Introduction Drug delivery techniques for pulmonary administration Manufacturing Techniques and process Formulations of Aerosol solutions or suspensions Propellants Important characteristics New Aerosol Technologies Summary

1. Presented by : Zerlealem Tsegaye
Date: July 19, 2021
Review of manufacturing
techniques, process and
technology: Aerosols
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2. Presentation Outline
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 Introduction
 Drug delivery techniques for pulmonary administration
 Manufacturing Techniques and process
 Formulations of Aerosol solutions or suspensions
 Propellants
 Important characteristics
 New Aerosol Technologies
 Summary

3. Introduction
 Aerosols have been defined as colloidal systems consisting of
very finely subdivided liquid or solid particles dispersed in and
surrounded by a gas.
 Commercialization of inhaled respiratory medicines was not
achieved until 1948, when Abbot Laboratories developed the
Aerohaler for inhaled penicillin G powder
 Then it was revolutionized the field in 1955 with the advent of the
pressurized metered dose inhaler (pMDI).
 These MDls quickly became the dosage form of choice for
inhalation therapy, especially for the treatment of asthmatics
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4. Introduction
 The review mainly discusses the manufacturing
techniques and process of Aerosols
 It provides information with respect to the drug
delivery devices for pulmonary administration and
available propellants.
 It provides an overview of currently available new
technologies of Aerosols.
 The most important characteristics that should be
taken care of in case of the pulmonary delivery
system are also discussed
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5. Drug delivery techniques for
pulmonary administration.
The three most commonly used delivery devices for
pulmonary administration
 Pressurized metered-dose inhalers
 Dry powdered inhalers
 Nebulizers
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6. Manufacturing Techniques
Milling
 Milling is a critical unit operation to prepare drug
particles for delivery by inhalation.
 It is described as a process where mechanical
energy is applied to physically break down coarse
particles into finer particles.
 In the typical production of an inhalable drug, bulk
active pharmaceutical ingredient crystals
obtained from a crystallization process are
filtered, dried, and micronised to the desired
particle size.
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7. Manufacturing Techniques
Milling
 The milling equipment required for micronization is
different from those that are commonly used for
routine comminution, which generally produce
particles larger than 10 µm and of relatively wide size
distributions.
 Compared to powders used for other solid dosage
forms, the critical physicochemical attributes of
inhalable particles are substantially different.
 For example, the aerodynamic diameter and
surface morphology of drug particles may influence
the DPI performance greatly.
 On the other hand, flowability of inhalable particles
meant for a carrier-based formulation is not as critical
compared to that of powders used in direct
compression of tablets.
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8. Manufacturing Techniques
Milling
 The two main types of mills used are
 Ball mills
 Fluid-energy mills, such as the jet mill, which is a well-established
technique used to manufacture dry powders for inhalation.
 Jet milling is the most useful technique; it reduces particle
size via high velocity particle–particle collisions.
 Unmilled particles are introduced into the milling chamber.
 Air or nitrogen, fed through nozzles at high pressure,
accelerates the solid particles. The particles collide and
fracture.
 While flying around the mill, larger particles are subjected to
higher centrifugal forces and are forced to the outer
perimeter of the chamber. Small particles exit the mill
through the central discharge stream.
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9. Manufacturing Techniques
Milling
 A ball mill is essentially a rotating cylinder loaded with
drug and “milling media” (i.e., balls that grind the drug
between each other as they tumble inside the mill).
 Ball milling is very slow and the process is poorly
scalable, which is why tumbling-ball mills are only
used for laboratory-scale.
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10. Manufacturing Techniques
 Other techniques for making micron-sized particles
involve spray drying and supercritical fluid (SCF).
 These important approaches allow the production of
particles with controlled and appropriate size and
shape.
 These techniques are distinctly different from milling
in that the particles are built up (i.e., particle size is
increased) whereas particle size is decreased
during milling.
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11. Manufacturing Techniques
Spray drying
 Spray drying is a one-step process that converts a
liquid feed to a dried particulate.
 The feed can be a solution, a coarse or fine
suspension or a colloidal dispersion (e.g.,
emulsion, liposome, etc.), which is first atomized to
a spray form that is put immediately into thermal
contact with a hot gas, resulting in the rapid
evaporation of the droplets to form dried solid
particles.
 The three fundamental operations of the spray
drying process are atomization, drying and
separation.
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12. Manufacturing Techniques
Spray drying
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 The design may be “open cycle”, where the drying
gas (usually air) is not recirculated and is vented to
the atmosphere.
 When spray drying from organic feeds, a “closed
cycle” layout is more suitable than an open one since
the risk of flammability and explosion is higher in the
latter when organic solvents are heated in the
presence of oxygen.
 In the closed cycle design, the heated gas, which is
usually nitrogen with less than 5% oxygen, is
recirculated, and a condenser is employed to convert
organic vapors to the liquid state 3/3/2024

