Advantages and challenges of the spray drying technology for the production of pure drug particles and drug loaded polymeric carriers

Advantages and challenges of the spray-drying technology for the production
of pure drug particles and drug-loaded polymeric carriers
Alejandro Sosnik, Katia P. Seremeta
PII: S0001-8686(15)00076-7
DOI: doi: 10.1016/j.cis.2015.05.003
Reference: CIS 1537
To appear in: Advances in Colloid and Interface Science
Please cite this article as: Sosnik Alejandro, Seremeta Katia P., Advantages and chal-
lenges of the spray-drying technology for the production of pure drug particles and
drug-loaded polymeric carriers, Advances in Colloid and Interface Science (2015), doi:
10.1016/j.cis.2015.05.003
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Advantages and challenges of the spray-drying technology for the
production of pure drug particles and drug-loaded polymeric carriers

Alejandro Sosnik
1*
and Katia P. Seremeta
2,3,4


1

Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials
Science and Engineering, Technion-Israel Institute of Technology, Technion City, Haifa,
Israel
2
Institute of Nanobiotechnology, National Science Research Council (CONICET),
Buenos Aires, Argentina
3
Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry,
University of Buenos Aires, Buenos Aires, Argentina
4
Department of Basic and Applied Sciences, Universidad Nacional del Chaco Austral,
Pcia. Sáenz Peña, Chaco, Argentina


*Corresponding author
Prof. Alejandro Sosnik, Ph.D.
Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials Science
and Engineering, Technion-Israel Institute of Technology
Technion City, 3200003 Haifa, Israel
Email: ,




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ABSTRACT
Spray-drying is a rapid, continuous, cost-effective, reproducible and scalable process for

the production of dry powders from a fluid material by atomization through an atomizer
into a hot drying gas medium, usually air. Often spray-drying is considered only a
dehydration process, though it also can be used for the encapsulation of hydrophilic and
hydrophobic active compounds within different carriers without substantial thermal
degradation, even of heat-sensitive substances due to fast drying (seconds or
milliseconds) and relatively short exposure time to heat. The solid particles obtained
present relatively narrow size distribution at the submicron-to-micron scale. Generally,
the yield% of spray-drying at laboratory scale with conventional spray-dryers is not
optimal (20-70%) due to the loss of product in the walls of the drying chamber and the
low capacity of the cyclone to separate fine particles (<2 µm). Aiming to overcome this
crucial drawback in early development stages, new devices that enable the production
of submicron particles with high yield, even for small sample amounts, have been
introduced into the market. This review describes the most outstanding advantages and
challenges of the spray-drying method for the production of pure drug particles and
drug-loaded polymeric particles and discusses the potential of this technique and the
more advanced equipment to pave the way toward reproducible and scalable processes
that are critical to the bench-to-bedside translation of innovative pharmaceutical
products.



Keywords: Spray-drying; pure drug particles; polymeric nanoparticles; polymeric
microparticles; nanocomposite microparticles; drug-encapsulation.
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Content
1. The spray-drying technique
2. Main advantages of the spray-drying process

3. Main challenges of the spray-drying process
4. Developments of the spray-drying technology
4.1 Introduction of the Nano Spray Dryer B-90
4.2 Scale-up from Mini Spray Dryer B-290 to industrial scale
4.3 Production of nanocomposite microparticles
5. Spray-drying process applied to overcome biopharmaceutical
disadvantages of drugs
5.1 Production of pure drug particles
5.2 Production of drug-loaded polymeric carriers
5.2.1 Prolonged and targeted drug delivery systems
5.2.2 Polymorphic changes of drugs after spray-drying process
5.2.3 Conservation of the activity of active agents after spray-drying process
5.2.4 Different routes of administration of drug-loaded polymeric carriers
6. Conclusions and perspectives towards translation into clinics






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1. THE SPRAY-DRYING TECHNIQUE
Spray-drying is a technique based on the transformation of a fluid into a dry powder by
atomization in a hot drying gas stream that is generally air [1]. The spray-drying process
consists of four fundamental steps: (i) atomization of the liquid feed, (ii) drying of spray
into drying gas, (iii) formation of dry particles and (iv) separation and collection of the dry
product from the drying gas [2-4]. Figure 1 shows a scheme of the conventional spray-

