Detailed Description of Application of ultrasound in pharmaceuticals and food industry (with examples). Reference: Chen, D., Sharma, S.K. and Mudhoo, A. eds., 2011. Handbook on applications of ultrasound: sonochemistry for sustainability. CRC press.

1. ApplicationofUltrasoundin
Pharmaceuticals&Food
Industry
--ByRunjhunDutta

2. Reference
HandbookOnApplicationsOfUltrasound
EditedByDongChen|SanjayK.Sharma|AckmezMudhoo
SonochemistryforSustainability
Chen, D., Sharma, S.K. and Mudhoo, A. eds.,
2011. Handbook on applications of ultrasound:
sonochemistry for sustainability. CRC press.

3. CONTENTS
ApplicationsofSonochemistryin
PharmaceuticalSciences
Robina Farooq
UltrasoundinFood
Technology
Taner Baysal and Aslihan
Demirdoven
Chapter5 Chapter8

4. Applications of Sonochemistry in
Pharmaceutical Sciences

5.  Pharmaceutics is a discipline of pharmacy that deals with all facets of the process to turn
new chemical entity (NCE) into proper medication.
 It deals with the formation of a pure substance into dosage form such as capsule,
injection, suppository, cream, ointment, eyedrop, inhaler, nasal spray, etc.

6. Extraction
Synthesis
of Drugs
02
Extraction
Ultrasound-
induced
Polymerizati
on &
Depolymeriz
ation
Photo-Acoustic
EvaluationofPharmace
uticalTablets
AnUltrasonicDrivenPowder
TransportSystem
Effect of Sonocrystallization in
Formation of Aerosols
Enzymatic And Microbial Inactivation
Transdermal
Drug Delivery
Ultrasound in
Pharmaceutical
Sciences

7. An Ultrasonic Driven Powder Transport
System
 The transport and dosage of granular materials are
important components of process engineering.
 The most accurate mixing process in chemical,
pharmaceutical, and food industries demands for an
exact control of powder feeding.
 A novel powder-feeding device is developed at the
Heinz Nixdorf Institute and is based on
piezoelectrically excited traveling waves suggested
by many workers on this principle.
 An acrylic pipe, which is stimulated to oscillations in
the form of traveling waves through piezoelectric
impulses, is used to convey the powder.

8. Mracek and Wallaschek (2005)
 A piezoelectric actuator is normally used for generating a progressive wave in an acrylic pipe.
 The acrylic pipe has specific damping properties that allow the excitation of a progressive flexural radial wave in
a pipe, using only a single piezoelectric actuator.
 An ultrasonic driven powder transport system was developed by Mracek and Wallaschek (2005), in which the
wave stimulation and expansion pipes are constructed from relatively strongly absorbing materials.
 The movement of a progressive wave in the acrylic pipe and especially the desired movement of the surface
points are essential for a powder transport .
 The developed ultrasonic driven powder system distinguishes itself from conventional dosage systems due to
simple structure, nearly no wear and tear in operation, cost-effective, and easy to integrate into existing
production plants.
 The technology also allows miniaturization, operation in the low voltage area, and a very careful, exact dosage.
 The experimental investigations of this prototype for ultrasonic powder feeding showed that it is possible to
feed small amounts of powder with extremely high quantitative accuracy.
 But it was also confirmed experimentally that the performance of this system, like most piezoelectric systems,
showed a significant sensitivity concerning environmental conditions (e.g., temperature, aging, load influence of
the outside, production inaccuracies).
 Therefore, ultrasound-driven powder-feeding system can be used for very accurate measurements and
movement of materials for the preparation of drugs.

9. Effect of Ultrasound on Synthesis of Drugs
 The advantages of ultrasound in chemical reactions, shorter reaction
time and higher yields, can be used in industrial application in
pharmaceutical or fine chemical industry.
 Sonochemistry can be used for fast reactions or in the synthesis of
expensive products.
 Scale-up problems can be solved with the aim to develop a
technically feasible process.
 Development of process technology (reactor design, process
simulation) is necessary.
 The most important factor is the establishment of a commercialized
process . Many studies on the effect of ultrasound on the synthesis of
drugs have been carried out and it is well documented.
 The interaction between ultrasound energy and the vibrational and
electronic levels of molecules is an indirect phenomenon.

