Physical Stability Studies

Title : Physical stability studies

Course Co ordinator : Dr. Smt. Jayanti Vijaya Ratana.

The job of the medicine is to give the therapeutic effect and so the most important thing is that the required drug content is available till the expiry date is over.
But the appearance and lack of any change in a physical sense are also important asthe patient only observes the exterior and any change from the original position may frighten him or bother him.
Some physical changes can have deleterious effects too. An emulsion may crack into two phases and thus different doses drawn from it may have different drug contents.
A suspension may have a hard cake as a sediment; as a result of which the supernatant may be bereft of all drug and a dose drawn from the bottom of the bottle may have toxic amounts of drug. A tablet may become soft and ugly or it may become  very hard and show very slow dissolution time as a result of which bio-availability  may not be good. Stability is the capacity of a drug product to remain  within  specifications established to ensure its identity, strength quality and purity.
So it is absolutely essential that for all formulations all areas in which instability is likely to occur are understood and stability is tested for. With each formulation the problems are different and their effects and solutions possible are also different.

Table No.1 tries to summarise the instability possibilities in different formulations.

Formulation

Likely physical
instability problems

Effects

Stability testing

Steps to prevent
instability
Oral solutions Loss of flavour

Change in taste

Presence of off flavours due to interaction with plastic bottle

Loss of dye

Precipitation

discoloration

Change in smell or feel or taste A “tester” should smell taste or feel the product and judge it qualitatively and quantitatively. The depth of taste may be judged for example as degree of saltiness or sourness on a scale of 1-5. The depth of flavour may be judged as type of flavour or level of flavour on a scale of 1-5. A colour standard may be used to describe the “intensity” of the discoloration.
Clarity should be studied.
Use of proper excipients and suitable packing materials.
Parenteral solutions

Physical instability occurs due to:

1) Interaction
of the contents with  the container.

2) Changes in
Chemical composition.

1. Discoloration due to photo chemical reaction or oxidation. Ex: thiamine hydrochloride
2. Presence of precipitate due to interaction with container or stopper.
3. Presence of “whiskers”. If some small pinholes are present in the ampule due to improper sealing the solution wicks out, the liquid evaporates and the solid settles on the outside. It further helps in wicking out more solution and long lines of crystals form on the outside of the vial which are called whiskers.
This may happen due to small hole (<0.5 ?m) going undetected or the crack developing during storage. 4. Clouds: A cloud will appear in the product due to: (i) Chemical changes (an ester eg.: polysorbate may hydrolyse producing an acid which is poorly soluble). (ii) Solubility product may be exceeded. (iii) The original preparation of a supersaturated solution or the use of a metastable form (ex: calcium gluceptate).
Change in appearance & in bioavailability. Use of a colour standard to describe the “intensity”of the discoloration. Extent of precipitate may be counted using a Coulter Counter or the number of vials having a precipitate may be counted. Since this precipitate formation is due to a reaction with container or stopper we have to store vials for testing by placing vials in different positions such as (1) upright, (2) on the side and (3) upside down. Periodic observation Study of clarity, pH, sterility, pyrogenicity, volume (for plasticcontainers) and extractables (for plastic containers) Clouding which may be a prelude to precipitation may occur due to loss of viscosity and this change in viscosity may be followed with a Cup and Bob Viscometer.Drastic changes in viscosity may happen due to bacterial contamination. Use of antioxidants 0.5%) Acetylcystane or 0.02 – 1% Ascorbic acid) or Chelating agents (0.01 – 0.075 sodium edetale) to prevent discoloration.
Change in stopper or material of the container will eliminate the problem.
Checking of the manufacturing process Increasing solubility by the use of cosolvents (eg: polyethylene glycol) or by other methods such as micellar approach or complexation will reduce clouding.
Suspensions Settling, caking, crystal growth Loss of drug content uniformity in different doses from the bottle and loss of elegance. 1. Subjective tests involving shaking the bottle
2. Rotating the bottle under reproducible
conditions and analyzing the supernatant for
drug content.
3. Freeze – thaw    testing.
4. X – ray   diffraction   study
5. Study of sedimentation rate and
sedimentation volume
6. Chemical  testing for the amount of the
preservative
7. Study of ph
Design of product based on proper pre-formulation studies.
Semisolids

(Ointments and suppositories)

1.  Changes in:
a)  Particle size,
b)  Polymorphic
state, or
hydration or
solvation state.
c) Consistency
d) drug release
rate
2. Caking or
coalescence.
3. Bleeding
Loss of drug content uniformity, loss of elegance and change in drug release rate. 1.Consistency by penetrometer
2.Feel to the touch
3. X - ray diffraction studies.
4. In-vitro drug  release study with diffusion
cell.
Design of product based on proper pre-formulation studies.

Emulsions

Creaming or cracking Loss of drug content uniformity in different doses from the bottle and loss of elegance. 1. Study of globule size
2.Study of rheological  behaviour with a Cup
and Bob iscometer.
3.Study of pH.
Design of product based on proper pre-formulation studies

Tablets

Change in
a) Disintegration
time,
b) Dissolution
profile,
c) Hardness and
d) Appearance
Change in drug release Testing for hardness, disintegration time, dissolution, appearance, friability, moisture content. Design of product based on proper pre-formulation studies.

Capsules

Change in
a)Appearance
b)Dissolution &
c)Strength
Change in drug release Testing for strength, moisture content, appearance, brittleness
and dissolution.
Design of product based on proper pre-formulation studies.
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