacillus paracasei
Bovine serum albumin
Microencapsulation of
Carbamazepine
of chicken egg)
Danazol
Product
Fig. 3. Schematic diagram of Spray Freezing into Vapour over Liquid

a
(Anandharamakrishnan, 2008).
Several studies have been performed using SFV/L for The rapid rate of freezing on contact with the cryogenic
proteins (Costantino et al., 2000, 2002) and other active liquid has been utilized for the pre-crystallization of the par-
pharmaceutical ingredients (Gombotz, Healy, Brown, and ticles of edible fat which finds potential applications in
Auer, 1990; Gusman and Johnson, 1990). The atomisation various food products. Pre-crystallisation by spray freezing
step has the most influence on the products obtained from is carried out by directing the fine particles of edible fat in
SFV/L and the instability of biological products due to pro- molten form along with an emulsifier, towards a spray of
tein adsorption at the iceewater interface is a major disad- liquid cryogen, which can be liquid nitrogen, liquid air or
vantage of SFV/L (Webb, Golledge, Cleland, Carpenter, liquid argon. The resultant pre-crystallised fat contains a
and Randolph, 2002). large quantity of individual crystals of very fine size and
take the form of a globule with entrapped pockets of oil.
Spray freezing into liquid (SFL) The advantage of this spray frozen fat crystals is that,
In contrast to SFV/L, with SFL the nozzle is inserted when returned to ambient temperature or the processing
beneath the surface and directly into a cold liquid temperature of the concerned food product, it consists of
(Fig. 4). The liquid can be a cryogenic liquid such as liquid fat globules in which the crystallisation of fat is already
nitrogen, argon, hydrofluoroether or pentane and these can complete and the emulsifier is associated with the oil-
be used at atmospheric pressure. Alternatively, a pressur- water interface. The incorporation of pre-crystallized fat in
ized system can be used, in which case liquid CO2, propane the ice-cream formulation eliminates the conventionally em-
or ethane can be used. The droplets begin to freeze instan- ployed unit operations of homogenisation and ageing
taneously after they are formed. The cryogen may be stirred (Brooker and Tomlins, 2004), thus reducing the processing
by an impeller inserted into the vessel to avoid clumping of time and consequently improve the process economics.
the particles. The frozen particles are then lyophilized to This pre-crystallised fat can also be incorporated into
obtain dry, free flowing powders. SFL works on the princi- different food matrices such as margarine and dough of bis-
ple of liquideliquid impingement between the pressurized cuit and bread. This application results in the formation of a
feed solution exiting the nozzle and the cryogenic liquid. uniform dispersion of crystalline solid fat in the surrounding
The much greater viscosity and density of a liquid matrix and results in a minimum requirement of fat to
compared to a gas means that much smaller droplets can achieve the desired functionality in the product. Evidences
be produced than when atomizing into a gas. Thus an are the unaffected loaf volume and crumb texture of bread
intense atomisation into extremely small (micronized) and diameter of biscuit prepared from the dough with pre-
droplets results (Hu et al., 2002). Ultra-rapid freezing rates crystallised fat (Brooker and Tomlins, 2009).
are thus achieved because of the low intrinsic temperature The ability of SFL to produce high surface area nanopar-
of the cryogen (e.g. liquid nitrogen is at 196 C) com- ticles with minimum loss in stability of active components
bined with the high specific surface area of the droplets has found many drug delivery applications (Yu, Garcia,
and high heat transfer coefficients. The very fast freezing Johnston, and Williams, 2004). It also generates significant
rates prevent the phase separation of solutes within the supersaturation and thus rapid nucleation rates of dissolved
feed solution and induce the rapid formation of amorphous substances (Hu et al., 2002; Rogers, Hu, Hu, Johnston, and
structures, which can reduce protein denaturation when Williams, 2002). The rapid nucleation and restricted growth
spray freezing (Engstrom, Simpson, Lai, Williams, and that occurs after crystallization lead to extremely small sub-
Johnston, 2007). micron domains.
However, some boil-off of the cryogen can occur due to
the heat introduced by the relatively warm feed stream.
This is called the “Leidenfrost Effect” and means that
some droplets may experience lower cooling rates due to
the insulating effect of the boiled off vapour. Engstrom,
Simpson, Lai, et al. (2007) observed this effect with liquid
nitrogen, but not when using iso-pentane as the cryogen.
The iso-pentane had a much lower tendency to evaporate
due to its much higher boiling point (27 C) and higher
heat of vapourization. It is useful as a cryogenic liquid as
it can be cooled (and therefore used as a liquid freezant)
down to 160 C before it freezes also.
Freeze drying
The subsequent freeze drying of the frozen particles can
be performed by the classical vacuum drying method (Al-
Fig. 4. Schematic diagram of Spray Freezing into liquid (Rogers, Hu, Hakim and Stapley, 2004; Amorij et al., 2007; Burke et al.,
et al., 2002). 2004; Costantino et al., 2000), atmospheric fluidized
bed freeze drying (Mumenthaler and Leuenberger, 1991) or pressure of water remains low. Hence the “atmospheric
by sub-atmospheric fluidized bed freeze drying freeze drying” (AFD) process which uses a cold gas
(Anandharamakrishnan et al., 2008; Anandharamakrishnan, (such as air, nitrogen or helium) as a water removal and
Rielly, and Stapley, 2010). heat transfer medium to cause sublimation of moisture
from a frozen material at or near atmospheric pressure
Conventional freeze drying (Mumenthaler and Leuenberger, 1991). The potential for
Once spray freezing is complete, the suspended frozen AFD was first demonstrated by Merymann in 1959. He
droplets are collected by sieves or separated after the showed that the drying rate of a material undergoing freeze
cryogen is allowed to boil off. In many cases, this is then drying is a function of ice temperature and the vapour pres-
followed by conventional freeze drying. This is particularly sure gradient between the site of water vapour formation
popular in conjunction with the SFL freezing method. The and the drying media rather than the total pressure in the
collected frozen droplets are transferred to pre-chilled drying chamber. He proposed that a convective freeze dry-
shelves (typically, 40 C) in a lyophilizer for subse- ing medium i.e. cold air stream, kept dry by a molecular
quent drying. The principles of drying by ice sublimation sieve desiccant or by a refrigerated condenser, should be
for this phase of the drying process are similar to that of circulated. This paved the way for freeze drying to be car-
the conventional freeze drying process. Specifically, the pri- ried out under atmospheric conditions.
mary drying phase is performed at low pressure and In conventional freeze drying, the latent heat of sublima-
2 Ce5 C below the product collapse temperature (Tc) tion is supplied by conductive or radiative heating. Howev-
to avoid collapse and maintain an elegant cake structure. er, this is difficult to apply uniformly to a powder. A
The end point of the primary drying phase is marked by uniform application of heat that would take advantage of
a sharp decrease in dew point temperature and by the end the small particle size would reduce drying times without
of this step 70e80% of water has been removed (which the risk of particle melting and collapse. Hence, to address
had been in the form of ice), while the remaining water re- the above issue, an alternative approach of contacting the
mains in the amorphous matrix. For unstable products, an articles with cold, dry gas in a fluidized bed was proposed
optional annealing step can be conducted before primary (Anandharamakrishnan et al., 2010; Leuenberger, Plitzko,
drying, during which the frozen samples are held at a tem- and Puchkov, 2006; Mumenthaler and Leuenberger,
perature between the melting point and the glass transition 1991). Fluidization is a phenomenon which occurs when
temperature (Tg) for a period of time. Annealing results in a fluid (gas or liquid) flows upward through a bed of parti-
the growth of larger ice crystals and further freeze concen- cles with sufficient velocity to support the weight of the
trates the solute phase which increases Tc, and allows for particles without carrying them away in the fluidized
primary drying at higher temperature which reduces the stream (Geldart, 1986). The fluidized bed has the advan-
time of primary drying. The larger crystals also produce a tages of excellent heat and mass transfer due to good con-
reduction in the SSA of the final product (including the in- tact between particles and fluids. It is suitable for large
ternal pore area). The use of an annealing step (for 2 h at scale operations with good mixing to allow even drying be-
shelf temperature of 0 C) before the beginning of the pri- tween particles leading to fast drying of the particles and