10. EXAMPLES
This application of ultrasound in the dehydration process was tested with other
amides. It was found that in these reactions amides could be dehydrated to the
corresponding nitriles in good yields and in a shorter reaction time (Aquino et al,
1998).
In 1984, Ando and coworker published a paper about reaction of benzyl bromide and
alumina supported potassium cyanide in toluene. This is the example that ultrasound
irradiation induces a particular reactivity leading to products differing in nature from
those obtained conventionally and is called sonochemical switching (this scheme can
synthesize with 61% yield in a shorter reaction time).

11. Ultrasound-induced Polymerization & Depolymerization
 The chemical effects of ultrasound include the formation of radicals and the enhancement of reaction rates at ambient
temperatures. The enhanced dissolution of a solid reactant or catalyst caused by renewal of the liquid at the solid–liquid
interface illustrates a mechanical effect induced by ultrasound.
 The formation, growth, and collapse of a cavity occur in 0-1 ms. The implosions of these cavities generate temperatures and
pressures of approximately 5000 K and 200 bar, respectively. The possibility of cavitation at high pressures creates several
interesting potentials in the development of ultrasound-induced chemical processes, such as, precipitation polymerization in
CO2, bulk ethylene polymerization, phase-transfer catalysis in liquid by using ultrasound.

12. MECHANISM
 It is possible to carry out radical polymerizations without the addition of initiator or catalyst. However, the
obtained yield for a bulk polymerization is rather low as a result of the increase in viscosity. A high viscosity
hinders cavitations and consequently the production of radicals. In order to overcome this conversion limitation,
precipitation polymerization can be a solution .
 Two types of precipitation systems are used in the high-pressure setup; systems in which the monomer acts
as reacting species and as anti-solvent for the polymer, e.g., ethylene systems in which carbon dioxide is
applied as anti-solvent, e.g., methyl methacrylate with carbon dioxide besides polymerization, depolymerization
also occurs through irradiation with ultrasound.
 Under sufficiently strong flow conditions around a cavitation bubble, the solvent drag force causes extension
of the polymer molecule. If the drag force on the stretched polymer molecule is larger than the bond
strength of the polymer, scission will occur. This scission will preferably occur in the middle of the chain.
Ultrasound-induced precipitation polymerization enables the production of well-defined polymers (MWD)
without conversion limitations used in many processes like pharmaceutics.

13. Role of Ultrasound in Extraction
 The ultrasonic extraction can shorten the extraction time from 24 h to <20 min as compared with the conventional cold
extraction technique.
 Solvent consumption is six times lower in ultrasonic extraction in contrast to similar conventional extraction methods.
 Ultrasound was also used to increase the extraction efficiency.

14. EXAMPLES
1. Carnosic acid extracted from the herb Rosmarinus officinalis using butanone, ethyl acetate, and ethanol as
solvents. Similarly, specific examples of the benefits include the extraction of tea solids from dried leaves with
water, using ultrasound and thus giving an improvement of almost 20% in yield at 60°C, approaching the
efficiency of thermal extraction at 100°C. A reduction in the maceration time from 8 h to 15 min has been
reported in the extraction of the alkaloid reserpine from Rawolfia serpentina . The efficiency surged in extracting
pharmacologically active compounds from Salvia Officinalis with some 60% of the target compounds extracted
within 2 h at ambient temperature.
2. Ultrasound is a reliable tool for the fast extraction of nicotine in pharmaceutical formulations. In order to extract
nicotine from the pharmaceutical formulations, the ground chewing gum sample, or small pieces of transdermal
patch was placed in 15 mL glass vial containing 10 mL heptane and sonicated for 20, 40, and 60 min at 37°C in
the ultrasonic bath. The results indicated that the recovery of nicotine enhances with increased sonication time.
The complete extraction of nicotine was obtained in <20 min from the transdermal patch and 60 min from the
chewing gum. Ultrasonic extraction reduced the extraction time from 24 h to <20 min in comparison with the
use of conventional cold extraction technique.

