Hai guys....... Today I want to share you the details mechanism of Dissolution. But It is a huge ocean to expalin. So I will explain Dissolution in three different sessions.....
Lets start............................
What is Tablet Dissolution?
When a dosage form is
swallowed, the rate at which it releases the active ingredient is critical to
ensure that the drug is delivered properly.
“The rate at which the drug is released is called the dissolution rate”
One of the problems
facing pharmaceutical manufacturers is to how optimise the amount of drug
available to the body, i.e. its bioavailability.
Inadequacies in
bioavailability can mean that the treatment is ineffective and at worst
potentially dangerous (toxic overdose). All kinds of factors affect this from
the formulation of the dosage form, size, shape, excipients, bindings and other
physical characteristics, to the pH, temperature and so on.
The actual drug
release in the human body can be measured in-vivo by measuring
the plasma or urine concentrations in the patient. However, there are certain
obvious impracticalities involved in employing such techniques on a routine
basis.
These difficulties
have led to the introduction of official in-vitro tests which
are now rigorously and comprehensively defined in the respective Pharmacopoeia
and recent harmonisation between the various Pharmacopoeia (notably the USP,
BP, EP and JP) has lead to global standardisation in the measurement of drug
release rates.
Tablet Dissolution Testing
When it comes to
measuring the release rates of drugs in a manufacturing environment then the
technique of Tablet Dissolution testing is employed.
Tablet Dissolution is
a standardised method for measuring the rate of drug release from a dosage form
and the key word here is “standardisation" because for any results to be
meaningful, it is essential that all the apparatus used for the testing,
produces the same sets of results given all other parameters are equal.
The principle function of the dissolution test
may be summarised as follows:
·
Optimisation of
therapeutic effectiveness during product development and stability assessment.
·
Routine assessment of
production quality to ensure uniformity between production lots.
·
Assessment of
‘bioequivalence’, that is to say, production of the same biological
availability from discrete batches of products from one or different
manufacturers.
·
Prediction of in-vivo availability,
i.e. bioavailability (where applicable).
Dissolution testing
was initially developed for oral dosage forms, but the role of the test has now
been extended to drug release studies on various other forms such as topical
and transdermal systems and suppositories.
Why Test?
From a manufacturing objective, the aim is to:
"Manufacture a dosage form in such a way that the
active ingredient is released from the dosage form in a predicatable way and
within a reasonable time in order for it to be absorbed by the body".
Drugs also need to be released in the right area of the
body - in the intestine instead of the stomach for example.
Most routine dissolution testing is used to confirm the
statement above.
When a dosage form is manufactured, there are a number of
parameters which need to be checked:
·
That the active ingredient is released in the predicted way
·
That the manufactured batch is the same as previous batches and
falls within the required levels.
·
That he product can be stored for the specified shelf life
without deterioration
·
To ensure that the dosage form does not break up in transit
·
To confirm that the drug is stable over time.
The Dissolution Test is a very useful tool and the only standardised way to generate scientific data that
enables comparison
In addition, standardised testing promotes globalisation
and harmonisation and also acts as a referee to identify mis-branded or
substandard products
Application of dissolution data
Testing the dosage form from production to the end of its
shelf life produces data that
·
Confirms immediate quality control
·
Ensures that the drug is still pharmaceutically active
throughout its shelf life
·
Includes stability testing within well defined and strict
criteria for each drug
·
Validates the manufacturing process and confirms therapeutic
equivalence
What is tested:
Dissolution testing is appropriate to a wide range of
products:
·
‘Traditional’ pharmaceuticals
·
Dietary supplements
·
Veterinary drugs
·
Other ‘remedies’
Theoretical
Concepts of Dissolution
The basic definition of dissolution rate for a solid
dosage form is as follows:
‘The amount of
active ingredient in a solid dosage form dissolved in unit time under
standardised conditions of liquid-solid interface, temperature and media
composition.’
First it is helpful to look at the way that a tablet breaks
down and begins to dissolve. This refers to disintegrating tablets which make
up a good proportion of the type of dosage forms tested
It is not unusual during dissolution testing to see
particles moving towards the base of the vessel or moving around in the
media. The behaviour of these particles effect the dissolution rate and so it
is useful to look at this in more detail later.
Dissolution Rates of Dosage Forms
There are many kinds of dosage forms of course and all of
them have a dissolution rate. The dissolution time can range from seconds to
hours or even days for implants.
Of course there are other dosage forms such as patches,
implants, creams etc. but the principles remain the same.
The interface between the dosage form, and in particular
the particles after deaggregation, and the dissolution media is critical and is
known as the Shear Rate.
Shear Rate & Sink Conditions
Shear Rate
This is a very complex relationship but includes the
interface between the surface of the solid and the rate at which fresh solvent
contacts it.
If a tablet particle were to be suspended in media with
no agitation at all, the liquid immediately around the tablet would become
saturated and dissolution would essentially stop.
As the media starts to move then the saturated film is
‘washed’ away and new media enables the dissolution to continue again.
Logically therefore, anything that affects the fluid dynamics or the way in
which a dosage form disintegrates and dissolves should be understood and
controlled
The Shear Rate depends on many variables including flow
pattern variables, turbulence, viscosity, surface tension and dissolved gasses,
which are in turn effected by other system variables to do with physical
parameters.
Before any of those can be examined however, it is
essential to ensure that there is sufficient media present to allow free
dissolution of the active ingredient into solution.
Sink
Conditions
If you put a spoon of sugar into a beaker of water it
will dissolve readily. A second spoon will also dissolve. But keep adding
spoonfuls and it becomes slower for the sugar to dissolve until at some point
it becomes impossible for any more to dissolve as the solution becomes
saturated.
Relating this to the dissolution of drugs, it is
essential that as a drug dissolves, the presence of the already dissolved drug
in solution should not affect the ability of more drug to be dissolved in any
way. i.e. the concentration of drug in solution should not be anywhere
other than the bottom of the saturation curve for that drug. Concentration
should never be close to the saturation point.
If the concentration level were to rise too high, the
dissolution rate of additional drug would be slowed and the data would cease to
be reproducible.
In order to ensure that sufficient media is present in
relation to the drug to be dissolved, typically 5 to 10 times greater volume of
media is used in respect to that saturation point at which dissolution would
slow. This is known as Sink Conditions – sufficient media to ensure un-impaired
dissolution.
This is typically why dissolution is performed in larger
volumes such as 900ml or 1litre. 500ml tests may be used where sink conditions
permit and the measurable level of the drug is lower. In recent years, the
introduction of microcapsules and very low dosage levels have led to mini
vessel tests in volumes as low as 100mls or 200mls, but in all these cases,
sink conditions are maintained. Conversely, if 1000mls is not enough volume,
then larger 2000ml vessels can be used, and above that volume USP4 can be
considered.
