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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5637_Библиотеки_им_академика_М_И_Перельмана
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194 C. Sarode et al.
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is an issue, using ultrasound leads to formation of small and uniform particles with
a greater control over their formation. Similarly, an ultrasonic spray freeze-drying
process also leads to creation of uniform, spherical, and porous particles. Even in the
case of ultrasound-assisted extrusion, by virtue of ultrasonic vibrations, a homogeneous dispersion of particles is created, resulting in better product. Crystallization
is one of the most significant operations in the pharmaceutical industry as more
than 90% of all active pharmaceutical ingredients (APIs) are crystals. The method
of crystallization determines the final crystal properties including particle size
distribution, form, and polymorphic composition, which also significantly affect
downstream processing and bioavailability. Ultrasound application in crystallization
provides advantages such as improved crystallization parameters like nucleation,
crystal growth, and distribution. It is also important to note that the application is
restricted to laboratories and the employment for industrial scale operations needs
to be explored.
Ultrasonic processing is dependent on various process parameters like pressure,
temperature, and viscosity as well as ultrasonic parameters such as frequency and
intensity. Ultrasound effects are mainly based on the vibrations induced by passage
of ultrasound and the generation of cavitating conditions. For example, in the
case of encapsulation, the governing mechanism is based on either the capillary
wave hypothesis or cavitation theory that eventually yields better quality product.
The capillary wave hypothesis focuses on the formation of a capillary wave with
crests and troughs on a vibrating surface, whereas cavitation hypothesis refers
to the formation of cavities leading to droplet formation from the liquid film
on the surface. The proper selection of the operating conditions usually allows
tailoring a given controlling mechanism that also decides the expected product
characteristics. This chapter offers such discussion on the governing mechanisms
for the improvement, the information on the possible reactor configurations, as well
as the selection of operating conditions for the specific applications of encapsulation
and crystallization. Such application of ultrasound under the desired conditions can
give advantages such as greater control over particle size, enhanced solubility of
drugs, controlled crystallization, and production of nanomaterials.
2 Drug Encapsulation
The global biopharmaceutical market is valued at US$ 228 billion in 2016. A
recent trend is to search for novel methods of drug development that will facilitate
drug production with increased efficiency and safety. There are many challenges
faced by the drug developers in the initial phases of which maintaining the
chemical and physical stability of the biopharmaceuticals during the manufacturing,
transportation, and storage phase is the main one. This is most relevant because the
stability of these biomolecules is largely dependent on a diverse range of factors
like temperature, pH, interface exposure, and mechanical stress faced [1]. Cell
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encapsulation is among the most well-known technology in the pharmaceutical
industry that provides a solution to these issues faced by the developers.
2.1 Encapsulation in Pharmaceutical Industry
Encapsulation is one of the crucial processes that has been subjected to continuous
innovation in order to guarantee the success of pharmacological therapies [2].
It is characterized as a process by which solid particles or liquid/gas droplets
are enclosed in an inert shell. This helps to isolate the core material from the
external environment [3]. Encapsulation results in the formation of particles that
have diameters of a few nm to a few mm [4]. There are various physical, chemical,
and mechanical processes that can be utilized for encapsulation of various materials.
Process selection depends on a variety of parameters like the nature of polymer,
desired particle morphology, and chemical characteristics of a drug like solubility
[5]. Stirring, static mixing, spraying, extrusion, and dripping are all common
methods for microsphere formation, but ultrasonic irradiation has recently become
a popular technique due to better efficiency and productivity [2]. Synthesizing
microspheres requires a great deal of knowledge about (1) core material, (2)
encapsulant, (3) core-matrix-environment interaction, (4) stability, and (5) core
release mechanism [6, 7].
Fundamental steps in encapsulation include incorporation of bioactive compounds, droplet formation, removal of solvent, microparticle harvesting, and drying
treatments [5]. The process output is extremely reliant on processing parameters like
solution conditions including temperature, concentration, pH, stirring rate, sonication conditions, etc. [8]. A key performance parameter indicating the efficacy of the
encapsulation process is the extent of entrapment, characterized by encapsulation
efficiency or adsorption capacity [9]. While designing a system of production for
any product, there are four factors that attain higher importance: encapsulation
materials, production process, final morphology, and ultimate application. Along
with these, other factors like the stability and functional properties of the bioactive
(core) component, process reproducibility, and targeted release profile should also
be considered. Caution should also be exercised to overcome certain drawbacks
of microsphere aggregation and adherence [10]. Increasing the encapsulation
effectiveness of a drug in drug carrier particles would result in a more potent
therapeutic effect with fewer side effects [8]. Thus, encapsulation offers advantages
to improve the solubility of the drug, reduce toxicity, and protect the drug from
external conditions such as pH, temperature, enzymes, and oxidation [8]. It also
increases the mechanical stability and achieve long-lasting matrices. It is possible
to use the encapsulating vehicle as a targeting platform, thus allowing the drug to
be delivered to specific cells in the body. Control of sustained or sequential drug
delivery by encapsulated cells in response to external stimuli or environmental
changes can also be brought about by encapsulation [11]. Table 1 provides details
about the commonly applied encapsulation techniques.
