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During the batch manufacture of solid dose pharmaceuticals, APIs are carefully combined with bulk materials to create the
final product. The production of a uniformly distributed, highquality mixture, however, is a challenging process for several
reasons:
- the low ratio of API to bulk material
- the production of unwanted byproducts during ingredient combination
- the possible introduction of contaminants
- mixing and temperature inconsistency.
Environmental factors, such as heat, moisture and light, may also affect the stability and quality of the final manufactured
product.
All of these are important considerations for regulatory authorities, which makes stringent testing for dose content uniformity
and potential contaminates an essential part of the manufacturing process to ensure the safety and effectiveness of pharmaceutical
products. Unfortunately, preparing solid dose samples for product analysis is one of the most time-consuming tasks in analytical
laboratories — partly because regulatory guidelines demand that large numbers of samples be prepared and tested. The introduction
of more complex dose forms, such as controlled release, has also created further challenges.
The most commonly used method for solid dose sample analysis is HPLC, which separates, identifies and quantifies compounds.
However, the solid dosage form must be first placed in a suitable solvent and prepared as a solution before HPLC analysis
can be used.
Preparing the sample
There are several difficulties associated with the preparation of the sample solution; many solid dose forms are resistant
to dissolution to enable them to pass into the stomach without breaking up, and special tablet coatings have also been developed
that control the site of drug delivery in the digestive system. Further challenges are presented by controlled release dosage
forms because they deliver the active ingredients with a specific dosing profile — in some cases releasing an active ingredient
during a 24h period — making their dissolution a lengthy and complex process.
Disadvantages of manual methods
The manual solid–liquid extraction process can be accelerated using a number of methods, including manual grinding, laboratory
stirrers and shakers, ultrasonic baths and probes, and highsheer homogenizers. All of these, however, have potential drawbacks.
Grinding
It is a somewhat disheartening fact that manual grinding with a pestle and mortar is still occurring on a routine basis in
many laboratories. Not only does this make preparation a tedious and laborious process, it also poses some significant health
and safety issues, particularly with potent active drug products.
Stirrers and shakers
Laboratory stirrers and shakers are routinely used to gently agitate solutions and encourage the dissolution process. Although
they are relatively cost-effective and simple to use, throughput usually dictates the use of multiple units, which take up
large areas of bench space. Complex controlled-release dosage forms also inevitably require extended periods of agitation,
with dissolution times of several hours.
Ultrasonic bath
An ultrasonic bath or probe applies highfrequency sonic energy to encourage break down of the tablet structure and can be
much faster than stirring or shaking. Pressure waves in the solution create and destroy small bubbles that release the energy
as intense heat at the point of their collapse; an effect known as 'cavitation'.1 This process causes generalized heating of a solution, but the inadvertent focusing of sound waves can create intense 'hotspots',
which leads to accelerated degradation of the formulation.
The location of ultrasonic processing equipment is also important as devices tend to be very noisy when in operation.