drying process. First, the fluid is fed into the drying chamber by a peristaltic pump
through an atomizer or nozzle that can be a rotary atomizer, a pressure nozzle or a two-
fluid nozzle and the atomization occurs by centrifugal, pressure or kinetic energy,
respectively [5]. The small droplets generated (micrometer scale) are subjected to fast
solvent evaporation [6,7] leading to the formation of dry particles that are separated from
the drying gas by means of a cyclone or bag filter that deposes them in a glass collector
situated in the bottom of the device [8,9]. Heng et al. described in detail the major
phases involved in spray-drying process [10]. In addition, a description of the
emergence and evolution of this technology and the hardware used in the process is
available in the literature [11]. The fluid feeds in spray-drying can be solutions,
suspensions, emulsions, slurries, pastes or melts [12-14]. Solid products obtained after
the process have the advantage of higher chemical and physical stability compared to
liquid formulations. In addition, they can be used as precursors for the production of
other suitable dosage forms such as capsules or tablets [15-17].
The operation configurations in spray-drying can be open-loop or closed-loop. The
former uses air as drying gas that is not re-circulated, while the latter an inert gas (e.g.,
nitrogen) that is re-cycled in the drying chamber throughout the entire process. The
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open-loop configuration is usually preferred in most of the cases since it is more cost-
effective and stable [18,19]. However, the closed-loop mode is used to prevent the
mixing of explosive gases [4] and for the manipulation of substances that are sensitive
to oxygen [20].
Regarding the direction of the drying gas flow with respect to the direction of the liquid
atomization, there exist two possibilities, co-current flow (same direction) and counter-
current flow (opposite direction) (Figure 2). In the first case, the final product is in
contact with the coolest air, hence is preferable for the drying of heat-sensitive materials
[2]. In the second case, the dry product is in contact with the hottest air and therefore it

cannot be used with temperature-sensitive materials, but is desirable in terms of higher
thermal efficiency. In addition, there are intermediate configurations with mixed flow
between co-current and counter-current [20-21].
The variables that affect the characteristics of the product and that can be tuned are (i)
process parameters, (ii) properties of the liquid feed and (iii) equipment design (Table 1)
[6, 9, 22-26]. For example, high flow rate of the liquid feed, large nozzle diameter and
high formulation concentration favor the formation of larger particles. Conversely, low
surface tension, high atomization pressure and small nozzle diameter render smaller
particles. Regarding the particles morphology, faster solvent evaporation rate (lower
point boiling) usually leads to particles that are more porous due to shorter time for the
droplets shrinkage [21,27-29]. Finally, the air outlet temperature is dependent on other
process variables [9,24]. Nandiyanto and Okuyama reviewed in detail the particle design
(i.e. control of size and morphology) during the spray-drying process to suit specific
applications [30].
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2. MAIN ADVANTAGES OF THE SPRAY-DRYING PROCESS
Spray-drying is a technique widely used in the pharmaceutical, chemical, materials,
cosmetic and food industries [3, 31-32]. The first patent concerning this technology was
in the early 1870s. Thereafter, spray-drying underwent a constant development and
evolution [11]. Patel et al. recently reviewed the patents employing spray-drying in the
pharmaceutical, the food and the flavor industry [33]. In general, this technique is very
appealing both under laboratory and industrial setups because it is rapid, continuous,
reproducible, single-step, and thus, scalable without major modifications [1,28,34]. In
this context, the final drying step required in other common techniques used to produce
particles (e.g., emulsion/solvent evaporation) is not required in spray-drying [35-37].
Moreover, a successful bench-to-bedside translation greatly depends on the fulfillment
of two conditions: scalability and cost-effectiveness. Spray-drying complies with both

[38,39]. Moreover, when spray-drying is compared to other drying processes commonly
used in industry such as freeze-drying, it is shorter and cheaper because it does not
involve deep cooling, usually associated with great energy consumption [32,40-43].
Therefore, some researchers have explored the use of spray-drying as an alternative
method to freeze-drying [2,17,44-46].
As previously mentioned, another remarkable advantage of spray-drying is the
possibility to dry a broad spectrum of compounds including heat-sensitive substances
without major detrimental effects [26,47]. This owing to the atomization of the liquid into
small droplets with high surface area-to-volume ratio that results in very fast solvent
evaporation [7]. For example, in a co-current flow setup, the product temperature is 10
to 20°C below the air outlet temperature [48,49]. Moreover, although during the drying
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process, the droplets could be exposed to high temperature, this exposure time is
extremely short (in the range of milliseconds or seconds) [18,35,50]. Under these
conditions, drug degradation is not anticipated [51]. The spray-drying technique was
conceived as a dehydration process used to prolong the lifespan of the product. At the
same time, it has increasingly attracted the interest of researchers to encapsulate drugs,
extracts, aromatic oils, pigments, and flavors within different types of carriers such as
polymeric nanoparticles (NPs) and microparticles (MPs) and nanocomposite MPs
[42,43,52]. In addition, spray-drying is a processing method with great inherent potential
to produce pure drug particles [39]. Table 2 summarizes the main advantages of spray-
drying over conventional methods for the production of pure drug particles and
polymeric carriers. A remarkable advantage is that the powders obtained by spray-
drying have better flow properties than the conventional formulations. For example,
Anish et al. obtained MPs of poly(D,L-lactide acid) (PLA) both by spray-drying and
double emulsion/solvent evaporation with angle of repose of 29.7º and 42.2º,
respectively, indicating excellent flow property in the first case and poor in the second