13. Manufacturing Techniques
Spray drying
 Once the liquid is atomized, droplets dry to solid particles
through intimate contact with heated gas in the drying
chamber.
 The important drying variables are inlet and outlet
temperatures, the drying gas medium, gas humidity,
gas flow rate and residence time, which all together
affect the final size, shape, density, crystallinity and
residual solvent content of the particles.
 To avoid agglomeration in powders, the humidity of the gas
medium must be sufficiently low, especially for hygroscopic
materials.
 In the case of an organic feed, the vapor must be removed
to reduce the residual solvent to pharmaceutically
acceptable levels.
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14. Manufacturing Techniques
SCF
 Its critical temperature makes SCF suitable for
processing heat-labile solutes at conditions close
to room temperature.
 The three main SCF processes are
 precipitation from supercritical solutions composed
of supercritical fluid and solutions (RESS),
 precipitation from gas saturated solutions (PGSS)
 precipitation from saturated solutions using
supercritical fluid as antisolvent (SAS).
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15. Manufacturing Techniques
SCF
 RESS involves dissolving the drug in a SCF
followed by rapid expansion of the fluid solution
across a heated orifice to cause a reduction in the
density of the solution, thereby decreasing the
solvation power of the fluid which leads to
precipitation of the drug.
 PGSS the SCF is dissolved in molten solute and
the resulting supercritical solution fed via an
orifice into a chamber to allow a rapid expansion
under ambient conditions.
 SAS relies on the capacity of an SCF to act as an
antisolvent is the most common method and
different variants of the technique have been
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16. Manufacturing Techniques
SCF
 The high solubility of carbon dioxide in organic solvents leads to
volume expansion when the fluids make contact.
 This leads to reduction in solvent density and parallel fall in
solvation capacity.
 Such reduction causes increased level of supersaturation, solute
nucleation and particle formation.
 In this process, the SCF is added to the particle formation vessel
that contains the drug solution of interest.
 The drug precipitates during the dissolution of the SCF in the
solvent.
 The SCF is generally introduced through the bottom of the
vessel and bubbled through the solution to achieve better mixing
of the solvent and antisolvent. Once the drug has precipitated
out, the solvent–SCF can be removed
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17. Manufacturing Techniques
 All three techniques allow production of inhalable
particles with a significant increase in Fine
particle fraction compared to jet-milled products.
 Anti-asthmatic drugs such as budesonide,
fluticasone, salmeterol, albuterol, terbutaline,
fenoterol and peptides such as insulin and
cyclosporine have been successfully produced by
SCF technology
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18. Manufacturing process
Blending of Powders for Inhalation
Blending can occur by three main mechanisms: convective, shear,
and diffusive blending
 Convective (or macro-) blending occurs when large fractions of
powder move randomly in the blender aided by a rotating blade
or tumbling action.
 Diffusive (or micro-) blending occurs when individual particles
move randomly to create a statistically uniform mixture at the
scale of several particles.
 Shear blending results from the forced movement of one layer of
powder over another due to velocity gradients.
 In mixtures containing free-flowing powders of similar particle
size and density, convective and diffusive blending in a low shear
blender can produce a sufficiently blended mixture.
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19. Manufacturing process
Blending of Powders for Inhalation
 Blending equipment may be classified based on their input
of blending energy as low shear, medium shear, or high
shear blenders.
 Examples of low shear blenders include the tumbling,
planetary, double cone, conical screw, and ribbon types of
blenders.
 The blender fill ratio, rotation speed, and blending time are
critical parameters of rotating blenders.
 High shear blenders are normally equipped with variable-
speed agitators which rotate in the powder bed and the
critical parameters include blender fill ratio, agitator speed,
and blend time.
 Each blender has its own predominant blending
mechanism and should be selected based on factors such
as processing time, degree of blend uniformity achievable,
and aerosolization performance after blending.
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20. Formulations Aerosol solutions or suspensions
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 Marketed respiratory solutions are generally
composed of drugs dissolved in aqueous, isotonic
solvent systems that may contain preservatives to
reduce microbial growth.
 preservatives, such as phenol and bisulfite, which can
contribute to airway irritation, coughing and
bronchoconstriction.
 In addition to an unpleasant taste, phenol is a
neurotoxin and is listed by the National Institute for
Occupational Safety and Health as being
occupational exposure hazard.
 To enhance chemical stability, sodium bisulfite and
ethylenediaminetetraacetic acid (EDTA) are
authorized in various preparations. Nevertheless, they
are both known to cause bronchoconstriction. 3/3/2024

21. Formulations Aerosol solutions or
suspensions
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 Sodium chloride (NaCl) and other salts are widely used to
adjust the osmolarity of solutions to approximately 300
mosmol/l.
 Attention must also be paid to the pH of the formulation
because, unlike the gastrointestinal tract, the lungs have
limited buffering capacity.
 Therefore, HCl, NaOH, citric acid, phosphates and
trometamol are commonly used to adjust the pH of the
solution to neutrality.
 Accepted surfactants such as polysorbates and sorbitanes
are generally present to aid dispersion or dissolution of the
drugs.
 A cosolvent such as ethanol may be used only in small
amounts because of alcohols’ propensity to irritate the
lungs. 3/3/2024

22. Propellants
 The propellant generally is regarded as the heart
of the aerosol package.
 In addition to supplying the necessary force to
expel the product, the propellant must also act as
a solvent and diluents and has much to do with
determining the characteristics of the product as it
leaves the container.
Types
 Liquefied gases
 Compressed Gases
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23. Important characteristics that should be
taken care
 Physical stability
 pH
 Osmolarity
 Viscosity.
 Size of the particles in aerosols
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24. New Technology
Technological advances in nebulizers
 The advancement includes
 Breath-enhanced
 Breath-actuated,
 Vibrating mesh nebulizers.
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25. New Technology
Technological advances of pMDIs
 Breath-actuated
 Coordination devices.
Spacers
Valved holding chambers (VHCs)
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26. Summary
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 The selection of the delivery device is a very significant
parameter in formulation design and is based on the desired site
of administration in the respiratory tract.
 The most important characteristics such as particle size,
viscosity, pH and physical stability should be taken care of in
case of the pulmonary delivery system.
 Milling and blending, spray dying and SCF are different
techniques and processes for the aerosol preparation.
 Each blender has its own predominant blending mechanism and
should be selected based on factors such as processing time,
degree of blend uniformity achievable, and aerosolization
performance after blending.
 Continued experimentation and optimization of milling and
blending processes will allow to improve manufacturing and
product performance.
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Thank you