mary drying phase was observed to reduce the hygroscop- low capital cost of construction. Hence the techniques of at-
icity of trehalose by decreasing the moisture uptake from mospheric spray freeze drying (ASFD) and atmospheric
approximately 4.5 %e3.5 % after 1 h exposure to 33% spray fluidized bed freeze drying (ASFBFD) came into ex-
RH (Sonner, Maa, and Lee, 2002). istence. These also have potential for heat integration mea-
Secondary drying is a relatively short step performed at sures which can produce large savings on energy as has
temperatures higher than primary drying to remove the re- been demonstrated in the freeze drying of vegetables
maining water/bound moisture in the amorphous phase via (Alves-Filho, Eikevik, Mulet, Garau, and Rosello, 2007).
evaporation. The key factor in this step is that the temper-
ature transition from primary to secondary drying should be Atmospheric spray-freeze-drying (ASFD) &
performed gradually to avoid product collapse, which may atmospheric fluidized bed spray-freeze-drying
occur in cases where the shelf temperature is higher than (AFBSFD)
the Tg of the product (Abdul-Fattah and Truong, 2010). In their review on atmospheric freeze drying, Claussen,
Ustad, Strommen, and Walde (2007) stated that atmo-
Atmospheric freeze drying spheric freeze drying has a relatively long residence time
Conventional freeze dryers are operated under vacuum because of internal resistances to mass transfer despite be-
which is one reason for the expense of the process (the ing advantageous in terms of product quality. They further
other is the large amount of energy required to operate stated that the rate controlling parameter is molecular diffu-
the condenser systems). However, there is no absolute sion of water vapour through the dry porous product struc-
requirement for freeze drying to take place under vacuum. ture. The early studies of Dunoyer and Larousse (1961) and
In principle, freeze drying is thermodynamically possible Woodward (1963) indicated that atmospheric freeze drying
even at higher overall pressures so long as the partial rates of small particles can be equivalent to vacuum freeze
drying. However, Heldman and Hohner (1974) further the surface of the filter system via a thin powder layer.
confirmed that a reduction of particle size and an increase Nevertheless, this work demonstrated that a frozen powder
in surface mass transfer coefficient appeared to be the could be dried via sublimation in only a matter of hours
most effective way to increase atmospheric freeze-drying which is much faster than conventional freeze drying.
rates. They predicted the effect of sample size on atmo- Later, Mumenthaler and Leuenberger (1991) investigated
spheric freeze drying, and the results showed a rapid the feasibility of dehydrating liquid foods and frozen phar-
decrease in drying time at reduced dimensions. They also maceutical solutions at atmospheric pressure using ASFD.
stated that for freeze drying with a very large surface Compared to the classical freeze-drying process, the
mass transfer coefficient, the time to dry a sample to any following differences were pointed out: (1) improved heat
given dimensionless moisture content should vary with and mass transfer between the circulating drying medium
the ratio of the square of the sample size. and the frozen sample; (2) high and homogeneous quality
Boeh-Ocansey (1983) dried pieces of carrot in a fluid- properties of the dry product with an increased retention
bed dryer at 5 C and 10 C and concluded that the dry- of volatile aromatic compounds in foods; (3) instead of a
ing time increases as the sample thickness is increased. cake, a fine, free-flowing powder with a large inner surface
Samples of limited thickness or below a certain critical area and good wetting and solubility properties was ob-
value tended to have higher drying rates in an atmospheric tained. Again, Leuenberger’s (2002) group successfully
dryer than in vacuum equipment. This led to the advent of produced an instant water-soluble drug (10e30 mm size)
synergizing atmospheric freeze drying with SFD. A fluid- using the SFV technique (Fig. 5) at atmospheric pressure.
ized bed was initially used for SFD to decrease the drying This process was a batch process using a counter current
time through convection of the drying gas (Malecki et al., flow of drying medium and feed liquid. However, the
1970). counter current operation lead to particle elutriation and
A combination of spray freezing with fluidization drying Leuenberger (2002) also observed the elutriation of parti-
in one chamber was proposed by Leuenberger (1987). In cles which were caught by the outlet gas-filter.
this process, spray freezing was accomplished by atomizing Wang, Finlay, Peppler, and Sweeney (2006) studied the
the solutions by top spraying against a fluidized bed of pul- feasibility of atmospheric spray freeze drying with heat-
verized dry ice. The frozen powder was then dried by an sensitive pharmaceuticals by using co-current flow. In this
upward flow of desiccated fluidizing air. The gas velocity process, the spray freezing of liquid droplets and conveying
in this fluidization drying was much higher than the termi- of frozen particles to the collection unit was performed in
nal velocity of frozen particles, so the fluidizing dense one step with the aim of improving the powder collection
phase stage at the bottom could not be maintained and efficiency. A novel SFD technology was developed which
the frozen particles were quickly conveyed to the filter sys- passed the gas supply through porous side walls of the dry-
tem. Thus, the drying process was actually accomplished at ing vessel (a cylinder of diameter 5.9 cm height 34 cm)
Fig. 5. Schematic diagram of atmospheric spray freeze drying apparatus (Leuenberger, 2002).
to address the problem of particle adhesion on the side higher fluidization velocity of the particles. The water up-
walls of the fluidized bed. The gas flow rate was increased take capacity of air was inversely proportional to the water
from low to high velocities to find a suitable gas velocity at capacity at atmospheric pressure due to the fact that the to-
which a strong enough gas cushion was built up on the sur- tal pressure is much higher than the partial pressure of wa-
face of the porous walls to prevent adhesion. This was ter in ice phase even at reduced pressures. The density of
found to be 0.11 ms1 when the gas flow rate and pressure the air is proportional to the total pressure, and as a conse-
for spraying was set at 0.6 SCFM and 3.0 psi. In such con- quence, the drying air velocity could not be reduced, but at
ditions, spray-freezing, conveying and uniform deposition lower pressures the fluidization air velocity could be set at
was successfully completed in one step for all the tested 1.5 to 2 times higher than at atmospheric pressure, so it was
formulations. possible to obtain shorter drying times of approximately
A problem with the atmospheric SFD process is the very 200 min.
large quantity of cold dry gas that needs to be circulated Khwanpruk, Anandharamakrishnan, Rielly, and Stapley
through the bed. As freeze drying has to be performed (2008) conducted sub-atmospheric spray-freeze-drying of
below the collapse temperature of the material, which can coffee and maltodextrin to obtain better volatile retention
be as low as 30 C, the ice phase exerts an extremely during drying. The two materials chosen had collapse tem-
low vapour pressure. Although recirculation of gas can alle- peratures of 30 C and 20 C respectively, which has
viate this problem to some extent, a huge quantity of gas potential to pose challenges for the SFD process. The fluid-
has to be supplied to the process and refrigeration and dry- ization vessel was pre-cooled to below 60 C with a cold
ing requirements for such a mass of gas would influence the nitrogen stream to avoid the possibility of particle collapse
economy of the process. A further consideration is that to during sample loading. The pressure in the fluidized bed
pass this mass of gas through the bed in a reasonable was regulated at 0.1 bara using a manual valve at the inlet
time requires a very large gas volume flow rate and hence to the fluidized bed apparatus. For coffee and maltodextrin,
velocity. This led to particles being swept out of the fluid- it took 1.75e2 h for drying instead of 24 h in a conven-
ized bed where they must be caught by a gas filter tional freeze dryer. Volatiles retention was comparable to
(Mumenthaler and Leuenberger, 1991) as already that of conventional freeze drying in both coffee and malto-
mentioned above. One means of addressing the problem dextrin. With maltodextrin, it was clear that the influence of
of circulating large mass flows of gas is to apply a partial the spray freezing step was found to be as important to vol-
vacuum to the fluidized bed process (Leuenberger et al., atile retention as the freeze drying step. Approximately half
2006). Thus the use of sub-atmospheric pressure in the of the volatile loss in the spray freeze dried samples was
SFD process came into existence. attributed to the spray freezing step.
Anandharamakrishnan et al. (2010) studied SF coupled
Sub-atmospheric pressure spray-freeze-drying with vacuum fluidized bed freeze dryer (VFBFD) of