one [26]. Finally, regarding the yield of the process, at industrial scale is generally close
to 100% [53].
3. MAIN CHALLENGES OF THE SPRAY-DRYING PROCESS
Regardless of the numerous advantages displayed by this technology, when traditional
spray-dryers are used, the yield strongly depends on the work scale. Thus, yields are
high in larger scale setups because the fraction lost is an increasingly smaller
component of the total production volume [37,54], while in laboratory scale they are still
far from optimal, the yield being in the 20-70% range [5,12,14]. Generally, low yield is
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due to the loss of product in the walls of the drying chamber, amounts being relatively
constant. In addition, fine particles (<2 µm) usually pass into the exhaust air due to
ineffective separation capacity of cyclone [8,53,55]. However, some separators (e.g.,
filter systems) are effective under industrial settings to increase the yield [8]. Cevher et
al. obtained spray-dried chitosan microspheres loaded with vancomycin hydrochloride
from a 1% v/v acetic acid solution containing different polymer:drug ratios (1:1, 2:1, 3:1
and 4:1, w/w) using a laboratory scale spray-dryer (Mini Spray Dryer B-191, Büchi) to be
implanted in proximal tibia of rats with methicillin-resistant Staphylococcus aureus
osteomyelitis [56]. After spray-drying, the microspheres were collected and weighed to
determine the production yield, values being relatively low (~47-50%) owing to the small
batch size (200 mL of 0.5% w/v polymer solution) and the loss of some liquid droplets
inside the wall of the drying chamber [56]. The production of particles at the nanometer
scale is limited not only by the low separation capacity of cyclone but also because
insufficient forces of liquid atomization (pressure and centrifugal) to obtain large amount
of submicron particles [23,57]. This phenomenon affects the size and size distribution
that might be crucial in the development of certain drug delivery systems, especially
envisioned for intravenous administration [58-60].
4. DEVELOPMENTS OF THE SPRAY-DRYING TECHNOLOGY

4.1 Introduction of the Nano Spray Dryer B-90
Aiming to overcome the main drawbacks of this technology and extend its application to
the production of more complex particle configurations, Büchi (Labotechnik AG,
Switzerland) introduced the Nano Spray Dryer B-90 which is the fourth and newest
generation of laboratory scale spray-dryers developed by the company following the
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previous generations (Mini Spray Dryers B-190, B-191 and B-290) [10]. This device is
suitable for the production of fine particles (300 nm-5 µm) with satisfactory yield, even
for small sample amounts (milligrams) [61,62]. This feature is very relevant especially at
the very early stages of product development and when expensive materials, such as
monoclonal antibodies, are used [63]. This spray-dryer contains a vibrating mesh spray
with small orifices (4.0, 5.5 or 7.0 μm) that is driven by a piezoelectric actuator at a
specific ultrasonic frequency (60 kHz) producing ultra-fine droplets that result in small
particles after drying with narrow and reproducible size distribution. Lee et al. obtained
spray-dried bovine serum albumin (BSA) NPs from aqueous solutions of BSA (1-2%
w/v) and Tween
®
80 surfactant (0.05% w/v) using Nano Spray Dryer B-90 with different
mesh spray size [5]. Figure 3 shows the scanning electron microscopy (SEM) images of
the particles obtained with 4.0, 5.5 and 7.0 µm spray meshes orifices, corresponding to
particles sizes of approximately 0.7, 1.2 and 2.6 µm, respectively [5]. A similar tendency
was observed by other authors where the average particle size and the size
polydispersity became smaller with decreasing mesh aperture sizes [64]. Moreover, this
innovative device contains a high-efficiency electrostatic powder collector that allows
high yields above 70% when process and formulation parameters undergo appropriate
optimization. In addition, it uses a laminar drying gas flow through the drying chamber
resulting in mild, uniform and instant heating [4-5,14,23,61]. On the other hand, it should

be noted that the diameter of the orifices of the vibrating mesh spray is smaller than the
nozzles of conventional spray-dryers (500-700 μm), resulting in higher processing times
and preventing the use of some highly viscous polymer solutions [57]. In addition,
sometimes products deposit as a heavy crust on the vibrating mesh of the device and
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not only reduce the yield but also might contaminate the fine particles collected due to
the burst of the crust on the collector [61]. Other limitation of the device is that the
vibrating mesh causes mechanical shear of atomization and shear-sensitive substances
can be altered [65]. Heng et al. reviewed on the advances of Nano Spray Dryer B-90 for
the production of NPs suited for several drug delivery applications and presented a
schematic diagram of this device and the functional principle of mesh vibration and the
electrostatic particle collector [10]. Several authors used this spray-dryer for the
production of NPs and MPs. For example, Li et al. evaluated its performance in the
production of polymeric particles using five representative wall materials (arabic gum,
whey protein, polyvinyl alcohol or PVA, modified starch and maltodextrin) dissolved in
ultrapure water (0.1, 1 and 10% w/w) [14]. The micrographs of SEM showed
homogeneous and spherical particles and the peak maxima of size distributions were
below 1 μm in all cases (Figure 4). The yield varied from 43.0% to 94.5%, according to
the type and concentration of the wall material [14]. Furthermore, the authors showed
the utility of this device for encapsulation of lipid nano-emulsions (<100 nm) obtained by
a low-energy method and mixed in a later stage with 1% w/w wall material aqueous
solution (weight ratio of 1:4). The non-aggregated submicron solid particles obtained
were re-dispersible in water without size increase. Finally, they also obtained nano-
crystals of both hydrophilic (sodium chloride, 0.1 and 1% w/w in water) and lipophilic
(furosemide, 1.25% w/w in acetone) compounds by spray-drying, resulting in
homogeneous powders with size peaks between 517 and 993 nm in the first case and
1.24 µm in the second case. The yield values were between 69.3% and 85.4% [14].

