Galenic Tests

Galenics denotes the lessons from the manufacturing of medicines. For a variety of reasons, the pure active ingredient does not make up the majority of the finished medication. With excipients, the active ingredient is made into an effective, tolerable and safe dosage form (e.g. tablet, capsules, injection solutions etc.). Depending on the dosage form, there exists in the European Pharmacopoeia (Ph. Eur.) and in the US Pharmacopoeia (USP) a number of galenic testing methods to provide support for the development of medicines and to ensure that their usage in patients can be analysed in a manner as near as is possible to real-life.

Some of the common tests are:

• Disintegration time
• Dissolution tests
• Resistance to crushing of tablets / texture analysis
• Bulk and Tap density
• Sieve analysis
• Particle size distribution
• Osmolarity
• Particulate impurities
• Uniformity of mass
• Dropping point
• Friability
• Removable content

As an FDA-approved and GMP-accredited contract laboratory in Switzerland with many years of experience, we provide support in the development of your products and the validation of analysis methods and the subsequent implementation of routine tests.

A variety of expertise in galenic testing 

In the galenic test, a wide variety of different physical and chemical analyses are used. An extensive inventory of equipment is required and every method requires specialised technical knowledge. This knowledge must be kept continually up to date to be able to react to legislative changes and new products. Projects require extensive planning and an established quality assurance system to generate data that conforms with the regulations. An example from dissolutions testing should explain which points are important here.

Dissolution tests of pharmaceutical products

Dissolution tests are important in the development of dosage forms and are also often an integral part of stability studies. In contrast to many other tests of the Pharmacopoeia, the methods for dissolution tests have been harmonised so that it is possible to fall back on international and uniform methods.

It is however often a long way to these routine tests. Beginning with the qualification of the corresponding systems, through to development, and ending with the analytical validation of the methods. Even in the case of modified release formulation, the use of automatic systems is obligatory. In all phases, particular attention should be paid to the current guidelines.

Equipment for dissolution testing

The classic equipment used in active ingredient release are the rotating basket and the paddle stirrer devices. They are particularly suitable for solid, oral dosing forms such as tablets, capsules, dragees and pellets both in quick release and retarded release form.
The advantages of these devices: world-wide standardisation and acceptance, a simple design and robustness.

There exists many years of experience with these devices, most of the current monographed methods make use of these techniques.

Additional equipment (flow cells, paddle-over-disk, reciprocating cylinders etc.) are also monographed and offer advantages in terms of test medium exchange, simulation of the gastro-intestinal tract or for release for active ingredients with low levels of solubility. Experience and recognition world-wide here is however substantially lower.

Qualification of the test equipment 

Dissolution equipment for testing must be qualified in accordance with GMP. This requires the one-off Installation Qualification (IQ) for the initial assembly or for a change in location of the equipment. Following on from that is the Operational Qualification, the inspection of the equipment properties and compliance with the corresponding specifications. In the case of automatic systems, the OQ means an increased level of effort, because the dosage accuracy and the qualification of measurement sensors also need to be taken into account. Finally, the system needs to be monitored for correct equipment functionality under operating conditions, the so-called Performance Qualification (PQ). Here the dissolution equipment will go through mechanical testing and adherence to the temperature and rotational speed will be monitored. Requalification of the devices must be performed every six months and this is therefore an extremely cost-intensive part of dissolution testing.  

Method development

In general, for method development for dissolution testing, the general regulations of the ICH Guidelines apply.

For the development of a release method, one can start off initially with a standard method. For example, for a quick release tablet, start off using the paddle method at 50 rpm with 0.1 M Hydrochloric acid as a medium. In the case of active ingredients with low solubility, the use of a solubilizer should be considered right from the start.

Release of the active ingredient from a pharmaceutical dosage form will be influenced by a variety of values. Some of these could be the pH-value of the release medium, the stirring speed, the type and/or the concentration of the solubilizer and also the type of sinker that is to be used. A watery release medium should be preferred and the volume should come to somewhere between 500 and 1000 ml. The pH value of the medium should ideally be somewhere between 1 and 6.8 and on no account should it be higher than 8. The recommended rotational speed of between 50 and 100 rpm should also be considered. In no case should the selected method exceed 150 rpm.

For testing the suitability of the method as part of the following stability testing, it is also very helpful to have a “good” and a “bad” batch of tablets as the selected method should in any case be able to discriminate. Here, the pH-value of the medium can both influence the solubility of the active substance and give the possibility of differentiating good batches of tablets from bad batches. When selecting the solubilizer, it should be ensured that the “sink-conditions” are achieved but that there has not been an unnecessarily large dosage, because that can have an effect of the tablet matrix. In the case of highly soluble active ingredients, it can also be sensible to insert very small amounts of solubilizers to avoid the formation of conglomerations. If a method has been selected, then the robustness of the release method should be monitored before analytic validation takes place. Should factors such as small changes in the pH value or salt concentrations have a great deal of influence, then the method will need to be specified or revised.

Method validation 

If the most “suitable” release method has been found, then analytical validation of this method should be done at the latest before clinical studies are begun. Validation should be performed using only qualified equipment (IQ, OQ, PQ) and should be carried out in accordance with the ICH guidelines.

Important aspects here are the specificity, the linearity, the accuracy and the precision of the measurement method. In most cases, these are either UV spectroscopic methods or HPLC methods. According to the type of method used, additional parameters such as robustness and filter inspections are also a part of validation.  

If light-sensitive substances are being tested, then it is recommended that investigations are performed in a yellow-light laboratory.

In the case of time-release tablets or modified release tablets with a release time of more than 8 hours, it is also sometimes problematic to carry this out using manual systems. Mostly, release is performed here in partially or fully automated systems. Here the issue of the transfer of a validated method to an automatic system arises.

Depending on the system to be used, the influence of the sampling unit (filtration, altered flow characteristics), of the cleaning effect, of spreading, of active ingredient adsorption and of specific equipment parameters (e.g. pumping periods) should all additionally be validated.

From the development stage to routine and stability testing 

While release profiles are frequently recorded in the method development stage, in the stability testing of quick release tables (20 to 30 minutes), often only one point releases are used. For modified release tablets however, a number of samples must be analysed, often over a period of 24 hours. In the event of high sample throughput during a stability study, this is only possible with partially or fully-automated systems. Therefore, specialised service laboratories offer development, validation and routine testing, for example during stability testing so that their own capacity can be used more flexibly.

What are the arguments for outsourcing? 

• Being free from routine work and the opportunity to focus on core tasks
• Capacity peaks can be overcome
• Independent results from an accredited contract laboratory

Our services in detail:

• Consultation about galenic tests
• Disintegration time
• Dissolution tests: Quick release, sustained release formulations, release according to USP dissolution devices 1 + 2 (paddle and basket)
• Hardness
• Bulk and compact volumes
• Sieve analysis
• Particle size distribution
• Osmolarity
• Particulate impurities
• Uniformity of mass
• Dropping point
• Additional services are according to the directory of services or upon request