(SASFD) whey protein (Fig. 6). The fluidization vessel had a volume
This technique is based on the concept that the drying of 0.022 m3. The VFBFD chamber was operated at three
gas is, after all, merely an inert heat transfer medium and different inlet gas temperatures of 10 C, 15 C and
plays no part in determining the driving force for mass 30 C at 0.1 bar pressure. Anandharamakrishnan et al.
transfer. It can be shown that when the pressure of the sys- (2010) were able to achieve drying times of 60, 65 and
tem is reduced tenfold, the mass of gas required for the pro- 100 min at the three inlet temperatures 10 C, 15 C
cess is also reduced by the same factor. The reduction in and 30 C respectively to produce a product of w8%
pressure also means that the density of the gas is also moisture content. The process could be monitored by
less. Thus the lower density at lower pressure would reduce measuring the bed temperature and a significant depression
the inertial (non-viscous) drag forces on the particles, and if in the temperature of the particle compared to the inlet gas
a low enough pressure were used, then particles (in theory) indicated that a significant degree of sublimative cooling
would not be elutriated from the bed. Hence a lower pres- (and hence drying) was taking place. Further, it was noticed
sure is desirable in terms of two factors i.e. reduction in the that operating at lower pressures increased the temperature
mass of gas required and the prevention of particle entrain- difference between the particle and gas due to its influence
ment (Anandharamakrishnan et al., 2010). However, it must on heat transfer coefficient between the gas and the particle
be emphasized that viscous forces do not drop off until bed. Larger temperature differences were also seen between
extremely low pressures are reached, and so for this reason inlet and outlet gas temperatures.
elutriation is always a potential problem.
Leuenberger et al. (2006) compared the spray-freeze- Morphology of spray freeze dried particles
drying process in a fluidized bed at normal and low pres- One of the benefits of the SFD technique is the ability to
sure. Three different pressure values were chosen: 150, produce particles of different microstructures to those pro-
300 and 1000 mbara. They could achieve a 3 fold reduction duced by other conventional techniques, such as spray dry-
in drying time by operating at pressures lower than at atmo- ing. Al-Hakim and Stapley (2004) performed a comparative
spheric pressure. The shorter drying time was attributed to a study on the morphology of spray dried versus spray freeze
Fig. 6. Photograph of spray-freezing chamber and the vacuum fluidized bed freeze dryer unit (Anandharamakrishnan, 2008).
dried (SFV) whey powders using scanning electron micro- Various studies have explored the role of spray freezing
scopy (SEM). The SEM images revealed a smooth, skin conditions on the morphology of SFD particles. Hindmarsh
forming behaviour of SD powder with slight deflation due et al. (2003 and 2007) studied the freezing in cold gas of
to the collapse of the shell during loss of moisture from single droplets of water and solutions containing different
the particle. On the contrary, the SFD whey powder ex- solutes such as sucrose, fat and whey protein concentrate.
hibited porous microstructure as expected from a freeze These were typically suspended on thermocouples coated
dried material, but could exhibit a surface layer covering with PTFE so that temperature data could be collected.
the porous microstructure below. The powders produced The authors ascertained that the microstructure of the solid-
had a low bulk density. ified droplets was directly related to nucleation and this in
The SFD microstructure is almost completely deter- turn was driven by the degree of supercooling achieved and
mined by what occurs in the freezing step, and if performed the rate of heat transfer from the droplet during freezing.
properly there should be no changes to microstructure dur- Considerable supercooling was routinely achieved (up to
ing the freeze drying step apart from the removal of water. 20 K), and was much larger than those normally encoun-
This was demonstrated in a study on whey protein isolate tered in conventional freezing. This is not unexpected
(Anandharamakrishnan et al., 2010) which showed that when one considers that the droplet volumes are extremely
changes in inlet gas temperature had no influence on the small in comparison to samples undergoing conventional
overall SFD particle morphology as long as collapse was freezing. Nucleation is a random process and the nucleation
avoided. An example SEM image is shown in Fig. 7 and rate is quantified by the number of crystals appearing per
this clearly shows that the fast freezing rates during SFD unit time per unit volume. The nucleation rate also in-
achieved much smaller pore sizes than that achieved from creases exponentially with increased supercooling.
freeze drying. Freezing only requires a single nucleation event in order
to trigger freezing throughout a sample, but with such small
volumes the probability of a nucleation remains very low
unless high supercooling is reached. Consequently it was
found that if the freezing gas temperature was higher than
a certain “nucleation temperature”, then a droplet could
remain super cooled for an indefinite amount of time
without nucleation occurring.
If the air temperature was low enough to induce nucle-
ation then the temperature at which nucleation occurred
(which depends on freezing rate) was found to heavily in-
fluence the cellular microstructure of the frozen droplet.
This is fine and uniform in case of rapid freezing, but
rougher at slower rates. Spray freezing of a single droplet
of coffee solution also indicated that the cooling rate was
a key parameter in microstructure development but its asso-
ciation with feed composition and temperature was com-
plex (MacLeod, McKittrick, Hindmarsh, Johns, and
Wilson, 2006).
A frequent observation with SFD particles has been the
Fig. 7. SEM image of SFD Whey protein Isolate powder formation of a solid surface layer that covers the porous
(Anandharamakrishnan, 2008). structure underneath (Al-Hakim et al., 2004; Hindmarsh
et al., 2007; Windhab, 1999). This can dramatically change reaches close to an equilibrium state of maximal freeze
the properties of the powder such as stickiness and flow. concentration. At this point the unfrozen domains become
Three different reasons for the formation of solute surface so viscous that they vitrify at this concentration. Rapid
layers have been postulated in the literature. Windhab cooling, on the other hand, is a non-equilibrium process
(1999) suggested that the outer layer was subject to the fast- as the temperature is reduced very quickly below the Tg
est cooling of anywhere in the droplet and that this region line with consequently little time for the formation and
was plunged into the glassy state before there was any time growth of ice crystals to occur. This leads to finer ice crys-
for ice crystallization to occur. However, Hindmarsh et al. tals (due to higher supersaturation) but also less ice forma-
(2007) rejected this theory as temperature gradients within tion and less freeze concentration as a result. Differences
the droplet are unlikely to be large and they had found that were consequently found between the morphologies of par-
the thickness of this layer decreased with increasing ticles produced by SFV/L and SFL methods, which were
freezing rate. They instead ventured two alternative expla- observed by SEM. SFV/L structures showed a characteris-
nations. One was that water may evaporate from the surface tically open cell structure but the SFL structures were more
before freezing occurs. This would lower the water concen- spherical in nature and much smaller (around 50 nm in
tration in the surface layer below that at which ice crystal- size). The Leidenfrost effect (see earlier) did not appear
lization can occur (this can be identified on a state diagram to be significant as the structures formed in liquid nitrogen
as the point of maximal freeze concentration). The second were similar to those produced in subcooled liquid iso-
theory was that solutes may preferentially distribute them- pentane.
selves at the surface shortly after atomisation. Such a mech-
anism has also been postulated for explaining the surface Factors affecting encapsulation efficiency and product
enrichment of certain components (particularly fats and functionality
proteins) during spray drying (see Kim, Chen, and A major technical hurdle in the particle engineering of
Pearce, 2009). Al-Hakim et al. (2004) found that this high value food and pharmaceutical bioactive compounds
covering layer sometimes did not appear. They postulated is the tendency of the particles to aggregate due to their sur-
that this may be due to having used a two-fluid nozzle. face energy being higher. This renders the product unstable
The nozzle introduces relatively warm air into the spray and prevents it from delivering its intended functional prop-
which chaotically mixes with the cold gas in the chamber erties at the target site. Protein denaturation, particularly at
