Preparing solid samples reliably and rapidly

Manual sample preparation methods for solid dose pharmaceuticals have a number of inherent disadvantages, primarily because they are time consuming and unpredictable. Although automated technologies can overcome these problems to some extent, they too have limitations. A new instrument for tablet sample homogenization, however, offers an effective solution that produces high-quality samples using low volumes in a short time frame.
Dec 01, 2009
Volume 21, Issue 12

(Martin Poole/Getty Images)
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.


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.

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