Scale up of liquid orals

PILOT PLANT SCALE-UP FOR LIQUID ORALS
GUIDED BY
Dr.Mahalaxmi Rathnanand
Associate Professor
Dept. of Pharmaceutics
MCOPS, MAHE
SUBMITTED BY
Vignesh Saravanan
Roll no: 190617005
MPHARM Industrial Pharmacy
SEM-II

Liquid orals
Liquid orals are the liquid dosage formulations
containing one or more active ingredients with or
without additives dissolved in a suitable vehicle meant
for oral administration.
INTRODUCTION
 Liquid dosage forms may be dispersed systems or solutions.
 In dispersed systems there are two or more phases, where
one phase is distributed in another.
 Viscous liquid generally shows a tendency to undergo
improper mixing by conventional impellers.
 Non-Newtonian liquids exhibit variability in the viscosity
due to the shear imparted by the impeller, this gradual
change in viscosity affects the mixing efficiency.
 Basically, the initial forces imparted to the viscous system
during the mixing process tend to dissipate quickly, Hence
adequately designed mixing equipment are needed for
efficient mixing of highly viscous liquids

Steps of liquid manufacturing process
1. Planning of material requirements
2. Liquid preparation
3. Filling and Packing
4. Quality assurance
SOLUTION:
A solution refers to two or more substances mixed homogeneously or
Homogenous mixture that is prepared by dissolving a solid and liquid
and represents a group of preparations in which the molecules of the
solute or dissolved substance are dispersed.
Scale up Parameter to be considered
1. Tank
 Material of the tank must not be additive to the product.
 Shape & size of the equipment must be selected according
to the batch size.
 In lab scale - flask/beakers are use
 In large scale- tanks (capacity-100 to 10000L) material-
polished stainless steel of different grades.
 Tanks are usually constructed of polished stainless steel
of different grades.
 Height of the filled volume in the tank should be precisely
maintained.

 For most mixing applications the ideal liquid level to tank
diameter ratio is 0.8, however, any ratio that is close to 1-to-
1 is sufficient.
 A ratio thatis too small does not allow proper axial mixing
in the tank. Anything less than a 0.6 ratio should be
avoided.
 Adequate clean up procedures developed.
 Passivation of SS (pretreating the SS with acetic acid or
nitric acid solution to remove the surface alkalinity of the
SS).
2. Mixing
 Factors considered
 Impeller type-radial flow for immiscible liquids & axial
flow impeller is for homogenization process.
 Impeller diameter-size should be relevant to the
production size process.
 Rotational speed of the impeller- low speed gives better
performance.
 Number of impellers-effectof number of blades depends
on the viscosity of the fluid, 3-7 impeller blades improves
the performance.
 Number of baffles-it affects the flow pattern & pressure
drop of the solution.
 Mixing capability of impeller.
 In lab scale- mixing is achieved by magnetic stirrers or by
simple hand-shaking.

 In large scale- Impellers, Air-jets, Fluid-jets and Baffle
mixers
 Simple mixing is essential to increase the flow of the liquids.
 If the liquid is of high viscosity, high electrical stirrer may be
used.
 But at high viscosity there is a chance for air entrapment.
 Air entrapment can be minimized by reducing the agitator
speed or by carrying out the mixing in a closed tank under
vacuum.
 Other alternative is the use of versator.
 Addition of ingredient in proper order have vital importance.
 The Z blade or sigma blades are specialized impellers
used to promote mixing in the region closer to the wall of
the mixing tank along with the narrow clearance between
the impeller blades and the wall of the mixing tank to
obtain maximum mixing efficiency.
 Problems: improper mixing
3. Filtration equipment (should not remove active or adjuvant
ingredients)
 During the pilot run the clarity of the filtrate should be
checked periodically in order to establish schedule for
changing the pads, cakes or cartridges depending on the
type of filtration employed.
 In filtration, filtration pads are used which is made up of
asbestos or cellulose.
 In lab scale- gravity & suction filters

 In large scale- vacuum filters, the plate & frame filter press
 Problems: precipitation, clogging of filter
4. Transfer & filling
 Filling is an important parameter in the transfer of liquid
from to tank or container.
 New batch should not be started until the previous batches
are completely filled & the tanks are emptied
 The rate and amount of fill is controlled by the size of the
stem orifice
 The volume of product delivered into the container is
determined by the volume of the filling chamber in which
the piston is operating.
 This volume can be changed by adjusting the length of the
piston’s stroke.
 Selection of equipment depends on viscosity, type of
packaging & surface tension.
 Lab scale- funnel & measuring cylinder
 Large scale- Gravimetric filling, Volumetric filling,
Constant volume filling
 Problems- Inaccurate filling levels, foaming & dripping
 Selection of equipment depends on viscosity, type of
packaging & surface tension.