Using the same equipment (with spray mesh diameter of 7.0 µm), Harsha et al. obtained
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mucoadhesive carbopol 934P microspheres loaded with sitagliptin (a new anti-diabetic
drug) from a solution of polymer and drug in water for sustained drug release after oral
administration [66]. The effect of three factors, namely carbopol concentration, inlet
temperature and feed flow rate, on the yield were studied by means of a central
composite design. The former two factors had major, while the latter had minor effect on
the yield; values under different settings ranged from 64% to 92% for a powder amount
of 500 mg. This allowed the optimization of the conditions for the preparation of
microspheres with high yield. Drug-loaded microspheres presented free flowing with
angle of repose of 24º and narrow size distribution in the 2-8 µm range [66]. Even
though, this new device has extended the possibilities of the spray-drying technique,
there are still limitations to scale up the process to the pilot and the industrial scales.
4.2 Scale-up from the Mini Spray Dryer B-290 to the industrial scale
Despite the remarkable advantages presented by the Nano Spray Dryer B-90 with
respect to previous generations of laboratory scale spray-dryers, the Mini Spray Dryer B-
290 enables the more straightforward scale-up of the process initially to pilot and later
on to industrial production [67]. However, to achieve this, equipment designed for larger
scale is required (see below). Table 3 summarizes the major differences between both
systems. Zhu et al. developed a formulation and production process at pilot scale to
stabilize a recombinant hemagglutinin (rHA) influenza antigen, HAC1, as a model
vaccine candidate [54]. First, eight HAC1 formulations containing different excipients
were produced using the Mini Spray Dryer B-290 and powders were characterized by
differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and SEM. Then,
the potency of the HAC1 antigen in all formulations was measured using a single radial
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immunodiffusion assay. Immunogenicity studies were conducted in mice to evaluate the
effect of the formulation components and the spray-drying process on the
immunogenicity of the HAC1 vaccine. Based on the in vitro evaluation of the antigen
content (process loss and stability), the antigen structure, the powder properties and the
in vivo immunogenicity, one formulation (containing 7.5% trehalose, 2.5% hydrolyzed
gelatin and 360 μg/mL HAC1) was selected for pilot scale-up using conditions that were
established in the laboratory scale spray-dryer. Three batches of 50 g particles in the
0.5-30 μm size range (100-fold larger than the laboratory scale) were obtained in a pilot
scale laboratory dryer BLD-1 (Bend Research, Inc., Bend, Oregon) with yields >90%.
Results of pilot scale formulation replicated the findings observed for the optimized
formulation at the laboratory scale. All three batches maintained stable physical
properties and antigen content throughout the 6-month stability study at storage
temperatures from -20ºC to 50 ºC. Moreover, they induced an immune response that
was equivalent to the bulk HAC1 vaccine control, suggesting that the pilot scale process
did not alter the immunogenicity of the HAC1 antigen and that the production process is
amenable to industrial scale production [54]. Due to the challenging nature of the scale-
up process, two important spray-dryer producers (Büchi Labortechnik AG and GEA Niro
A/S in small and large scale, respectively) reported on a practical procedure to scale up
a spray-drying process from Mini Spray Dryer B-290 to Niro MOBILE MINOR
TM
(pilot
plant spray-dryer) with two-fluid nozzle [68]. The critical process conditions were
maintained constant during the scale-up, while those with the least impact were
adjusted. In this way, they produced a powder with similar residual moisture content
(~0.05 kg water/kg powder) and similar particle size (~20 µm), but at a higher production
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rate (feed flow rate of 1.41 kg/h instead of 0.60 kg/h) [68]. Laboratory scale is
appropriate for use in preclinical stages of drug development. These results place the
Mini Spray Dryer B-290 as a reliable laboratory scale model to optimize the process
parameters towards the larger production scale required in the clinical stage [69].
4.3 Production of nanocomposite microparticles
One strategy to minimize the loss of fine particles during the separation and collection
step in traditional spray-dryers is to produce MPs composed of self-assembled NPs with
or without carrier materials (nanocomposite MPs) where the size growth increases the
collection extent. Furthermore, these MPs are more physically stable than the NPs
because the smaller size of the NPs could lead to strong inter-particle interactions and
subsequent aggregation [60, 70-73]. Oliveira et al. observed these interactions between
NPs obtained from aqueous solutions of different polymers (arabic gum, cashew nut
gum, sodium alginate, sodium carboxymethyl cellulose and Eudragit
®
RS100) and a
model drug (vitamin B12) by means of the Nano Spray Dryer B-90 [57]. NPs were
subjected to agglomeration during the drying process resulting in micrometer particles
when determined by a laser diffraction technique. However, when they were analyzed
by SEM, individual NPs clustered together were observed, which explained the greater
size determined by laser diffraction [57]. To prevent irreversible aggregation phenomena
of the NPs after spray-drying, “spacer” excipients such as sucrose, trehalose, and
leucine can be used [74]. In addition, in some cases, the small size and the insufficient
inertia of the NPs limit their administration. For example, NPs with a small aerodynamic
diameter (d
ae
) between 100 nm and 1 µm cannot be used for inhalation because the
small size precludes their retention in the airways and favor their elimination by
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exhalation [63,75]. Therefore, NPs could be replaced by nanocomposite MPs with a
more suitable d
ae
in the 1-5 µm range that undergo deposition in the lung [73,76,77].
Hadinoto et al. obtained large hollow carrier particles without carrier materials from
suspensions of biocompatible acrylic polymer NPs loaded with a model drug (salbutamol
sulfate or aspirin) initially obtained by a nanoprecipitation technique [71]. The large
hollow aggregates particles, whose shells were composed of primary NPs, exhibited a
large geometric diameter (d
g
~ 10-15 µm) but with a small d
ae
(1≤ d
ae
≤3 µm) highly
suitable for dry powder inhaler (DPI) applications with ability to disassociate into primary
NPs once they are exposed to alveolar lung region. SEM images of the large hollow
nanoparticulate aggregates are presented in Figure 5A (aspirin-loaded particles) and
Figure 5B (salbutamol sulfate-loaded particles) and it is noteworthy that some very fine
particles (d
g
≤3 µm) also were observed. In addition, Figure 5C,D showed the
nanoparticulate aggregates that compose the surface of the large hollow particles [71].
On other hand, water-soluble carbohydrate excipients such as lactose, sucrose,
trehalose or mannitol increase the size of the drug carrier to the micrometer scale and
maximize lung deposition and retention [75,78,79]. These excipients are widely used
due to their non-toxicity and biodegradability after pulmonary administration [70,80]. In
addition, the United States Food and Drug Administration (US-FDA) has approved them