leading to the spray droplets encountering gas pockets at interfaces, is also a major issue in pharmaceutical applica-
different temperatures, and resulting in varying cooling tions involving therapeutic proteins. Here, formulation stra-
rates. These cooling rate differences may then lead to the tegies can play a major role in combating the challenges
different topologies. posed by agglomeration and protein denaturation. In the
Faster cooling rates than in SFV can be achieved using case of SFD such formulation methods include the use of
SFL and SFV/L methods, and these consequently lead to freezing adjuvants, the inclusion of appropriate wall mate-
finer microstructures (Costantino et al., 2000; Engstrom, rials to provide an encapsulation effect and an emulsifica-
Simpson, Lai, et al., 2007; Yu et al., 2004). Yu et al. tion step prior to atomisation. The effects on particle
(2004) studied the morphology of protein nanostructured morphology, stability and functional characteristics have
microparticles produced by SFL and compared their results been studied.
to those of Costantino et al. (2000), who had performed a Costantino et al. (2000 and 2002) observed that specific
similar study by contacting the feed spray with four liquid surface area (SSA) was an important factor influencing pro-
nitrogen sprays (a variation on the SFV/L technique). SFL tein stability, since denaturation is facilitated at interfaces.
powders showed a particularly fine microstructure due to Yu et al. (2004) suggested that the air-particle interface
the very rapid freezing rates, with structural feature of the was particularly conducive to denaturation as proteins
order of 500 nm or less. Similar microstructures could be that were subject to SFL without a subsequent freeze drying
produced using Costantino’s method when good atomisa- step showed much less denaturation than with a freeze dry-
tion conditions were produced. ing step. Therefore proteins are more stable with a reduced
Engstrom, Simpson, Lai, et al., 2007 further studied the SSA. However, a high SSA is preferred for sustained
link between cooling rate and particle morphology for pro- release, encapsulation and low water solubility excipients,
tein particles produced by SFL and SFV/L (referred to by and SFD naturally produces particles with a high SSA.
the authors as “SFD”) using liquid iso-pentane and liquid Hence striking a balance between the level of protein stabil-
nitrogen. The authors explored the impact of rapid freezing ity to be achieved and these other factors needs to be
in terms of the vitrification process during spray freezing. achieved (Costantino et al., 2002).
Vitrification refers to the passing of the material into the Costantino et al. (2000) found that complexation with
glassy state, i.e. below the glass transition (Tg) line on the zinc (a freezing adjuvant) decreased SSA and offered pro-
state diagram. During conventional freezing, plenty of tection against aggregation at the interface by forming a
time is allowed for ice formation to occur and freeze con- suspension. Further, instead of becoming more concen-
centration is thus able to take place until the solution trated upon ice crystallization, the zinc-protein complex
in solution was removed from the bulk water phase and pre- form micron or sub-micron stable particles. Stable micro-
vented the proteins from being exposed to the iceewater capsules of DHA were obtained with the SFD process
interface. The same authors extended the above study to with very lower oxidation levels (13%) in comparison to
find the influence of other formulation variables on particle SD (33%) and FD (31%).
size and stability of BSA during SFD (Costantino et al.,
2002). Firstly, the effect of concentration of excipient free SFD e a comparison with SD and FD
protein was studied. It was seen that at higher protein con- The uniqueness of SFD can be appreciated by the
centrations there was a marked increase in particle size comparative studies done hitherto. As mentioned earlier,
along with a minor improvement in stability. Furthermore, Karthik and Anandharamakrishnan, (2013) compared the
the influence of different excipients such as trehalose, morphology, encapsulation efficiency, oxidative stability
mannitol, surfactants and ammonium sulphate was investi- and rehydration properties of encapsulated DHA particles
gated. The addition of trehalose had a marked impact on produced using SFD with those from FD and SD methods.
improving protein stability, even at the lowest level tested. The SFD particles were spherical with fine pores on the sur-
The explanation given was that the presence of excipients face while powder from FD formed a cake-like structure
provided a “shielding” effect to the protein hence showing with a highly porous surface. SD encapsulated powder
a higher level of stability than formulations without excip- had a smooth surface morphology with spherical structure
ients with comparable SSA. Another factor which contrib- (Fig. 8). As discussed earlier, the porous structure of the
uted to the increased level of stabilization was the powder obtained from SFD and FD was attributed to the
preservation of structure upon dehydration. Although ice crystal formation in the freezing step and the subsequent
mannitol was not as capable as trehalose in the stabilization sublimation in the freeze drying stage. The highly porous
of BSA, its presence also afforded a significant decrease in spherical shaped particles produced using SFD exhibited
the protein degradation even at the lowest level tested. On rehydration properties (rehydration time: 30e50 s) compa-
the other hand, whilst ammonium sulphate was able to offer rable to that produced using FD (36e48 s) and far superior
protection, the greatest degree of stabilization occurred at than that from SD (89e102 s). The parameters, percentage
the lowest ratios of salt-to-protein tested. This was likely oxidation during drying and oxidative stability under
to be due to the tendency of ammonium sulphate to crystal- different storage conditions also proved SFD (14% oxida-
lize which would reduce the availability of the salt, and it tion) to be an advantageous technique against SD and FD
also appeared to increase particle size. (33% oxidation). In contrast, the encapsulation efficiency
SFD can also be used to encapsulate lipids. Karthik and of SFD microencapsulated DHA was lower (70.8%) than
Anandharamakrishnan, (2013) used whey protein isolate as FD (73.1%) and SD (82.2%). This study also reported a
a wall material (1:1 core to wall ratio) for the preparation of two-thirds reduction in processing time between the SFD
docosahexaenoic acid (DHA) emulsions for microencapsu- (4 h) and conventional FD (11 h) processes. Similar results
lation by SFD with a Tween-40 emulsifier (3.0% w/w). The were reported by Khwanpruk et al. (2008) and Wang et al.
addition of wall materials in an appropriate ratio to the feed (2006). While the former study reported a decrease in dry-
suspension also plays a role in stabilizing the spray freeze ing time from 24 h (conventional FD) to 1.75 h (SFD) in the
dried particles by encapsulating the active compound and case of 20% (w/w) coffee solution, the latter reported a
hence protecting the active compound against oxidation. reduction from 1-2 days to 1e2 h correspondingly, with
The addition of an emulsifier and a homogenization step 20% mannitol solution. The differences in reduction can
prior to atomisation of the feed solution during SFD helps be attributed to the varying processing temperatures em-
to achieve much smaller and uniform droplet sizes which ployed according to the nature of feed material used in
on further atomisation and instant freezing are retained to these studies.
Fig. 8. Comparison of the morphology of (a) Spray-freeze-dried (3000X); (b) Freeze dried (2000X) and (c) Spray dried (3000X) DHA microencapsulate
(Karthik and Anandharamakrishnan, 2013).
Dolly, Anishaparvin, Joseph, and Anandharamakrishnan drying operations, CFD simulation tools are now often
(2011) reported similar observations to the above study used because measurements of air flow, temperature, parti-
with respect to the morphology and rehydration properties cle size and humidity within the drying chamber are very
of microencapsulated Lactobacillus plantarum. In addition, difficult and expensive to obtain in large-scale dryers
the survival rate of the probiotic cells was found to be (Kuriakose and Anandharamakrishnan, 2010).
higher with SFD than SD (20% lower survival than SFD) Anandharamakrishnan et al. (2008) developed a 3D
but slightly less than FD (4e6% higher survival than CFD simulation of the co-current SFV process using Fluent
SFD). This was due to thermal injury to the cells caused 6.3 using discrete phase modelling. The model was also
by the high temperature operation and rapid drying rate able to track particles. Thus not only can the model predict
during SD and the atomisation stress on live cells during gas temperatures and velocities, but also particle tempera-
spray-freezing stage of the SFD process. tures, velocities, and residence times. Impact positions of
The above two studies show that SFD has an edge over particles on the walls of the vessel could also be modelled