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cet
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devi
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cet
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devi
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cet
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devi
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cetal.[13]
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devi
Zuidam and Shimoni [4], Roos and
Livney [12], Ðor
place in a hot chamber with concurrent
evaporation of water
Zuidam and Shimoni [4], Ðor
al. [13]
compound takes place in a cold
chamber after spraying
Zuidam and Shimoni [4], Roos and
´
cetal.[13]
¯
devi
Livney [12], Ðor
particles fluidized by air
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cetal.[13], Sanguansri and
¯
devi
Augustin [7], Jyothi, et al. [3]
Ðor
and freeze-drying under low pressure
Zuidam and Shimoni [4], Ðor
or vacuum
al. [13]
with active compounds after passage
through orifices or extruder
Zuidam and Shimoni [4], Roos and
´
cetal.[13]
¯
devi
Livney [12], Ðor
biopolymer-with-water in oil under
conditions of shear
Zuidam and Shimoni [4], Roos and
Livney [12], Sanguansri and Augustin
aqueous coating and use concentric
[7]
nozzles to press simultaneously water
phase through outer nozzle and oil
Zuidam and Shimoni [4], Ðor
phase through inner nozzle
al. [13], Sanguansri and Augustin [7],
Jyothi et al. [3]
under turbulent conditions along with
actives resulting into three-phase
formation followed by cross-linking
Zuidam and Shimoni [4], Roos and
for increasing stability
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cetal.[13]
¯
devi
Livney [12], Ðor
aqueous phase
Liquid/solid 20–200 10–20 Matrix Solidification of molten core
Method Core Size (μm) Active load (%) Morphology Principle References
Table 1 Encapsulation techniques
Spray drying Liquid/solid 10–400 5–50 Matrix Atomization of core material takes
Spray
cooling/chilling
Solid 5–5000 5–50 Reservoir Coating material is sprayed onto solid
Liquid 1– 1000 1–95 Matrix Mixing the core in a coating solution
Fluidized bed
coating
Lyophilization/freeze
drying
Melt extrusion Liquid/solid 300–5000 5–40 Matrix Extrusion of melt takes place along
Liquid/solid 10–1000 5–50 Various Phospholipids are dispersed in an
Emulsification Liquid 10–1000 20–50 Matrix Gelling agent is added to emulsion of
Co-extrusion Liquid/solid 150–8000 70–90 Reservoir Dissolve active in oil phase, prepare an
Simple coacervation Liquid/solid 20–500 40–90 Reservoir Oil and water emulsions are mixed
Liposome
entrapment
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2.2 Ultrasound in Drug Encapsulation
Ultrasound has been used for decades now in various therapeutic applications
with focus on targeted drug delivery. However, these targeted deliveries based
on cavitation phenomena (acoustic pressure waves bringing about collapse of
gas bubbles due to their oscillations) are not the only advantages of ultrasound
usage [14]. The energy produced by ultrasonic processes was discovered to be
capable of effectively degrading and breaking down biopolymers at a low cost.
Ultrasound has grown into a powerful tool for extracting and modifying different
biopolymers in order to increase solubility, reduce viscosity, and improve yield
in recent years [15]. Ultrasound is also used in the processing stage to prepare
microspheres and microparticles through their integration in various conventional
processes. Ultrasonic spray drying, ultrasonic spray freeze drying, ultrasoundassisted extrusion, and ultrasonic spray polymerization are the main approaches
applied in encapsulation for obtaining microspheres.
Ultrasound (US) is a cyclic sound wave with a frequency above 20 kHz [16],
which creates pressure variations in the medium. The main ultrasound parameters
that affect the characteristics and levels of benefits obtained in varied applications
include frequency, intensity, and duration [17]. Based on the operating frequency,
we can identify three distinct sets of applications in the pharmaceutical industry:
(a) High frequency: A low-energy ultrasound with a frequency of 3–10 MHz that
is typically used to trigger release at specific points in the body, as well as an
analytical methodfor determining physicochemicalproperties like composition,
structure, particle size, and flow rate [18].
