Filling and packaging of liquid dosage form:

The method used for filling a liquid dosage form depends on following:

 Characteristics of the liquid (viscosity, surface tension, foaming ability)

 Type of package
 Production output

Three basic methods are used for filling of liquid dosage forms:

1. Gravimetric filling
2. Volumetric filling
3. Constant level filling

Gravimetric filling:

In this, a particular weight of liquid is filled into the container. This type of filling is rare in use
because it can be used only for highly viscous liquid or to fill large size containers.

Volumetric filling:

In this, a given volume of liquid is filled into the container using the displacement piston action.
Each filling station is equipped with a measuring piston and cylinder. The fill amount is
measured by the stroke of the piston which can be varied from machine to machine.

Disadvantages:

 Highly viscous liquids can block the piston causing loss of fill accuracy
 Highly thin liquids can cause dripping of the drops from the filling point of machine
 If container is oversized then filling appears loose and if container is undersized then
filling appears overfill, hence container to be filled should have uniform size

Constant level filling:

In this, each container is filled to the same level hence it is also called as fill-to-a- level method.
It uses the container for controlling the filling of each unit which means that any change in size
of the container causes change in the net fill per unit.

Methods for constant level filling:

In older days, the siphon method was used. But due to slowness of this method, slight
modifications in siphon method are used which are following:

 Vacuum filling
 Gravity-vacuum filling
 Pressure-vacuum filling

Problems associated with liquid filling machines:

 Excessive foaming ability:

It can be minimized by following:

 Reduction in turbulence of the liquid

 Using the closed system to prevent the entry of air or other gases that help in foaming
 Use of defoaming devices
 Decrease in speed of machine

Evaluation of syrup:
Following evaluation parameters are carried for syrup:

Physical stability:

The syrup must be clear. No solid particle should be present in syrup.

Light transmittance test:

A light transmittance meter is used to check the color of syrup. In this, a syrup sample is checked
for color by passing the light through the sample. The percent of transmitted light is compared to
light transmittance rates for different grades.

pH measurement:

The pH of syrup is measured using the pH meter which should be in range of 6-7.

Solubility:

The solubility of syrup is determined and it should be soluble in water.

Refractive index:

The refractive index of the syrup is determined and it should be in range of 1.4608-1.4630.

Determination of sucrose concentration:

Concentration of sucrose is very important in syrup because high amount of sucrose in syrup
may cause crystallization of syrup while low amount may cause loss of preservative property of
syrup. The concentration of sucrose in syrup is determined using analytical tools HPLC or U-V
spectrophotometer.

Content uniformity:

In this, take 10 containers having syrup and emptied content of each container. Then determine
the drug assay of content of each container as per method prescribed in monograph of that drug
in Pharmacopoeia. The preparation complies with the test if not more than one value is outside
the 85%-115% limit of average value and none value is outside the 75-125% limit. If 1-3 values
are outside the 85-115% limit value but none is outside the 75-125% limit of average value then
test is performed for another 20 containers. Then not more than 3 values should be outside the
85-115% limit and none should be 75-125% limit of average value.

Evaluation of elixirs:
Physical stability:

The elixir should appear as clear liquid and no solid particle should be present in elixir.

Viscosity determination:

Viscosity of elixir is determined using various viscometers like Ostwald viscometer, cup & bob
viscometer, Brookfield viscometer etc.

pH determination:

pH of elixir is determined using pH meter and it should be in range of 6-7.

Refractive index:

Refractive index of elixir is determined and it should be optimum as per different pharmacopeias.

Determination of alcohol:

The alcohol concentration in elixir is in range of 5-40% and it is determined using HPLC or UV
spectrophotometer.

Content uniformity test: Same as in syrup

Emulsion:
Following evaluation parameters are carried out for emulsion:
Ageing and temperature:

An emulsion is said to be stable if it meets the following:

Age (Time) Storage temperature Limit

60-90 days 45-50°c Emulsion should not show
5-6 months 37°c any visible change at these
12-18 months 25°c conditions

Freeze thaw cycle:

In this test, emulsion is subjected to store at too high temperature and too low temperature in
alternating cycles. This exposure is repeated many times and emulsion stability is evaluated after
each cycle.

Age Storage Freeze thaw cycles Limit

(Time) temperature No. of cycles Between Temperature
1 month 4°c 2-3 -20°c to 25°c No visible sign of
48 hours 4°c 6-8 Refrigeration temp. to separation
45°c

Centrifugation:

Centrifugation of emulsion increases the gravity and increase in gravity leads to increase in
creaming (instability of emulsion) which can be used to evaluate the shelf life of emulsion
rapidly. Centrifugation at 3750rpm in a centrifuge for 5 hours is equivalent to effect of gravity
for one year.