SD and FD techniques in terms of product stability and qual- and collection efficiencies determined. Three cases were
ity, and establish SFD as an effective microencapsulation taken into consideration namely: (i) spray freezing with a
technique. Maa, Nguyen, Sweeney, Shire, and Hsu (1999) solid cone spray, (ii) spray freezing with a hollow cone
provided a comparison of the physical characteristics of pro- spray, and (iii) a modified spray freezing chamber design
tein powder produced by SD and SFD. Under the same with a solid cone spray. The finite volume method was
atomisation conditions, SFD resulted in larger, porous parti- used to solve the partial differential equations of the model.
cles (w8e10 mm) than SD (w3 mm). It was shown that the This model included the effect of the heat latent heat of
SFD particles retained the spherical shape created during the fusion in the model by incorporating it into a modified spe-
atomisation stage by immediate freezing. In SD, the atom- cific heat capacity which was spread evenly over the range
ized droplets shrunk from 10 mm to 3 mm upon water 10 to 0 C. Both solid and hollow cone sprays were simu-
removal by hot air drying. Also, the shape of dried particles lated and the results suggested that a hollow cone spray was
was dependent on the drying conditions and protein formu- more effective in cooling the particles uniformly, but
lation which was not observed in SFD. yielded low particle collection efficiency (13%). The au-
thors suggested that the above could be partially overcome
Recent developments in SFD by increasing the diameter of the product outlet to give par-
In recent years, the trend in SFD has moved towards ticle collection efficiencies of 57%. The solid cone spray
more precise control of particle size, microstructure and appeared to show slightly better collection efficiencies for
product functional properties. The use of novel atomisation a narrow outlet spray-freezing rig, although the freezing
techniques such as the use of ultrasonic and four fluid was less uniform.
nozzle atomizers for controlling particle size and aerody- In terms of the freeze drying step, Liapis and Bruttini
namic properties (discussed in the section on atomisation), (2009) applied a heat and mass transfer model to model
and SFD of nanosuspensions are in the spotlight now. How- the conventional freeze drying of spray frozen particles in
ever, mathematical modelling and numerical simulation vials or on trays. Simulation results indicated that particle
studies such as computational fluid dynamics have based materials require longer primary drying times than
increased the scope for identifying design improvements solution based materials (conventional freeze drying).
in the process and also in troubleshooting to avoid process This was due to reductions in the heat and mass transfer ca-
related problems. pabilities of particle based materials and the development
of a secondary porous dried layer near the surface of the
Modelling of SFD processes lower heating plate during the primary drying stage. The re-
One aim of numerical modelling is to optimize operating sults indicated that the drying rate during the primary dry-
conditions to obtain better productivity without significant ing stage increases with a decrease in product height and
loss of quality (or even improve quality). Numerical models increases in particle diameter and packing porosity.
have been proposed with the aim of predicting the drying Song and Yeom (2009) also developed a numerical simu-
time, temperature history, and temperature distribution dur- lation of the heat and mass transfer which was applied to the
ing the process (Song and Yeom, 2009). Computational SFD process of ovalbumin. They used the “sorption-subli-
Fluid Dynamics (CFD) is one such simulation tool, which mation” model to study the sublimation-condensation phe-
uses powerful computers in combination with applied nomenon that occurs during the freeze drying step of
mathematics to model fluid flow situations and aid in the partially saturated porous media. The numerical model was
optimal design of industrial processes. The method com- based on the finite volume method in a fixed grid. The nu-
prises solving equations for the conservation of mass, mo- merical results showed that the spray frozen particles
mentum and energy, using numerical methods to give required a very long drying time because of the increased
predictions of velocity, temperature and pressure profiles mass transfer resistance and the decreased heat conduction
inside the system. In recent years CFD has been increas- rate in the product. The development of a secondary sublima-
ingly applied to food processing operations. In spray- tion interface near the bottom surface was also observed and
this interface prolongs the drying time by acting as an insu- Scope for future research
lating layer. It appears that the very low thermal conductiv- Still, there is a scope for future research in the field of
ities associated with freeze dried porous structures are the SFD. From the literature it is clear that research into
further exacerbated by the powdered nature of the product. the use of SFD is far more prevalent in the pharmaceutical
The mathematical models presented are considered to arena than in the food sector, mainly due to the very low
offer a capability for the design, optimization, and control margins associated with the food industry. The technique
of the SFD process as well as of a process involving the can be fine-tuned in terms of obtaining a tailor made final
drying of frozen particles in packed beds. However, no product with a defined particle structure which would
models of fluidized bed drying have been presented in the deliver the intended functional properties, especially in
literature to date. the case of high value foods with bioactive molecules or
compounds with high volatility. The spray freezing step
Limitations of SFD needs more understanding in terms of potential factors,
Every process has its own merits and demerits. It is al- that influence the freezing kinetics and droplet structure
ways important to understand the limitations of any tech- during spray freezing and ultimately the particle structure
nique. When conventional freeze drying is employed at the time of final freeze drying step. The economic
after the spray freezing step of SFD, the major disadvan- viability of the process on an industrial scale is still debat-
tage is the high fixed and operating cost (Wolff and able due to the vacuum conditions required in the case of
Gibert, 1990). This is due to the energy intensive operation conventional SFD techniques, large requirements for drying
demanded by the requirement of vacuum and the batch gas in the case of ASFD, and particle elutriation and
mode operation which leads to additional cost (Di contamination on the wall with ASFBFD. Hence, there is
Matteo, Donsi, and Ferrari, 2003). Although the atmo- scope for future research in the area to overcome the above
spheric freeze drying is seen as a solution for this limita- listed gray areas and make SFD an advantageous process in
tion, the cost per kg of dry product depends on the food industry just like other existing successful industrial
drying temperature. Hence, the cost increases drastically drying techniques.
with feed materials whose frozen solution have a low
eutectic (Te) or glass transition temperature (Tg) and hence Conclusion
require a low drying temperature. Further, the prototypes of This review elaborated the potential of SFD as a tech-
spray freeze dryers reported in the literature (Mumenthaler nique to produce highly valued shelf stable biological and
and Leuenberger, 1991) are found to be too large for food products with superior quality than existing drying
extremely high-valued pharmaceutical products, but too techniques. From the previous studies described in this re-
small for the freeze-drying of foods, owing to the indeter- view, it is clear that series of innovations have been built
minate Te and Tg values of most of the food products into this process to make it more and more precise and ad-
(Leuenberger, 2002). vantageous in terms of product nature and quality. A greater
Aside from the challenges associated with the cost and understanding on the process factors that influence particle
logistics of handling and developing a scaled up process microstructure during spray freezing and freeze drying
for liquid nitrogen, there are several process challenges in steps of varied food products is still required across the
SFD. The disadvantage with the SFV/L technique, particu- wide variety of compositions used in foods and bio-
larly when being used for biological products, is the loss products. With the advent of highly sophisticated modelling
of protein stability during the atomisation step. The atomisa- and simulation techniques such as CFD, it is possible to
tion step in the ambient gas creates a large gas liquid inter- optimize the process parameters of SF and SFD that can
facial area for protein adsorption and unfolding (Webb et al., lead to better designs and process control of spray freeze
2002). In addition, the rapid cooling of liquid droplets pro- dryers.