(b) Medium frequency:Therapeutic ultrasound with frequency ranging between 0.7
and 3.0 MHz normally used in physical therapy.
(c) Low frequency: A high-energy power ultrasound with frequency in the range
of 20–800 kHz used in various processes like spraying, freezing, extraction,
drying, etc. [17, 19].
To carry out an ultrasonic treatment, various approaches based on different
configurations can be used. However, certain ways of inserting an ultrasonic probe
or submerging in an ultrasonic bath are the most commonly applied ones. Any
ultrasound-based system comprises three parts: generator, transducer, and delivery
system. To drive the transducer assembly, the generator converts the electricity
into the desired alternating current at ultrasonic frequency. The transducer then
converts the current into vibrations. Finally, the vibration is relayed to the ultrasonic
reactor by the delivery system [18]. Ultrasonic systems may result in a better-quality
product, at reduced cost. The costs are lower due to the absence of any moving parts,
which leads to less maintenance needs. The technology is also easy to install and
can be retrofitted easily.
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Ultrasonic Atomization for Spray Drying
Spray drying of biotherapeutics is a well-known technology to enable stabilization
and functionality for drug delivery applications. It helps to improve flow properties,
increase the solubility of poorly water-soluble drugs, and allows drying heatsensitive materials [20]. Evaporation from an atomized feed is accomplished by
combining the spray with the drying medium. It consists of four steps: atomization,
mixing of spray and air, evaporation, and product separation [21]. The atomization
phase involves drying leading to the formation of desired particles with required
physicochemical and morphological properties [22]. The most critical atomizer
characteristics are drop size uniformity, spray homogeneity, and control over
droplet size distribution. However, the heterogeneous distribution of particles as
a result of conventional encapsulation processes results in irregular drug release
characteristics. To avoid this, ultrasonic atomization has been explored in an effort
to produce uniform particles [23].
Ultrasonic atomization is a novel spray-drying technique in which fluid is fedinto
the chamber through an ultrasonic atomizer resulting in the formation of particles
of smaller sizes [21]. Ultrasonic atomization is a robust and a novel single-step
process that has scale-up potential to generate particles with a reasonably uniform
size distribution [24]. It is largely used in the biopharmaceutical and pharmaceutical
industries for spray drying with major advantages such as continuous manufacturing
and formation of particles with uniform particle size and distribution [1]. Process
parameters, liquid physicochemical properties, and equipment parameters are the
factors normally used to accurately obtain the desired product characteristics [2].
The tip of a horn has a small orifice that vibrates ultrasonically in a longitudinal
mode and is used to feed the fluid at a controlled rate, and thus, small droplets of
uniform size can be created [5].
Advantages of Ultrasonic Spray Drying
1. It is a continuous process with good reproducibility and scale-up potential.
2. The obtained particles are uniform and fine resulting in narrow size distribution.
3. Atomization increases the available surface area for the finished product, which
improves mass transfer and diffusion.
4. Due to increased particle surface area and increased contact of particles with
drying air, operation at lower temperatures is possible.
5. Pressurized fluid is not needed, thus minimizing the energy cost of pressurizing
as well as the space for additional equipment.
6. Low velocity atomization decreases the required diameter of drying chamber,
thus lowering equipment cost. Low velocity spray has the added benefit of
reducing material loss due to particle adhesion to the chamber wall.
7. It has a lower shear and thermal stress compared to the conventional nozzles,
thus preserving the chemical and physical integrity of the product.
8. Evaporation rates are higher due to the smaller particle sizes.
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9. The particle density is easily controlled.
10. Large apertures can be used in ultrasonic atomizers to solve the problem of
nozzle clogging.
11. It is easier to maintain and operate.
12. Better retention of quality of bioactive compounds due to shorter particle
residence time [25, 26].
Disadvantages of Ultrasonic Spray drying
Industrial scale operation is limited due to low throughput, heat generation, and lack
of suitable large-scale designs. Some of the disadvantages of the ultrasonic spraydrying process include the following:
1. Ultrasonic spray drying is only applicable to the Newtonian fluids with low
viscosities.
2. The cavitation efficacy of liquids with a higher viscosity is much lower.
3. The ultrasonic spray units require large quantities of hot air for the evaporation
purpose because the decreased pressure is the main driving force for moisture
evaporation.
4. Due to their smaller design and low area of vibrating surface, high-frequency
atomizers have a limited volume handling ability [25].
Principle
The ultrasonic atomization can be achieved by vibrating a liquid layer using
ultrasound transmission into liquid attained using piezoelectric crystal vibrating at
a high frequency. Alternatively, an electromechanical device that consists of two
piezoelectric disks tightened by a support element and a mechanical amplifying
element typically constitutes an ultrasonic atomizer [2]. Normal atomizers use
nozzles based on mechanical energy. However, ultrasonic atomizers use just low
vibrational energy to produce drops.