as pharmaceuticals [50]. In these cases, excipient MPs act as inert carriers of NPs
enabling their fast release due to the high aqueous solubility of microcarriers [81].
Therefore, a requisite of these systems is that the MPs re-disperse or disassociate
completely into primary NPs when they are exposed to the physiological medium
because the NPs have the ability to delay or avoid unwanted mucociliary clearance [48,
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79,80]. Figure 6 schematizes the decomposition of nanocomposite MPs into NPs after
pulmonary administration [72]. Ungaro et al. developed tobramycin-loaded poly(D,L-
lactide-co-glycolide acid) (PLGA) NPs embedded in an inert microcarrier of lactose
referred to as nano-embedded MPs (NEM) for pulmonary prolonged delivery system
[75]. Tobramycin-loaded PLGA NPs were prepared by a modified emulsion/solvent
diffusion technique in the presence of helper polymers such as PVA and alginate to
optimize size, surface properties, drug loading and release up to one month. These
drug-loaded NPs (250-300 nm) displayed good in vitro antimicrobial activity against P.
aeruginosa planktonic cells. Then NPs were dispersed in a lactose aqueous solution
and this dispersion was diluted with ethanol (ethanol/water ratio 1:1) for obtaining NEMs.
Dispersions were processed in a Mini Spray Dryer B-190 equipped with a high-
performance cyclone and the produced NEMs displayed very good flow properties with
about 100% of the capsule content being emitted during aerosolization and very low
mass median aerodynamic diameter (MMAD) of approximately 3.4 µm. In vivo
biodistribution studies showed that PVA-modified alginate/PLGA NPs reached the deep
lung after intra-tracheal administration in rats (Figure 7) [75]. Following this same
concept, other authors developed nanocomposite MPs for suitable pulmonary
administration [48,70,72,78,80,82]. However, the performance of DPIs highly depends
on formulation and device design and usually DPIs producing d
ae
of 3-6 µm deposit