duces a large iceeliquid interface which was found to dena-
ture proteins (Costantino et al., 2000). Rogers et al. (2002) Acknowledgements
also state that as the solvent freezes during SFV/L the active The authors wish to thank Prof. Ram Rajasekharan, Direc-
ingredient (AI) becomes supersaturated in the unfrozen re- tor, CSIR-CFTRI, Mysore for encouragement and support
gions of the atomized droplet enabling the AI crystals to and Ms. Padma acknowledges the Department of Science
nucleate and grow. This hinders the process of rapid freezing & Technology, India for the award of INSPIRE Fellowship.
and promotes particle growth and hence larger particle sizes Authors also wish to thank Mrs. R. Rajam for her help.
and lower specific surface areas. Similar observations were
made by Gombotz et al. (1990) and Gusman and Johnson References
(1990) during the SFD of active pharmaceutical ingredients.
The requirement of a vacuum with conventional freeze Abdul-Fattah, A. M., & Truong, V. L. (2010). Drying process methods
for biopharmaceutical products: an overview. In F. Jameel, &
drying and the large amounts of cold dry gas in the S. Hershenson (Eds.), Formulation and process development
ASFD process also jeopardize the economy of SFD pro- strategies for manufacturing Biopharmaceuticals (pp. 705e737).
cesses as already explained in previous sections. Hoboken, New Jersey: John Wiley & Sons, Inc.
Adams, T. H., Beck, J. P., & Menson, R. C. (1982). Novel particulate freeze drying. 2. Effect of formulation variables on particle size
compositions. US Patent 4,323,478. and stability. Journal of Pharmaceutical Sciences, 91(2), 388e395.
Al-Hakim, K., & Stapley, A. G. F. (2004). Morphology of spray-dried D’Addio, S. M., Chan, J. G. Y., Kwok, P. C. L., Prud’homme, R. K., &
and spray-freeze-dried whey powders. InDrying e Proceedings of Chan, H.-K. (2012). Constant size, variable density aerosol
the 14th International Drying Symposium (IDS 2004), (Vol. C pp. particles by ultrasonic spray freeze drying. International Journal of
1720e1726). Pharmaceutics, 427, 185e191.
Al-Hakim, K., Wigley, G., & Stapley, A. G. F. (2006). Phase Doppler Di Matteo, P., Donsi, G., & Ferrari, G. (2003). The role of heat and
anemometry studies of spray freezing. Trans IChemE, Part A, mass transfer phenomena in atmospheric freeze-drying of foods in
Chemical Engineering Research and Design, 84(A12), a fluidized bed. Journal of Food Engineering, 59, 267e275.
1142e1151. Dolly, P., Anishaparvin, A., Joseph, G. S., & Anandharamakrishnan, C.
Alves-Filho, O., Eikevik, T., Mulet, A., Garau, C., & Rosello, C. (2007). (2011). Microencapsulation of Lactobacillus plantarum (mtcc
Kinetics and mass transfer during atmospheric freeze drying of red 5422) by spray-freeze-drying method and evaluation of survival in
pepper. Drying Technology, 25, 1155e1161. simulated gastrointestinal conditions. Journal of
Amorij, J. P., Saluja, V., Petersen, A. H., Hinrichs, W. L. J., Microencapsulation, 28(6), 568e574.
Huckriede, A., & Frijlink, H. W. (2007). Pulmonary delivery of an Dunn, D. B., Masavage, G. J., & Sauer, H. A.. (1972). Method of
inulin-stabilized influenza subunit vaccine prepared by spray- freezing solution droplets and the like using immiscible
freeze drying induces systemic, mucosal humoral as well as cell- refrigerants of differing densities. US Patent 3,653,222.
mediated immune responses in BALB/c mice. Vaccine, 25, Dunoyer, J. M., & Larousse, J. (1961). Experiences nouvellessur la
8707e8717. lyophilisation. Trans. Eighth National vacuum Symposium (pp.
Anandharamakrishnan, C. (2008). Experimental and computational 1059e1062).
fluid dynamics studies on spray-freeze-drying and spray-drying of Engstrom, J. D., Simpson, D. T., Cloonan, C., Lai, E. S.,
proteins. Ph.D. thesis. UK: Loughborough University. Williams, R. O., Kitto, G. B., et al. (2007). Stable high surface area
Anandharamakrishnan, C., Gimbun, J., Stapley, A. G. F., & lactate dehydrogenase particles produced by spray freezing into
Rielly, C. D. (2008). Application of computational fluid dynamics liquid nitrogen. European Journal of Pharmaceutics and
(CFD) simulations to spray-freeze drying operations. 16th Biopharmaceutics, 65, 163e174.
International Drying SYMPOSIUM (IDS 2008) (pp. 537e545). Engstrom, J. D., Simpson, D. T., Lai, E. S., Williams, R. O., &
Anandharamakrishnan, C., Rielly, C. D., & Stapley, A. G. F. (2010). Johnston, K. P. (2007). Morphology of protein particles produced
Spray-freeze-drying of whey proteins at sub-atmospheric by spray freezing of concentrated solutions. European Journal of
pressures. Dairy Science and Technology, 90, 321e334. Pharmaceutics and Biopharmaceutics, 65, 149e162.
Barron, M. K., Young, T. J., Johnston, K. P., & Williams, R. O. (2003). Fellows, P. J. (1998). Food processing technology e Principles and
Investigation of processing parameters of spray freezing into liquid practice (2nd ed.). New York: CRC Press (Chapter 21).
to prepare polyethylene glycol polymeric particles for drug Filkova, I., Huang, L. X., & Mujumdar, A. S. (2007). Industrial Spray
delivery. AAPS Pharm Sci Tech, 4(2), 1e13, Article 12. drying systems. In A. S. Mujumdar (Ed.), Handbook of industrial
Bhandari, B. R., Patel, K. C., & Chen, X. D. (2008). Spray drying of food drying (pp. 215e256). Boca Raton: CRC Press.
materials e process and product characteristics. In X.-D. Chen, & Garmise, R. J., Staats, H. F., & Hickey, A. J. (2007). Novel dry powder
A. S. Mujumdar (Eds.), Drying technologies in food processing (pp. preparations of Whole Inactivated influenza Virus for Nasal
113e159). United Kingdom: Blackwell Publishing Ltd. Vaccination. AAPS PharmSciTech, 8(4), E1eE9.
Boeh-Ocansey, O. (1983). A study of the freeze-drying of some liquid Geankoplis, C. J. (2006). Transport processes and separation process
foods in Vacuo and at atmospheric-pressure. Drying Technology, principles (includes unit operations) (4th ed.). New Delhi: Prentice
2(3), 389e405. Hall of India Private Limited (Chapter 9).
Briggs, A. R., & Maxwell, T. J. (1976). Method of preparation of Geldart, D. (1986). Gas fluidization technology. Chichester: John Wiley.
lyophilized biological products. US Patent 3,932,943. Gombotz, W. R., Healy, M. S., Brown, L. R., & Auer, H. E. (1990).
Brooker, B. E., & Tomlins, R. I. (2004). Manufacture of ice cream. WO Process for producing small particles of biologically active
2004017747 A1. pharmaceuticals. WO/1990/013285.
Brooker, B. E., & Tomlins, R. I. (2009). Cryogenic crystallisation of fats. Gusman, M. I., & Johnson, S. M. (1990). Cryochemical method of
EP 1 285 584 B1. preparing ultrafine particles of high-purity superconducting
Burke, P. A., Klumb, L. A., Herberger, J. D., Nguyen, X. C., oxides. Application (pp. 13). US: US, (SRI International, USA).
Harrell, R. A., & Monica, Z. (2004). Poly(Lactide-Co-Glycolide) Heldman, D. R., & Hohner, G. A. (1974). An analysis of atmospheric
Microsphere formulations of Darbepoetin Alfa: Spray drying is an freeze drying. Journal of Food Science, 39(1), 147e155.
alternative to encapsulation by spray-freeze drying. Henczka, M., Baldyga, J., & Shekunov, B. Y. (2006). Modeling of
Pharmaceutical Research, 21(3), 500e506. spray-freezing with compressed Carbon dioxide. Chemical
Buxton, I. R., & Peach, J. M. (1984). Process and apparatus for freezing Engineering Science, 61, 2880e2887.
a liquid medium. US Patent 4,470,202. Her, J.-Y., Song, C.-S., Lee, S. J., & Lee, K.-G. (2010). Preparation of
Cheow, W. S., Ng, M. L. L., Kho, K., & Hadinoto, K. (2011). Spray- kanamycin powder by an optimized spray freeze-drying method.
freeze drying production of thermally sensitive polymeric Powder Technology, 199, 159e164.
nanoparticle aggregates for inhaled drug delivery: effect of freeze- Hindmarsh, J. P., Russell, A. B., & Chen, X. D. (2003). Experimental
drying adjuvants. International Journal of Pharmaceutics, 404, and numerical analysis of the temperature transition of a
289e300. suspended freezing water droplet. International Journal of Heat
Claussen, I. C., Ustad, T. S., Strommen, I., & Walde, P. M. (2007). and Mass Transfer, 46, 1199e1213.
Atmospheric freeze drying e a review. Drying Technology, 25, Hindmarsh, J. P., Russell, A. B., & Chen, X. D. (2007). Fundamentals
957e967. of the Spray freezing of foods e microstructure of frozen droplets.
Costantino, H. R., Firouzabadian, L., Hogeland, K., Wu, C. C., Journal of Food Engineering, 78, 136e150.
Beganski, C., Carrasquillo, K. G., et al. (2000). Protein spray-freeze Hu, J., Johnston, K. P., & Williams, R. O. (2003). Spray freezing into
drying. Effect of atomisation conditions on particle size and liquid (SFL) particle engineering technology to enhance
stability. Pharmaceutical Research, 17(11), 1374e1383. dissolution of poorly water soluble drugs: organic solvent versus
Costantino, H. R., Firouzabadian, L., Hogeland, K., Wu, C. C., organic/aqueous co-solvent systems. European Journal of
Carrasquillo, K. G., Cordova, M., et al. (2002). Protein Spray Pharmaceutical Sciences, 20, 295e303.
Hu, J., Rogers, T. L., Brown, J., Young, T., Johnston, K. P., & Nguyen, X. C., Herberger, J. D., & Burke, P. A. (2004). Protein
Williams, R. O. (2002). Improvement of dissolution rates of poorly powders for encapsulation: a comparison of spray-freeze drying
