Preparing solid samples reliably and rapidly

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Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-12-01-2009, Volume 21, Issue 12

Manual sample preparation methods for solid dose pharmaceuticals have a number of inherent disadvantages, primarily because they are time consuming and unpredictable.

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.

(Martin Poole/Getty Images)

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.

Highsheer homogenizers

Highsheer homogenizers use a rapidly rotating bladed probe, which is introduced into the container holding the tablet and solvent mixture, to mechanically break up the tablet. Homogenizers are potentially dangerous, as well as noisy, and cross-contamination can occur if the device is not correctly cleaned and maintained after every use. Performance may also vary with time and between devices, and the physical nature of highsheer homogenization means that both sample and solvent contamination warrant careful consideration.

Automated methods

Because of the challenges associated with manual methods, companies commonly seek to implement automated solutions, which use robotics to replace human manual interaction. Using automated technology for sample preparation eliminates variability in the method, operator or environment, and enables unattended operation, which provides savings in cost and time.

Most automated solutions for sample preparation simply take existing manual models and apply robotics and software to emulate the serial activity of a human operator. The most established example of tablet processing automation is the Zymark TPW,2 which has been available in essentially the same form for more than a decade.

For the majority of solutions, automation is traditionally built around the application of traditional benchtop homogenization methods, such as ultrasonic probes or highsheer homogenization, with all the inherent limitations previously described with the addition of complex method development and validation.3–5 Although the human interaction is removed, the cycle times are comparable to good manual processing. By comparing the responses of many laboratory analysts, using automated or manual methods, "30sample preparations" is the 8h limit for both analyst and machine.

An alternative approach

The RTS SolidPrep (RTS, UK) is a recently-introduced technology for tablet sample preparation that ensures extremely rapid homogenization and extraction, irrespective of the dose form used. During its development, process data were collected by an independent third-party and provided initial evidence of the technology's efficiency.6

Ibuprofen was selected as one of the control assays, primarily because of the overthecounter availability of a wide and representative range of dose forms. Development tests were performed to validate and optimize the extraction performance for different dose forms. Example evaluation protocol with data are shown in Table 1. It can be seen from the data that matrix effects may become significant when large numbers of tablets are processed in the comparatively small tube processing volume.

Table 1: Extraction data from a product development assay screen.

Using the SolidPrep instrument, samples are processed in sealed disposable tubes containing the tablets, extraction media and specialized ceramic milling beads. The system rapidly agitates the sample tubes, resulting in a wet milling and vortexing action that rapidly disintegrates the tablet and extracts the active drug products. Compared with traditional sample preparation, this method offers several advantages:

  • Up to five samples can be processed simultaneously on a single instrument.

  • The sample and solvent are contained in a disposable tube so the risk of operator exposure is reduced and there is no glassware to clean.

  • The use of low volumes of solvents reduces overall solvent usage, as well as reducing the costs associated with solvent disposal.

  • A controlled mechanical homogenization for all types of formulation that homogenizes significantly faster than currently-established laboratory processes.

  • The closed processing vessels eliminate crosscontamination and reduce analyst exposure to potentially harmful drug particles and vapours.

  • A uniform thermal environment provides a consistent environment without hot spots and does not accelerate drug degradation.

Most importantly the equipment provides a controlled mechanical homogenization that has proven to be capable of homogenizing all types of formulation tested to date significantly faster than the currently established laboratory processes. A number of studies performed by pharmaceutical companies during field trials of the technology support this observation.7 Field trials compared the sample preparation processing times of solid dose forms using manual methods and SolidPrep. During the trials, the time for complete homogenization, with full recovery of drug content, was recorded for different tablet formulations using each method and, in many cases, SolidPrep recorded time savings of up to 98%. Specific details of formulations tested during field trials are the subject of confidentiality agreements; however, permitted data from a selection of customer studies are summarized in Table 2.

Table 2: RTS SolidPrep customer field testing data.


In most cases, existing benchtop sample preparation methods, typically based on the use of volumetric glassware, can be easily adapted to work with the RTS SolidPrep system. Some aspects must be considered during adaption; for example, the smaller working volume limit of 50 mL means that the solvent system may have to be optimized to work with lower volumes (because of solubility issues). For this reason RTS is developing consumables with a larger volume capacity.

Accelerated homogenization can inevitably create bottlenecks in other areas of the sample preparation process; however, the use of volumetric dispensers and diluters, centrifuges, novel filtration techniques and UPLC technology can mitigate these problems. This allows new ways of working, for example, it is possible to provide sample results within 1 h of sample receipt, which enables the productivity of laboratory staff to be increased dramatically.

In one instance, customer workflow was optimized around the SolidPrep equipment. A volumetric bottle top dispenser, with 'class A' capability8 was used for the initial rapid media dispensing. Following, processing in the SolidPrep, aliquots were prepared and clarified in a benchtop microcentrifuge. Optimization of the injection volume on the HPLC also maintained column loading while eliminating the requirement for a dilution step. With this optimized workflow, an analyst was able to comfortably process 120 content uniformity sample preparations in a normal working day.


To satisfy the demands of regulatory authorities, all new products must be rigorously tested in a qualitycontrolled environment. Sample preparation during the analytical process, however, is challenging and time-consuming. Although there are manual and automated methods that can help, few solutions are universally applicable without extensive method development, and that can realistically help an analyst break the '30 sample preparations' per day barrier.

SolidPrep fully automates the homogenization and drug extraction process, and avoids the complications of traditional automated technologies, which merely emulate manual methods. Recent testing has demonstrated the effectiveness of SolidPrep in reducing the overall time taken to prepare a sample for analysis. Thus, this new automated method presents an efficient and cost-effective solution for the preparation of solid dose samples for analysis.

Mark Fish is Business Unit Director, Drug Delivery Automation, RTS Life Science (UK).

Mike Pollard is Technical Sales Manager, Drug Delivery Automation, RTS Life Science (UK).


1. K.S. Suslick, "The Chemistry of Ultrasound", in The Yearbook of Science & the Future (Encyclopaedia Britannica, Chicago, IL, USA, 1994) pp 138–155.

2. Sotax, Zymark TPW3 Tablet Processing Workstation

3. W.F. Shamrock, K. Reilly and D.K. Lloyd, J. Pharm. Biomed. Anal., 21, 1225–1232 (2000).

4. S.M. Han and A. Munro, J. Pharm. Biomed. Anal., 20, 785–790 (1999).

5. I. Toro et al., J. Pharm. Biomed. Anal., 36, 57–63 (2004).

6. Hall Analytical Laboratories (Manchester, UK)

7. J. Faulkes, "Overview of medium throughput automation", AstraZeneca presentation at Advances in pharmaceutical laboratory efficiency, JPAG (London, UK, October 2008).

8. ASTM E694–99(2005) Standard Specification for Laboratory Glass Volumetric Apparatus