Centrifugation speed temperature Limit

2000-3000 rpm 25°c Emulsion should not show
any visible change

Agitation:

It is considered that excess agitation of emulsion cause breaking of emulsion or prevent the
formation of stable emulsion. Example: Production of butter from milk.

Age for agitation temperature Limit

24-48 hours on reciprocating 25°c & 45°c Emulsion should not show
shaker (60 cycles/minute) any visible change
Phase separation:

The phase separation can be determined by visual inspection but rate and extent of phase
separation of emulsion can be determined by only by measuring the volume of separated phase
which involves the withdrawl of small amount of emulsion from top and small amount from
bottom of emulsion and compare the composition of both by analysis of oil content, water
content and any other additives.

Viscosity:

Viscosity is an important parameter to assess the shelf life of the emulsion. Any change in
viscosity can cause instability of emulsion. Viscosity of emulsion is determined by cone plate
type device because most of the emulsions are non-newtonian. Decrease in viscosity indicates
the poor shelf life of emulsion because decrease in viscosity causes increase in coalescence due
to increase in globule size.

Zeta potential:

Zeta potential is determined by moving boundary method and micro electrophoresis method.
Emulsions having high zeta potential (negative or positive) are electrically stabilized while
emulsions having low zeta potential tend to flocculate, coagulate leading to poor stability.
Generally at high zeta potential, force of repulsion exceeds the force of attraction causing stable
system.

Suspension:
Following evaluation parameters are used for suspension:

Sedimentation method:

It is the most important parameter for evaluation of stability of suspension. Sedimentation

volume is the ratio of ultimate volume of sediment to the original volume of the suspension. In
this method, sedimentation volume is measured using the formula:

F = Hu / Ho

Where:

F is the sedimentation volume

Hu is the ultimate volume of the sediment after the sedimentation
Ho is the original volume of the suspension taken in measuring cylinder
  The value of sedimentation volume (F) generally lies between less than 1 to 1 or in some
suspension it may exceeds from 1. The larger the value of F, better will be suspension.
 Sedimentation volume is plotted against the time. If the graph is horizontal then
suspension is stable or if there is any change in graph then suspension is unstable.

Degree of flocculation:

Degree of flocculation (β) is the ratio of the sedimentation volume of the flocculated suspension
(F) to the sedimentation volume of deflocculated suspension ( F ∞ ). It can be calculated by:

F
β=
F∞

Hu
H
β= o
H∞
Ho

β=H u / H∞

Redispersibility:

If a suspension produces sediment upon storage then it should be readily dispersible so that dose
uniformity can be maintained. The amount of shaking to achieve it should be minimum. Various
redispersibility tests have been done to check it.

Viscosity:

The viscosity of the suspension is studied at different time intervals using viscometer.
A stable suspension have high apparent viscosity at low rate of shear due to which suspended
particles either settle slowly or remain suspended without settling.
Viscosity can be determined by stoke’s law:

V = d2 (Ps – Po) g / 18η

Where,
V is the rate of settling of particles
d is the diameter or size of the particles
Ps is the density of disperse phase
Po is the density of disperse medium
η is the viscosity of the disperse medium
g is the gravitational constant
On the basis of this equation, V is inversely proportional to the η (Viscosity). It is clear that on
increasing the viscosity of disperse medium, rate of settling of particles decreases. So particles
settle down slowly or remain suspended in the medium which form a stable suspension.

Zeta potential:

Zeta potential is determined by moving boundary method and micro electrophoresis method.
Suspensions having high zeta potential (negative or positive) are electrically stabilized while
suspensions having low zeta potential tend to aggregation of solid particles leading to poor
stability. Generally at high zeta potential, force of repulsion exceeds the force of attraction
causing stable system.

Particle size:

 The stability of a suspension also depends upon the particle size of the disperse phase. An
ideal suspension should have particle size of 0.5- 5µm.
 According to stoke’sequation, increase in particle size also increases the rate of settling of
particles and cause instability of suspension.
 Larger particles settle down rapidly than smaller particles.
 Particles greater than 5µm cause gritty nature to the suspension and may cause irritation
if injected or instilled into the eye.
 Particles larger than 25µm cause blockage of the needle if given by parenteral route.
 If particle size is very small then particles form easily hard cake at the bottom of the
container. So the particle size of the suspension should neither be too large nor too small.
Sometimes, on storage of suspension particles may grow and lead to formation of lumps or
aggregates due to temperature fluctuations. It is because on high temperature, solubility is high
and as temperature is down then particles crystallize out. It occurs generally with poorly water
soluble drugs.