about 40-70% of the dose in the mouth-throat region due to inertial impaction, whereas
particles in the size range 400-900 nm achieve near zero deposition in this region [83].
Therefore, an excipient enhanced growth (EEG) strategy that delivers an inhaled
submicron particle formulation to minimize depositional losses in mouth and throat was
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proposed. The particles combined drug and hygroscopic excipients that after inhalation
absorb humidity of the lungs, increasing the particles size (2-4 µm) and weight and
ensuring lung deposition [83]. Thus, Son et al. developed a submicrometer powder
formulation suitable for EEG application from a convenient DPI platform using albuterol
sulfate, mannitol, L-leucine, and poloxamer 188 as model drug, hygroscopic excipient,
dispersibility enhancer and surfactant, respectively [83]. The combination particles were
obtained from a water:ethanol (80:20% v/v) solution containing 0.5% solids using the
Nano Spray Dryer B-90. Figure 8 shows a SEM image of an optimized formulation with
d
ae
of 2.3 µm that exhibited excellent aerosolization properties using a conventional DPI
(Aerolizer
®
), with only 4.1% of mouth-throat deposition using a realistic model. In
addition, emitted doses were greater than 80% of the capsule content [83].
5. SPRAY-DRYING PROCESS APPLIED TO OVERCOME BIOPHARMACEUTICAL
DISADVANTAGES OF DRUGS
5.1 Production of pure drug particles
Micro and nanotechnology strategies represent very effective means to overcome
biopharmaceutical drawbacks and sustain, control and target the release of drugs. For
example, drugs with poor aqueous solubility often exhibit limited oral absorption and
erratic bioavailability because the dissolution rate is the limiting factor for the absorption.

Thus, the slow dissolution rate is compensated by the administration of higher doses
[84-87]. A strategy to overcome this drawback is the production of NPs and MPs of pure
drug that provide a larger surface area-to-volume ratio and hence a faster drug
dissolution rate than the raw material [88]. The effect of the size on the dissolution rate
is expressed by the Noyes-Whitney equation [89,90]
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dC = D x S x (C
S
– C)
dt V x h

Where C is the concentration of a substance in solution, t is the time, dC/dt is the
dissolution rate, D is the diffusion coefficient of the substance, S is the surface area of
the solid, V is the total volume of the medium, h is the thickness of the diffusion layer
and C
S
is the saturation solubility of the substance in the solvent.
This equation indicates a directly proportional relation between the dissolution rate and
the specific surface area of the solid [88]. Thus, increased drug dissolution rate allows a
faster absorption rate and thus, it is usually associated with enhanced bioavailability
[89]. Spray-drying is a potential technology to produce pure drug particles with their
associated benefits [14,64,91,92].
5.2 Production of drug-loaded polymeric carriers
Many drugs undergo degradation in the physiological environment, this phenomenon
leading to a decrease of the bioavailability [86]. Therefore, the incorporation of the drug
into particles could protect the cargo against harsh conditions such as chemical and
enzymatic degradation [28,93]. For example, Seremeta et al. encapsulated the anti-HIV

didanosine within poly(epsilon-caprolactone) (PCL) MPs both by suspension and simple
emulsion followed for spray-drying to avoid its fast gastric degradation that leads to low
oral bioavailability (20-40%) [51]. The device used in this study was a Mini Spray Dryer
B-191. Drug-loaded MPs were spherical with average diameter between 36 and 118 μm
(Figure 9) and yield between 37.7% and 64.9%. Oral administration of the optimized
formulation to rats resulted in a statistically significant 2.5-fold increase of the drug
bioavailability with respect to a didanosine aqueous solution (Figure 9C) [51]. Spray-
drying enables the encapsulation of active agents of diverse physicochemical properties
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within different polymer matrices (synthetic, semi-synthetic or natural origin) under very
mild and non-detrimental conditions and with high encapsulation efficiency (%EE) and
loading capacity (%LC) [16,94]. An additional advantage is that this technology is less
dependent on the solubility of the drug and the polymer than other methods [37] (Table
2). The particles can be obtained directly by spray-drying of solutions or suspensions
containing the compounds to dry or by atomizing particles pre-formed by emulsification,
de-solvation or solvent displacement method. The particles obtained in both cases
present different features. Usually when the particles are produced by a previous
method and this technology is used to remove the solvent where the particles were
suspended, the size of the particles remains practically unchanged after re-dispersion in
aqueous media [95,96]. Beck-Broichsitter et al. obtained two formulation types loaded
with sildenafil (as model drug) for pulmonary administration using Nano Spray Dryer B-
90 [23]. In first the case, submicron-to-micron particles (567-1129 nm) were produced by
spray-drying of organic solutions of drug and PLGA. In the second case, composite MPs
(2.8-4.4 µm) were obtained from aqueous suspension of drug-loaded PLGA NPs
produced by emulsion/solvent evaporation followed by spray-drying. The surface of
submicron particles was smooth (Figure 10A) while the surface of composite MPs was
decorated by single NPs (Figure 10B) and thus exhibited a larger specific surface area.

Upon contact with aqueous media, the composite MPs underwent disintegration into
individual NPs with only a negligible increase in mean particle size. Aerodynamic
parameters after aerosolization of both particle types were appropriate for deposition in
deep lungs (≤ 4 µm). The in vitro release assays showed that composite MPs released
the drug within 90 min, while the drug release from submicron particles was
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considerably sustained (480 min) which is a key requirement on pulmonary drug delivery
[23].
For the production of particles, hydrophobic polymers such as PCL (80,86,97-100), PLA
[26,35,101] and PLGA [44,74,82,98,102-106], or hydrophilic ones such as chitosan
[25,45,56,94,107-111], alginate [37,112], poly(vinylpyrrolidone) (PVP) [113,114],
hydroxypropylmethylcellulose (HPMC) [69] and gelatin [50,115] are initially dissolved in
organic or aqueous solvents, respectively, and then spray-dried. In the former, the main
advantage is the use of solvents with low boiling point. For example, the use of
dichloromethane (40ºC) or acetone (56ºC) avoids problems of sticking and
agglomeration. The reason is that they evaporate at a temperature that is lower than the
melting temperature of the most extensively used polymers such as PCL (T
m
= 55-60ºC)
or the glass transition temperature of others such as PLGA (T
g
= 40-60ºC) or PLA (T
g
<
60ºC) [28,35,98]. In addition, organic solvent combinations can be used to adjust the
solubility of the polymer and the drug and the boiling point that results in particles with
the desired properties. In the latter case, the advantage of water is associated with the