water soluble APIs using novel spray freezing into liquid and spray drying of Darbepoetin Alfa. Pharmaceutical Research,
technology. Pharmaceutical Research, 19(9), 1278e1284. 21(3), 507e514.
Karthik, P., & Anandharamakrishnan, C. (2013). Niwa, T., Shimabara, H., & Danjo, K. (2010). Novel spray freeze-
Microencapsulation of docosahexaenoic acid by spray-freeze- drying technique using four fluid nozzle e development of
drying method and comparison of its stability with spray-drying organic solvent system to expand its application to poorly water
and freeze-drying methods. Food and Bioprocess Technology, soluble drugs. Chemical & Pharmaceutical Bulletin, 58(2),
6, 2780e2790. 195e200.
Kho, K., & Hadinoto, K. (2011). Optimizing aerosolization efficiency Niwa, T., Shimabara, H., Kondo, M., & Danjo, K. (2009). Design of
of dry powder aggregates of thermally sensitive polymeric porous microparticles with single micron size by novel spray
nanoparticles produced by spray-freeze-drying. Powder freeze drying technique using four fluid nozzle. International
Technology, 214, 169e176. Journal of Pharmaceutics, 382, 88e97.
Khwanpruk, K., Anandharamakrishnan, C., Rielly, C. D., & Quast, D. G., & Karel, M. (1968). Dry layer Permeability and freeze-
Stapley, A. G. F. (2008). 16th International Drying Symposium drying rates in concentrated fluid systems. Journal of Food
(IDS2008) (pp. 1066e1072). Science, 33(2), 170e175.
Kim, E. H. J., Chen, X. D., & Pearce, D. (2009). Surface composition of Rahmati, M. R., Vatanara, A., Parsian, A. R., Gilani, K.,
industrial spray-dried milk powders. 2. Effects of spray drying Khosravi, K. M., Darabi, M., et al. (2013). Effect of formulation
conditions on the surface composition. Journal of Food ingredients on the physical characteristics of salmeterol xinafoate
Engineering, 94, 169e181. microparticles tailored by spray freeze drying. Advanced Powder
Kuriakose, R., & Anandharamakrishnan, C. (2010). Computational Technology, 24(1), 36e42.
Fluid Dynamics (CFD) applications in spray drying of food Ratti, C. (2008). Freeze and vacuum drying of foods. In X. D. Chen, &
products. Trends in Food Science and Technology, 21, 383e398. A. S. Mujumdar (Eds.), Drying technologies in food processing (pp.
Leach, W. T., Simpson, D. T., Val, T. N., Anuta, E. C., Yu, Z., 225e251). Singapore: Blackwell Publishing.
Williams, R. O., et al. (2005). Uniform encapsulation of stable Rochelle, C., & Lee, G. (2007). Dextran or hydroxyethyl starch in
protein nanoparticles produced by spray freezing for the reduction spray freeze dried trehalose/mannitol microparticles intended as
of burst release. Journal of Pharmaceutical Sciences, 94(1), ballistic particulate carriers for proteins. Journal of Pharmaceutical
56e69. Sciences, 96(9), 2296e2309.
Leuenberger, H. (1987). Process of drying a particulate material and Rogers, S., Wu, W. D., Saunders, J., & Chen, X. D. (2008).
apparatus for implementing the process. US Patent 4,608,764. Characteristics of milk powders produced by spray freeze drying.
Leuenberger, H. (2002). Spray Freeze drying e the process of choice Drying Technology, 26, 404e412.
for low water soluble drugs? Journal of Nanoparticle Research, 4, Rogers, T. L., Nelsen, A. C., Hu, J., Brown, J. N., Sarkari, M.,
111e119. Young, T. J., et al. (2002). A novel particle engineering technology
Leuenberger, H., Plitzko, M., & Puchkov, M. (2006). Spray freeze to enhance dissolution of poorly water soluble drugs: spray-
drying in a fluidized bed at normal and low pressure. Drying freezing into liquid. European Journal of Pharmaceutics and
Technology, 24, 711e719. Biopharmaceutics, 54, 271e280.
Lewin, L. M., & Mateles, R. I. (1962). Freeze drying without vacuum, a Rogers, T. L., Hu, J., Hu, Z., Johnston, K. P., & Williams, R. O. (2002).
preliminary investigation. Food Technology, 16(1), 94. A novel particle engineering technology: spray-freezing into
Liapis, A. I., & Bruttini, R. (2009). A mathematical model for the spray liquid. International Journal of Pharmaceutics, 242, 93e100.
freeze drying process: the drying of frozen particles in trays and in Rogers, T. L., Nelsen, A. C., Sarkari, M., Young, T. J., Johnston, K. P., &
vials on trays. International Journal of Heat and Mass Transfer, 52, Williams, R. O. (2003). Enhanced aqueous dissolution of a poorly
100e111. water soluble drug by novel particle engineering technology:
Liu, Y., Zhao, Y., & Feng, X. (2008). Energy analysis for a freeze-drying spray-freezing into liquid with atmospheric freeze-drying.
process. Applied Thermal Engineering, 28, 675e690. Pharmaceutical Research, 20(3), 485e493.
Lopez-Quiroga, E., Antelo, L. T., & Alonso, A. A. (2012). Time scale Saluja, V., Amorij, J.-P., Kapteyn, J. C., de Boer, A. H., Frijlink, H. W., &
modeling and optimal control of freeze drying. Journal of Food Hinrichs, W. L. J. (2010). A comparison between spray drying and
Engineering, 111, 655e666. spray freeze drying to produce an influenza subunit vaccine powder
Maa, Y.-F., Nguyen, P.-A., Sweeney, T., Shire, S. J., & Hsu, C. C. for inhalation. Journal of Controlled Release, 144(2), 127e133.
(1999). Protein inhalation powders: spray drying vs spray freeze Sauer, H. A.. (1969). Method and apparatus for freeze-drying. US
drying. Pharmaceutical Research, 16(2), 249e254. Patent 3,484,946.
MacLeod, C. S., McKittrick, J. A., Hindmarsh, J. P., Johns, M. L., & Schiffter, H., Condliffe, J., & Vonhoff, S. (2010). Spray-freeze-drying of
Wilson, D. I. (2006). Fundamentals of spray freezing of instant nanosuspensions: the manufacture of insulin particles for needle-
coffee. Journal of Food Engineering, 74, 451e461. free ballistic powder delivery. Journal of the Royal Society
Malecki, G. J., Shinde, P., Morgan, A. I., & Farkas, D. F. (1970). Interface, S483eS500.
Atmospheric fluidized bed freeze drying. Food Technology, 24, Semyonov, D., Ramon, O., Kaplun, Z., Levin-Brener, L., Gurevich, N., &
601e603. Shimoni, E. (2010). Microencapsulation of Lactobacillus paracasei
Masters, K. (1991). Spray drying handbook (5th ed.). Harlow: by spray freeze drying. Food Research International, 43, 193e202.
Longman Scientific & Technical. Song, C.-S., & Yeom, G.-S. (2009). Experiment and numerical
Merymann, H. T. (1959). Sublimation freeze-drying without vacuum. simulation of heat and mass transfer during a spray freeze-drying
Science, 130(3376), 628e629. process of ovalbumin in a tray. Heat and Mass Transfer, 46, 39e51.
Mueannoom, W., Srisongphan, A., Taylor, K. M. G., & Hauschild, S. Sonner, C., Maa, Y.-F., & Lee, G. (2002). Spray Freeze Drying for
(2012). Thermal ink-jet spray freeze drying for preparation of protein powder preparation. Journal of Pharmaceutical Sciences,
excipient free salbutamol sulphate for inhalation. European 91(10), 2122e2139.
Journal of Pharmaceutics and Biopharmaceutics, 80, 149e155. Sweeney, L. G., Wang, Z., Loebenberg, R., Wong, J. P., Lange, C. F., &
Mumenthaler, M., & Leuenberger, H. (1991). Atmospheric spray Finlay, W. H. (2005). Spray-freeze-dried liposomal ciprofloxacin
freeze-drying: a suitable alternative in freeze drying technology. powder for inhaled aerosol drug delivery. International Journal of
International Journal of Pharmaceutics, 72, 97e110. Pharmaceutics, 305, 180e185.
VanDrooge, D. J., Hinrichs, W. L. J., Dickhoff, B. H. J., Elli, M. N. A., Woodward, H. T. (1963). Freeze drying without vacuum. Food
Visser, M. R., Zijlstra, G. S., et al. (2005). Spray freeze drying to Engineering, 35, 96e97.
produce a stable D9 e tetrahydrocannabinol containing inulin- Wolff, E., & Gibert, H. (1990). Atmospheric freeze-drying part 2:
based solid dispersion powder suitable for inhalation. European modelling drying kinetics using adsorption isotherms. Drying
Journal of Pharmaceutical Sciences, 26, 231e240. Technology, 8(2), 405e428.
Wang, Y., Kho, K., Cheow, W. S., & Hadinoto, K. (2012). A comparison Yeom, G.-S., & Song, C.-S. (2010). Experimental and numerical
between spray drying and spray-freeze drying for dry powder inhaler investigation of the characteristics of spray-freeze drying for various
formulation of drug-loaded lipid polymer hybrid nanoparticles. parameters: effects of product height, heating plate temperature,
International Journal of Pharmaceutics, 424, 98e106. and Wall temperature. Drying Technology, 28(8), 165e179.
Wang, Z. L., Finlay, W. H., Peppler, M. S., & Sweeney, L. G. (2006). Yu, Z., Garcia, A. S., Johnston, K. P., & Williams, R. O. (2004). Spray
Powder formation by atmospheric spray-freeze-drying. Powder freezing into liquid nitrogen for highly stable protein
Technology, 170, 45e52. nanostructured microparticles. European Journal of Pharmaceutics
Webb, S. D., Golledge, S. L., Cleland, J. L., Carpenter, J. F., & and Biopharmaceutics, 58(3), 529e537.
Randolph, T. W. (2002). Surface adsorption of recombinant human Yu, Z., Johnston, K. P., & Williams, R. O. (2006). Spray freezing into
interferon-c in lyophilized and spray-lyophilized formulations. liquid versus spray-freeze drying: Influence of atomisation on
Journal of Pharmaceutical Sciences, 91, 1474e1487. protein aggregation and biological activity. European Journal of
Windhab, E. J. (1999). New developments in crystallization processing. Pharmaceutical Sciences, 27, 9e18.
Journal of Thermal Analysis and Calorimetry, 57, 171e180.