SUSPENSION:
A pharmaceutical suspension is a coarse dispersion in which
internal phase (therapeutically active ingredient) is dispersed
uniformly throughout the external phase.
Parameters to be considered:
 Addition and dispersion of suspending agents (Lab scale
– sprinkling method & Production scale – vibrating feed
system) suspended drug particles should not settle rapidly
thereforesuspending agents are added, they must not be too
viscous to pour it from container,the particles that settle to
the bottom of container must not form a hard cake and
should be redispersed homogenously upon shaking the
container. Dispersion produced by colloidal mill or an
immersion homogenizer.
 Hydration/Wetting of suspending agent: the use of
wetting agent allows removing the air from the surface and
to easy penetration of the vehicles into the pores.
 Time and temperature required for hydration of
suspending agent: If heat is used during the manufacture,
care must be taken during the cool-down of the product to
prevent settling. Increase in temperature for hydration of
suspending agents causes moisture loss, physical and
chemical instability. Increase in time of hydration causes

optimum moisture loss. So time and temperature should be
maintained throughout the process.
 Mixing speeds (High speed leads to air entrapment): this
should be considered while formulating suspension, mixing
speed should be maintained at same rpm throughout the
process and mixing speed should be optimum to avoid air
entrapment, and avoid agglomeration.
 Versator: During manufacture of suspensions, care must
be taken to get the drug suspended properly without the
incorporation of excess air, which can affect not only the
viscosity of the finished product but also the dispensing of
the correct amount of drug, hence Versator is used to
remove entrapped air.

 Mesh size: the one which is chosen must be capable of
removing the unwantedforeign particulates but should not
filter out any of the active ingredients such a sieve can
only be selected based on production batch size trials.
Size ranges from - submicron to 100 μm.
EMULSION:
Emulsion is the thermodynamically unstable system consisting
of at least two immiscible liquid phases, one of which is
dispersed as globules in other liquid phase, stabilized by the
presence of emulsifying agents.
 Temperature: it should be optimum as required by
particular emulsion. It is critical to the quality of final
product. Elevated temperature alters the partition
characteristic of the emulsifier & preservatives results in
instability.
 Mixing equipment: should be optimum and relevant to the
production size batches. Emulsion is mixed using various
impeller mounted on a shaft, degree of agitation is
controlled by speed of impeller rotation, but pattern of
liquid flow & the resultant of efficiency of mixing are
controlled by the type of impeller, its position in the
container, presence of baffles & shape of the container.
 Homogenizing equipment: homogenizer used to produce
fine droplets by compressing the liquid & passing it
through the flat disc. Shearing stress applied is ranging

from 500-5000psi, Size depends on the viscosity & the
interfacial tension of a system.
• Lab scale – ultrasonic homogenizer
• Large scale- High-Pressure Homogenization
 In-process or final product filters: Selection of filter the
mesh size chosen must be capable of removing the
unwanted foreign particulates but should not filter out any
of the active ingredients.
 Screens, pumps and filling equipment: Fill pump allow
the product to remove from the machine at the end of
production. As now automated equipment are available in
the market and many companies they adopted such huge
equipment that can only done screening, pumps and filling
in a unit operation. 0.22μ cartridge filters are used
commonly for sterile preparation of emulsion. Large scale-
centrifugal pump.
 Phase volumes: In an emulsion the relative volume of
water to oil is expressed as phase volume ratio. Normally
emulsion are prepared with a volume ratio of 50:50, The
upper limit of 74% of oil can be incorporated in an
emulsion but this may lead to breaking of emulsion, this
value is referred as critical point. Critical point is defined
as the concentration of internal phase above which the
emulsifying agent cannot produce a stable emulsion of the
desired type.
 Phase viscosities:it is of great importance for stability and
pourability, as viscosity increases, the terminal settling
velocity decreases.

 Phase densities: by adjusting the density of the phases to
the same value we can increase the stability of emulsion.
Oil phase density can be enhanced by adding brominated
oil when oil is an external phase.
 Filling rate & volume: new batch shouldn’t be started
until the previous batch is completely filled & tanks are
emptied.
Filling rate should be optimized so that the increased rate
may cause incorporation of excessive amount of air into
the product, gravimetric method is commonly used for
filling.
In process quality control test
Solution
Appearance:
− Clarity test- it is carried out to check the particulate matter
in the sample.
− Oral solution should be clear & free from any precipitate.
− Discoloration or cloudiness of solution may indicate
chemical degradation or microbial contamination.
Uniformity of content:
− According to BP this test is carried for oral solutions, oral
drops, with a content of active substance less than 2 mg or
less than 2 percent of the total mass.