15. Photo-Acoustic Evaluation of Pharmaceutical Tablets
 With ultrasound In photo-acoustics, the ultrasound is generated by means of pulsed laser illumination.
 Normally, photo-acoustical methods are used in applications where a touching ultrasonic transducer
would damage the sample or it itself would be damaged. This can be the case with porous and
hygroscopic systems, e.g., pharmaceutical tablets, where the use of a coupling liquid would be
detrimental to the structure of the tablets.
 Despite its low efficiency in producing ultrasound, the so-called thermoelastic regime is attractive in
many applications, because the phenomenon is nondestructive to the samples and the theory of such
nondestructive testing is well-established.
 Variations in porosity, density, and sodium chloride content of microcrystalline cellulose tablets were
found to be related to parameters extracted from the through-transmitted ultrasonic wave forms.
 By using the amplitudes and ultrasonic velocities of these wave forms, it was possible to obtain values
of a transverse to longitudinal amplitude ratio, and also elastic parameters. The transverse to longitudinal
amplitude ratio and the amplitudinal Poisson’s ratio (Poisson’s ratio is a measure of the simultaneous
change in elongation and in cross-sectional area within the elastic range during a tensile or compressive
test) were indicative of structural variations, e.g., changes in the porosity and the sodium chloride
content of tablets.
 Changes in mechanical structure can affect the physical and biopharmaceutical properties, and in some
cases even the chemical stability, of pharmaceutical tablets.

16. Effect of Sonocrystallization in Formation of Aerosols
 Sodium chloride aerosols have been widely used as part of bronchial provocation tests to identify people
with active asthma and exercise-induced asthma and those who wish to enter particular occupations (e.g.,
police, army) or sports (e.g., diving). It has become practical to prepare dry NaCl powder that can be
delivered using dry powder inhalers (DPIs) instead of traditional nebulizers.
 Preparation of traditional nebulizers is energy intensive and time consuming and can induce impurities into
the product. It also has several other disadvantages including inadequate control of particle size, undesired
particle shape, surface charge modifications, decreased crystallinity, and possible chemical degradation. These
disadvantages of the micronization process ultimately jeopardize the NaCl powder performance.
 Sono-crystallization offers several advantages including production of smaller sized crystal as compared to
conventional crystallization as well as cost-effectiveness of apparatus. The process can be run at ambient
conditions and the reaction vessel involved is of simple geometry, making the cleaning process simple for
the pharmaceutical requirements.
 Another important advantage is that crystal growth occurs at lower supersaturation levels, where initial
growth is controlled; the size distribution of the products is narrower than uncontrolled conventional
crystallization process.
 The limitations of conventional crystallization techniques in the processing pharmaceutical ingredients for a
number of dosage forms typically require the need for micronization.

17. Application Of Ultrasound In Transdermal Drug Delivery
Transdermal drug delivery offers several advantages over traditional drug delivery systems such as oral delivery
and injections—the attractive attributes of transdermal drug delivery includes avoidance of first-pass
metabolism, elimination of pain that is associated with injection, and the opportunity for the sustained release
of drugs.
However, the efficiency of transdermal transport of molecules is low because the stratum corneum of the
human skin is an effective and selective barrier to chemical permeation . Indeed, the low permeability of the
stratum corneum is the key reason that only a small number of low molecular weight drugs are currently
administered using this route. The mechanisms are developed for the transdermal transport of drugs at low
frequency ultrasound .
In vitro permeation enhancement of several low molecular weight drugs under the same ultrasound conditions
is reported . It is hypothesized that since the absorption coefficient of the skin varies directly with the
ultrasound frequency, high-frequency ultrasound energy would concentrate more in the epidermis, thus leading
to higher enhancements.
They found that a 20-min application of ultrasound (0.2 W per square cm) at a frequency of 2 MHz did not
significantly enhance the amount of salicylic acid penetrating the skin. However, 10 MHz ultrasound under the
same conditions resulted in a 4-fold increase and 16 MHz ultrasound resulted in about a 2.5-fold increase in
transdermal salicylic acid transport.