non-toxicity and the reduction of the risk of explosion [1,114]. Furthermore, mixtures of
water and suitable water-miscible organic solvents such as ethanol could reduce the
final boiling point of the solvent system and enable the spray-drying at lower
temperature [74,80,83].
5.2.1 Prolonged and targeted drug delivery systems. Noteworthy that the use of suitable
polymers could also modulate the release of the encapsulated drug, prolonging the
particles/mucosa interaction and increasing the amount of drug that is absorbed [116].
This would also ensure constant plasma drug concentrations for more prolonged time
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[49,117-120]. For example, Gavini et al. obtained spray-dried chitosan hydrochloride or
glutamate MPs for nasal administration of carbamazepine that due to its poor water
solubility has slow and irregular gastrointestinal absorption [121]. Firstly, a solution of
drug in acetone and an aqueous solution of chitosan salt were homogenized and then
fed at a Mini Spray Dryer B-191. The volume surface diameter (d
vs
)

of MPs was
approximately 2 µm with narrow size distribution and high %EE (89-95%). The loading
of carbamazepine into MPs led to an improvement of the in vitro dissolution/release rate
in phosphate buffer (pH 7.0) with respect to pure drug (powder raw), mainly due to
mucoadhesiveness. In vivo tests in sheep showed that the nasal administration of
carbamazepine-loaded chitosan glutamate MPs remarkably increased the area-under-
plasma concentration-time curve (AUC) by 5.6-fold compared to the pure drug powder
(Figure 11). In addition, the time to reach the maximum plasma concentration (t
max
) at

10 min after administration of the MPs indicated very rapid drug absorption from the
nose (Figure 11) [121].
The particles also could target drugs to specific sites, contributing to decrease the
effective dose, the administration frequency and/or the drug systemic toxicity and thus,
improve patient compliance [36,47,122,123]. For example, Crcarevska et al. designed a
targeted oral delivery system of Eudragit
®
S100-coated chitosan-Ca-alginate MPs
loaded with budesonide against inflammatory bowel diseases in the colonic region using
spray-drying process [124]. Both alginate and chitosan exhibit mucoadhesive properties
involving interactions with the intestinal mucus layer. In addition, enteric coating of MPs
with acid-resistant Eudragit
®
S100 avoided the nonspecific and premature adherence to
other parts of gastrointestinal tract such as stomach (pH 2.0) and allowed colon-specific
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delivery (pH 7.4) of budesonide over a more prolonged period of time. This system
accelerated the healing in a rat model of induced colitis compared to uncoated MPs and
drug suspension [124].
5.2.2 Polymorphic changes of drugs after spray-drying process. Spray-drying can induce
polymorphic changes or amorphization of the encapsulated drug and enhance its
solubility and dissolution rate [85,114,125]. For example, Tran et al. developed solid
dispersion NPs to enhance the physicochemical properties and bioavailability of
raloxifene (poorly water-soluble) using spray-drying [114]. The formulation was prepared
dissolving PVP K30 and Tween
®
20 in water and dispersing raloxifene. The resulting

dispersion was fed to a Mini Spray Dryer B-190 and particles had a mean size of
approximately 180 nm. DSC and XRD assays showed that raloxifene changed from a
crystalline to an amorphous state after spray-drying (Figure 12). This change and size
reduction led to a significant increase in aqueous solubility and dissolution rate of drug.
Furthermore, oral administration at rats of the formulation showed higher maximum
plasma concentration (C
max
, 3.3-fold) and AUC
0-∞
(2.3-fold) than the pure drug powder
[114]. Oh et al. produced NPs loaded with flurbiprofen (poorly water-soluble) by
solidifying a nanoemulsion using sucrose as carrier via spray-drying [126]. After
reconstitution, NPs (300 nm) improved the dissolution rate by a factor of about 70,000
compared to flurbiprofen powder due to transformation of the drug from a crystalline to
an amorphous form and the reduction of the size to the nanoscale. When these NPs
were orally administered to rats, the AUC of the drug was about 9-fold higher than the
one of the commercial product [126]. The change from a crystalline to an amorphous
form also stresses the potential of spray-drying to produce pure drug NPs [39].
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5.2.3 Conservation of the activity of active agents after spray-drying process. The
conservation of the activity of active agents encapsulated after spray-drying process is
important, especially in the case of sensitive substances such as proteins and genes.
Several studies showed that encapsulated products retained their activity after the
spray-drying process [17,37,82,98]. For example, Jensen et al. encapsulated siRNA
within of NPs of PLGA into nanocomposite MPs by double emulsion/solvent evaporation
and spray-drying intended for inhalation and confirmed that the integrity and biological
activity of siRNA were preserved after process [82]. The siRNA extracted from the