− According to IP this test should be carried out for the
preparation containing active ingredient less than 10
percent also
− According to IP & BP the preparation complies with
the test if not more than one individual content is
outside the limits of 85 percent to 115 percent of the
average content and none is outside the limits of 75
percent to 125 percent of the average content.
pH:
− The pH value of a solution is determined
potentiometrically by means of a glass electrode, a
reference electrode and a pH meter either of the digital or
analogue type or by using pH paper.
Viscosity:
− The property which is directly related to its flow
resistance.
− The test is carried out to ensure optimum viscosity of the
medium so that the stable dosage form can be formed.
− Methods used are to determine viscosity are:
 U tube viscometer
 Brook field viscometer
 Capillary viscometer
 Rotating viscometer
 Cone plate viscometer
 Spindle viscometer

Suspension
Appearance:
 The appearancein a graduated glass cylinder or transparent
glass container is noted
 It is checked for-uniformity of color, appearance of
sediment, any brakes or air pockets in the sediment & any
coagulation material adhering to the inside wall of the
container.
Photo microscopic examination:
 Estimate & detect the changes in the particle size
distribution & crystal shape.
 By attaching the Polaroid type camera to microscope we
can distinguish between flocculated & non- flocculated
particles.
Density:
 Decrease in density indicates the presence of entrapped air
within the structure of the suspension. Hydrometers are
used to measure the density.
pH:
 pH of the phases of suspension also contribute to stability
& characteristic of suspension.

 pH is measured before & after mixing using pH paper or
pH meter & ensured that optimum level of pH is
maintained.
Viscosity:
Stability of suspension is dependent on sedimentation rate
of dispersed phase which is dependent on the viscosity of
the dispersion medium. Viscosity is measured before
mixing with the dispersed phase and also after mixing and
is determined by Brookfield viscometer.
Emulsion
Viscosity:
 As viscosity increases flocculation of globules will be
reduced. Simultaneously the Brownian movement of
globules will also be hindered leading to cleaning.
The viscosity of suspension and emulsion can be measured
by
− Cup and Bob viscometer
− Cone and plate viscometer
Phase inversion:
 Phase inversion means a change of emulsion type from
o/w to w/o or vice versa.
Content uniformity:

 For proper dosing of the dosage form it is necessary that
the active ingredient is uniformly distributed throughout
the dosage form. Samples are withdrawn from the
dispersed phase after micronisation and after mixing with
dispersion medium, assayed to fine out degree of
homogeneity.
Liquid orals manufacturing layout

Conclusion:
• The pharmaceutical technologist confronted with a scale up
problem could prepare his or her mind to increase the
likelihood of successful scaling of formulation components
and the product by:
 identifying the physical and chemical phenomena
involved in the pharmaceutical manufacturing process;
 understanding whether and how these phenomena are
affected by a change in scale (i.e., are they dependent on
volume, area, or length)
 identifying or determining the physicochemical properties
(e.g., density, particle size, viscosity) of the formulation
components and the products relevant to scalability
 using dimensional analysis to reduce the number of
variables required to characterize a process as the
manufacturing scale changes;
 using software that enables the estimation of equipment
performance and material characteristics.

Reference:
 The Theory and Practice of Industrial Pharmacy: Leon
Lachman, Herbert A Lieberman, Joseph L Kanig: Section
IV: Chapter 23: Pilot Plant Scale-Up Techniques: Page No.
681 – 710
 “Scale Up of Liquid and Semisolid Manufacturing
Processes” by Lawrence H. Block
 CVS Subrahmanyam “text book of physical pharmaceutics”
page no:195-205,366-423
 https://pharmacynotesfree.blogspot.com/2017/04/emulsions
.htm
 https://www.researchgate.net/publication/292130182_Phar
macopoeial_Standards_and_Specifications_for_Pharmaceu
tical_Oral_Liquid_Preparations
 https://www.slideshare.net/adeelislam60/pharmaceutical-
suspensions-88161516

Scale up of liquid orals

More Related Content

What's hot (20)

Similar to Scale up of liquid orals (20)

More from Parag Behura (10)

Recently uploaded (20)

Scale up of liquid orals