Pneumatic nozzles have many disadvantages like inability to generate lower
particle size, wide distribution of droplet sizes, partial segregation of the mixture’s
components, irregular surface morphology, structural defects, unsuitable coating
material properties, and clogging problems. Moreover, a correlation can be observed
between the particle size and equipment dimensions. An increase in size will
see a corresponding increase in associated costs due to requirement of larger
equipment. This can be avoided by using ultrasonic energy. Ultrasonic spray drying
improves particle formation and leads to a narrow and homogenous particle size
distribution [2,26]. Liquid atomization attempts to break off liquid into tiny droplets
from the surface of solids by creating disturbances in the normal direction. These
disturbances can be created using various methods. However, if they are induced
using vibrations by ultrasonic energy passage, the process is known as ultrasonic
atomization [25].
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Two kinds of hypothesis have been put forth to explain ultrasonic atomization:
capillary and cavitation. The capillary wave hypothesis is based on the Taylor
instability.The main consideration of this hypothesis is the capillary wave formation
on the vibration surface. These waves are composed of crests and troughs [5].
Typically, during the operation, the first step is the formation of a thin liquid film on
the surface. Atomizers are used to circulate this liquid feed at a desired flow rate.
Ultrasonic vibrations can be obtained due to piezoelectric crystal vibrations at high
frequencies (usually in the 20 kHz to 3 MHz range). During the atomization process,
capillary waves will be formed on the liquid surface. Their wavelength is dependent
on the ultrasound parameters such as frequency of ultrasound, power supplied,
and liquid physicochemical properties. Liquid viscosity, density, concentration, and
surface tension are the main properties deciding the capillary wavelength, which
ultimately decides the size of droplet formed through ultrasonic atomization. When
the vibrations produced are sufficiently higher than the liquid surface tension, waves
will begin to pinch off into small droplets and atomization occurs [2, 25].
The cavitation theory, on the other hand, considers that cavitation in the
liquid film on the surface is responsible for the formation of droplets. It states
that the transmitted wave with its series of compression and rarefaction cycles
results into void formation. As they grow, these droplets expand, grow to a maximum, and collapse immediately when they become unstable. When these cavities
collapse, particularly near the surface, liquid droplets are ejected immediately.
The cavitation hypothesis for atomization is normally applied to high-energyintensity systems. The governing mechanism is also dependent on many factors
like vapor pressure and gas content of the liquid, as well as the presence of
luminescence [2, 5].
Equipment
Ultrasonic atomizers are process intensification instruments as they work at low
velocities and also generate droplets using lower energy thanconventional atomizers
[22]. Under certain volumetric flow rateconditions, the use of an ultrasonic atomizer
can reduce the energy demand by about 10 MJ/m
A typical ultrasonic atomizer consists of a nozzle for spraying, an extended
length for allowing flow, and an ultrasonic generator [23]. A traditional ultrasonic
atomizer consists of a vibrating plate with a concentric hole. Liquid feed enters
through this hole with the help of a centrifugal or a peristaltic pump and spreads
on the surface. There is a need to reduce feed viscosity to prevent clogging in
tubes; a pump aids in this process and allows for uniform and reproducible feeding
[22, 24]. The vibrating plate is connected to a transducer that is powered by an
electric generator which allows the power supplied to the atomizer tip to be varied.
Various frequency generators may also be used to regulate the operating frequency
to obtain a desired shape [27]. As a conventional ultrasonic atomizer runs risk of
blocking immediately after starting the atomization process, a new atomizer with
carrier air design can be used (Fig. 1)[26]. Depending on the application, geometric
3
[5].
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Fig. 1 Schematic diagram of
an ultrasonic atomizer. (1)
Connection for oscillator, (2)
connection for liquid, (3)
connection for carrier air, (4)
protecting cap, (5)
piezoceramic element, (6)
carrier air, (7) actual
atomizer, (8) atomizer jet [26]
parameters like the diameter of the concentric hole or the disk can also be varied
along with operating conditions such as temperature, surface tension, and viscosity
of liquid [2].
Applications
Ultrasonic atomization has been used for processes with feed containing low
viscous Newtonian fluids. The frequency of operating nozzle ranges from 30 kHz
to 2.5 MHz and results in the formation of particles with excellent uniform particle
size distribution and a particle size range of 10–100 microns. Due to lower shear
stress, it can also be employed widely for pharmaceuticals as their degradation is
lowered [25].