nanocomposite MPs appeared intact and of the same size as before spray-drying
process when evaluated by gel electrophoresis (Figure 13). In addition, there was no
significant difference between the activity of the siRNA extracted from nanocomposite
MPs and the positive control siRNA determined in cell transfection assays [82].
5.2.4 Different routes of administration of drug-loaded polymeric carriers. Finally, the
particles loaded with drugs obtained by spray-drying could be administered by different
routes such as oral [127-132], pulmonary [12,23,82,133,134), ophthalmic [93,111,135],
parenteral [22,38,136], nasal [60,120,121,137], and vaginal [138], stressing its great
versatility. For example, Başaran et al. obtained NPs of chitosan of different molecular
weights (low, medium and high) loaded with cyclosporine A (10 and 25% of the polymer)
for ocular administration. For this, an ethanol solution of cyclosporine A was added to an
acidic chitosan solution and the final solution was spray-dried via Mini Spray Dryer B-
190 to obtain the NPs [111]. These had spherical shape and size between 317 and 681
nm with positive zeta potential ranging between +22 and +35 mV. The NPs of chitosan
of medium molecular weight showed higher %EE of cyclosporine A and more uniform
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release patterns in simulated tear fluid hence were selected for in vivo assays in sheep.
Results in vivo studies showed cyclosporine A content even after 72 h in both aqueous
and vitreous humour samples indicating enhanced ocular penetration and prolonged
cyclosporine A release from NPs [111]. This example indicates that in some cases, the
use of conventional spray-dryers also results in particles in the nanometer scale. In
another work, Bhowmik et al. developed a melanoma cancer vaccine based in MPs of
albumin, ethylcellulose, HPMC acetate succinate and antigen (obtained from Cloudman
S-91 melanoma cancer cells) [38]. The MPs were obtained from aqueous solutions of
polymers and antigen using the Mini Spray Dryer B-191. They presented spherical
surface and mean particle size between 0.625 and 1.4 µm. Antigen-loaded MPs were
administered in suspension with citrate buffer and polyethylene glycol via transdermal

route in mice during 8-week. Subsequently, mice were challenged with live S-91 tumor
cells to evaluate the efficacy of the vaccination. The transdermal vaccinated mice
showed no measurable tumor growth 35 days after tumor injection, while the non-
vaccinated control group of animals developed a palpable tumor after approximately 11
days [38]. Zhang et al. developed a spray-dried mucoadhesive and pH-sensitive
microspheres formulation based on a poly(methacrylate) salt intended for vaginal
delivery of a model HIV microbicide (tenofovir) to prevent HIV transmission [138]. To
prepare tenofovir-loaded microspheres, different amounts of Eudragit
®
S-100 and drug
were added in deionized water with an appropriate amount of sodium hydroxide to
achieve complete salification. The solution was then spray-dried using a Mini Spray
Dryer B-290. The formulation and process parameters were screened and optimized
using a fractional factorial design. The optimal microspheres formulation had spherical
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shape with average size of 4.73 µm (Figure 14), yield of 68.9%, %EE of 88.7%, %LC of
2% w/w and Carr’s index of 28.3. These microspheres released over 90% of its payload
within 60 min in the presence of simulated human semen (pH 7.6). Conversely, only
20% of the drug was released under the acidic pH conditions of the normal vagina due
to the low solubility of the polymer. Microspheres were non-cytotoxic and non-
immunogenic to vaginal/endocervical epithelial cell lines, and non-toxic to normal
vaginal flora. In vitro tests showed that their mucoadhesion was 2-fold higher than that
of a hydroxyethylcellulose gel formulation [138].
6. CONCLUSIONS AND PERSPECTIVES TOWARDS TRANSLATION INTO CLINICS
Spray-drying is widely used due to it is a rapid, continuous, reproducible, cost-effective,
easily scalable and one-step process. This technology is not only used for dehydration
and conservation of products but also for encapsulation of substances within different

carriers such as polymeric particles. The particle sizes obtained are at submicron-to-
micron scale and could be administered by different routes. The fast drying process
avoids significant degradation of the encapsulated drugs and allows the preservation of
their activity after the process. Although this technology has been used for many years,
it is still undergoing evolution. In this context, the introduction of new equipment that
enables the production of finer particles with narrower size distributions and that
prevents high product loss on the walls of drying chamber has been fundamental to
envision the scale-up of production process developed in the laboratory to pilot and
industrial scales. However, the available equipment does not allow scale-up to large
scale as a conventional spray-dryers do. In the same context, the investigation of new
materials that can be processed by spray-drying is another relevant pillar to consolidate