Spray-Freeze-Drying: A Novel Process For The Drying of Foods and Bioproducts

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Trends in Food Science & Technology xx (2014) 1e21

When Heldman and Hohner (1974) then mathematically

Table 1. Applications of spray-freeze-drying.

Application Temperature Temperature of freeze Reported physical properties Reference

Table 2. Summary of findings from different SFD methods.

Process Product Focus & findings Researchers

Semyonov et al. (2010)

19.2 to 97.7 m2/g

Fig. 2. Time - Temperature data during spray freezing of a droplet of

coffee solution (MacLeod et al., 2006).

nucleation rate are the two important factors that influence

the microstructure of the frozen droplets. This then carries

parameters on particle microstructure is discussed in a later

section on morphology. Different studies performed using

SFV and their outcomes are summarized in Table 2.

Spray freezing into vapour over liquid (SFV/L)

through a nozzle positioned a small distance above a

boiling cryogenic liquid (Fig. 3). The droplets may begin

to solidify while passing through the vapour gap and then

1976; Buxton and Peach, 1984; Dunn, Masavage, and

Sauer, 1972; Sauer, 1969). A variation on the method was

tacted the spray with a liquid nitrogen spray which was

Fig. 3. Schematic diagram of Spray Freezing into Vapour over Liquid

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