Ultrasonic atomization has mainly been utilized in pharmaceutical manufacturing to explore encapsulation techniques for drugs or altering distribution profiles
with the aim of creating novel drug delivery systems [2]. Various techniques like
coaxial ultrasonic atomization have also been explored for drug encapsulation [23].
Because of the rapid evaporation of the solvent, the temperature of the droplets can
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be held far below that of the drying air, making spray drying ideal for use in both
heat-sensitive and heat-resistant materials [21].
As a specific example, it can be mentioned that darbepoetin alfa, a synthetic type
of glycoprotein hormone that regulates red blood cell development, was effectively
encapsulated using ultrasonic atomization. Particle production using ultrasonic
atomization was found to depend on various parameters like feed flow rate, atomization strength, and form of polymer material. Ultrasonic nozzles were capable
of producing droplets of comparable median diameter, around 60 μm or less. The
encapsulation efficiencies observed were near 100%. Moreover, it was shown that
using ultrasound made the process more robust and reproducible. The synthesized
microspheres also reflected excellent physical and chemical characteristics [2]. In
another study, it was reported that as compared to atomization using two-fluid
nozzles, ultrasound atomization produced higher yields, ranging from a 62% to 77%
increase in absolute yield for zirconia to a 47% to 78% increase in absolute yield
for ZTA [27]. As another example, Paiva et al. reported collection of about 60% of
the atomized feed over the membrane in a dried powder form using the ultrasound
spray-drying system. Further, it was found that the product particles were spherical
in shape with a diameter size distribution of 0.2–2.6 μm. The mean diameter was
found to be about 1.7 μm[21].
Ultrasonic Spray Freeze Drying
Ultrasonic spray freeze drying (USFD), a combination of spray drying and freeze
drying, is a newly developed technique used in a diverse range of applications
like for the development of drug delivery systems [28]. It is also referred to as
lyophilization and is the sublimation process of a frozen solvent (usually water)
under reduced pressure. Since it uses a low processing temperature, this method
is ideal for heat-sensitive and perishable materials [29]. This method can produce
microparticles with a distinctive internal structure and a large specific surface area,
which is highly desirable [30].
The steps involved in this process are atomization, rapid freezing, and lyophilization. It works by trapping the solute in a frozen droplet before lyophilization. The
rapid freezing step decreases the amount of solute diffusion, which reduces the
probability of particles (nano/micro) aggregating [31]. Thus, spray freeze drying
has more advantages than spray drying as it results in lesser particle aggregation. It
also has other advantages such as uniformity and greater flexibility of controlling
particle size and density. It is the most commonly used method for producing stable
dry powders of biologics in industry, but it is a time-consuming, complex, and
expensive batch process that necessitates a significant financial expenditure due to
the requirements of cryogenic facilities. Thus, one should assess the process based
on the added advantages obtained for the specific application in question [31].
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Advantages
As compared to methods like spray drying or freeze drying, spray freeze drying
especially using ultrasonic nozzles has the following advantages:
• Lower temperatures for reduced drying.
• Ability to process extremely heat-sensitive products.
• High process efficiency (yield greater than >90%).
• Particle characteristics can be finely regulated.
• Highly porous particles.
• Processing time is significantly lower.
• It promotes instant rehydration.
• Controlled particle size distribution.
• Particles have high specific surface area.
• Particles retain their spherical shape throughout.
• Excellent compatibility with a variety of excipients and biopharmaceuticals.
• It enhances the apparent solubility of poorly water-soluble drugs.
• Minimization of phase separation between drug and excipients owing to the
ultrafast freezing process [28, 32, 33].
Disadvantages
Almost all spray freeze-drying approaches are still experimental and scaled only
for laboratory purposes. This is true for ultrasonic spray freeze-drying process too.
Industrial and regulatory aspects such as process qualification, scale-up and scaledown potential, and good manufacturing practice have seldom been discussed [33].
Method
The main steps involved in the spray freeze-drying (SFD) process are spraying,
freezing, and drying.
(a) Spraying: Dispersion of bulk liquid solutions into droplets.
(b) Rapid freezing: Droplets solidify as they come into close contact with a cold
solvent.
(c) Lyophilization: Sublimation drying of the frozen material at a very low temper-
ature and pressure [33].
The main concept behind the spray freeze-drying process is to decrease the
drying time. This is done by rapid atomization of a liquid by passing into a low
temperature zone that is maintained normally with cryogens (e.g., liquid nitrogen).
Following this, the frozen particles are sublimated under atmospheric pressure.
This is brought about by a reduction in product dimensions, which leads to an
improvement in heat and associated mass transfer, thus reducing freezing and
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