18. Ultrasonic Irradiation of Toxic Effluent
In recent years, considerable interest has been shown on the application of ultrasound for hazardous chemical
destruction, including among others the degradation of chlorinated hydrocarbons, aromatic compounds, pesticides,
explosives, dyes, and surfactants.
Sonication is a process wherein ultrasound waves are irradiated into a liquid medium to destroy the contaminants.
Examples
1. The effect of ultrasound power density and power intensity on the destruction of various estrogen compounds that
include 17α-estradiol, 17α-estradiol, estrone, estriol, equilin, 17α-dihydroequilin, 17α-ethinyl estradiol, and norgestrel were
conducted in single component batch and flow-through reactors using 0.6, 2, and 4 kW ultrasound sources. The
sonolysis process produced 80%–90% destruction of individual estrogens at initial concentration of 10 μg L−1 within
40–60 min. The estrogen degradation rates increase with increase in power intensity of ultrasound.
2. The degradation of triphenylphosphine oxide (TPPO) in water, a toxic compound typically found in effluents from the
pharmaceutical industry by means of ultrasonic irradiation at 20 kHz.

19. CONCLUSION
Advantages of Ultrasound in Pharmaceuticals
 Shorter reaction/preparation time
 Reduction of the sample preparation time
 Usage of small amounts of material
 Efficient and minimum expenditure on solvents &
reagents
 Increasing of the sample throughput.

20. Extraction
Filtration
02
Viscosity
Separation
Emulsion
Crystallization
Antifoaming Action
Fermentation
Enzymatic And Microbial Inactivation
UltrasoundinFood
Technology

24. US Application During Food Processing
 US results in permanent changes in food materials in
liquid systems through cavitation.
 US activates microorganisms and enzymes to preserve
or decontaminate foods, particularly when US is
combined with heat and high-pressure techniques.
 An increasing number of industrial processes utilize
US to aid in the process of mixing materials, form
foams and agglomerates, precipitate dust, improve
filtration efficiency, dry products, and extract solid
materials and bioactive compounds from vegetables
and food.
 US technology can replace traditional sanitization
methods
 US does not alter the organoleptic properties of foods.

25. US is considered an emerging and promising technology in
the food processing industry, since it produces permanent
mechanical, chemical and biochemical changes in liquids
(due to intense cavitation) and gases (for the generation of
high intensity acoustic fields) on the processes of
homogenization, mixing, extraction, filtration,
crystallization, dehydration, fermentation, and degassing
through its antifoaming actions, reduction of particle sizes,
temporary or permanent modifications of viscosity,
modulation of the growth of living cells, cell destruction and
dispersion of aggregates, inactivation of microorganisms and
enzymes, and sterilization of equipment.
US in Food Processing

26.  The interaction of the acoustic energy with a food mainly occurs
through a liquid medium since the cavitation and the physical and
chemical actions induced by US play an important role in the
changes in the quality of a food during its transformation.
 Indeed, the implosion of bubbles creates an unusual substrate for
chemical reactions by mechanically breaking the cell envelope and
improving the transfer of intracellular material.
 At the solid and liquid interface, even the water jet formed by
transient cavitation might contribute to some changes in the global
properties of a food product.
 All the chemical and physical effects of US are microscopic;
however, the interactions of these chemical and physical reactions
induced by cavitation with the food manifests itself through
macroscopic changes that are perceived by the consumer in terms
of consistency, colour and flavour.
USincompositionalanalysisoffoods

27. High-frequency/low-energy US (diagnostic US) is mainly used as an analytical
technique for quality control and processing steps, and for non-destructive
inspection that has been applied to determine the concentration, viscosity, and
composition of food, among other parameters.
The application of high energy/intensity US (US power) improves the quality
of processed foods and results in characteristics similar to the fresh product
(colour, consistency, flavour, and nutrients).

28. THANK YOU