Filtration is central to drug dissolution testing in pharmaceutical quality control (QC) and drug development. Dissolution testing determines how fast a drug is released from the dosage format by measuring the amount of active pharmaceutical ingredient (API) dissolved at specific time points as samples are withdrawn from the dissolution vessel.
The key role of filtration in dissolution testing
Filtration separates the dissolved drug from the undissolved dosage components, stopping the dissolution process. This effectively freezes the sample state, making sure it accurately represents a single and specific time point during dissolution. Samples must be filtered immediately after they are withdrawn, enabling sample analysis that determines the amount of drug dissolved.
Good sample preparation with efficient filtration is necessary not only for accurate results, but also to protect expensive analysis equipment. Downstream analysis is often carried out through HPLC or UV-vis spectrophotometry, so impurities may cause damage and potential clogging to the HPLC column.
Evaluating potential filter membranes during method validation can help you optimize the technique before transferring the dissolution test process to the QC lab. This optimization can also help maximize result accuracy and reproducibility.
Considerations when choosing a filter for dissolution testing
Multiple factors contribute to the effectiveness of sample filtration and subsequent accuracy and consistency of downstream analyses. Filter secection must take into consideration the solvents and the APIs being investigated, as well as your methods, equipment and workflows. For HPLC analyses, chemical compatibility and low levels of extractables are always important considerations for reducing the risk of new contaminants interfering with results.
The filter material can adsorb limited quantities of drug onto its surface. The rate and level of this adsorption varies between filter materials. For example, regenerated cellulose (RC) and glass fiber (GF) have reduced adsorption compared with nylon.
|>TIP||Adsorption can artificially lower the apparent concentration of a drug in downstream analysis. Initial flushing with the sample (e.g., 2 mL) might be necessary to saturate the filter before taking a representative sample.|
|>TIP||If a filter device is used for more than one time point for the same sample, flushing will not be necessary at every time point. Validation tests can identify the sample volume that needs to be flushed and the number of samples that can be filtered before clogging.|
These tests enable analysts to set up an autosampler to flush and replace filters automatically according to the standard operating procedure (SOP).
Pore size and efficiency
The efficiency of a filter will vary depending on the size of undissolved drug and excipient particles.
Validating pore size for each drug dosage form during method development can help to maximize filtration efficiency and reduce particulates entering downstream analysis instruments.
Agitating samples encourages any particulates to dissolve. Drug levels compared between agitated and unagitated samples after filtration can be used to validate the efficiency of filtration.
|>TIP||Recommendation for the final membrane is to choose the 0,2 um pore size in uHPLC and 0,45 um pore size in HPLC. For spectrophotometry, there is no recommendation as it is dependent on the sample and the procedure which was used.|
Dissolution media varies depending on the simulated environment required. The combination of pH, ionic strength, surfactant, and other factors can influence the choice of filter material.
|>TIP||Selecting filter materials with broad chemical compatibility, and validating against various media, will simplify the selection of filtration devices across different sample types.|
Materials better suited to aqueous samples, for example, will resist non-aqueous media. The resulting back pressure can slow down manual and automated filtration and affect data accuracy. Forcing a sample through an incompatible filter might, in rare cases, risk damaging the membrane.
Polytetrafluoriethylene (PTFE) and RC are compatible with a range of solvents. Most solutions filtered during dissolution testing are aqueous, so hydrophilic membranes are typically used. H-PTFEand RC are hydrophilic, so they are compatible with aqueous solution and organic solvents. However, RC have limitations with organic solvents.
Any filter material, or indeed any component of a system, has the potential to release extractables when it encounters dissolution media. Extractables only become an issue if they absorb at the same wavelength as the API.
Comparing the UV spectra of filtered and unfiltered samples can reveal any influence of extractables on drug measurement.
RC is an example of a material that generally has low levels of extractables, making it well suited for preparing various sample types prior to HPLC.
Excipients are pharmaceutically inactive substance, such as fillers and preservatives, that are included in a drug formulation. Some drug dosage formulations produce high levels of excipients during dissolution testing. These excipient particles can quickly clog filters, affecting filtration efficiency and the accuracy of analyses.
|>TIP||Where clogging is a risk due to high excipient load, stacked filters containing glass fiber (GF) pre-filters can help, Designed for difficult-to-filter samples, the GF traps coarse particles, preventing them from reaching and clogging the final membrane.|
Membrane options for disolution testing
Polytetrafluoroethylene (PTFE) membranes have broad chemical compatibility, so they are a good choice. This membrane can be either hydrophobic or hydrophilic.
- The hydrophobic PTFE is a good option for filtering organic solvents.
- The hydrophilic PTFE has different polarity due to surface treatment. It requires an additional washing step to reduce extractables which might later interfere with your analysis. This membrane type can then be used with aqueous and organic solvent. It has a low analyte /protein-to-drug binding characteristic which helps maximize membrane recovery. Therefore, the hydrophilic PTFE membrane is good choice for dissolution testing.
Regenerated cellulose (RC) and polyvinylidene fluoride (PVDF) are also great examples of membranes which have broad chemical compatibility compared to hydrophilic PTFE, low extractable levels and low analyte binding.
Nylon membranes can also be used for dissolution testing, but they tend to have strong drug binding characteristics that might lead to inaccurate API quantitation. However, you can reduce the level of impurities and alleviate some of the drug binding by pre-rinsing the filter. It’s possible to minimize impurities in both nylon and hydrophobic PTFE syringe filters this way.
Stacked syringe filters include glass fiber (GF) pre-filters before the final membrane. This design helps filter difficult samples, where typical syringe filters would get clogged. The best option for highly-particulate samples would be to use a filter with a GF prefilter that has been tested to meet the requirements of your dissolution testing application.
Filter choice is key for reliable results
Filter selection influences the accuracy and reliability of dissolution data. An initial validation identifies the various influencing factors, helping to select the most appropriate filter based on the properties of your API and dissolution media.
Try our filter selector tool to help identify the most appropriate membrane filter for your application. Or, contact Cytiva Scientific Support for help with any aspect of your dissolution testing process.
High performance syringe filters
Whatman™ PTFE Membrane Filters ‒ WTP Range
Regenerate cellulose RC membranes
Amersham™ Hybond™ P 0.45 PVDF blotting membrane
Puradisc syringe filters:
Whatman™ Puradisc™ H-PTFE Syringe Filters
Stacked syringe filters:
Whatman GD/X™ filter
Whatman™ Roby automated syringe filters