Automation in dissolution testing
Dissolution testing is an essential process in the pharmaceutical industry for evaluating the rate of release of an active pharmaceutical ingredient (API) from its dosage form.
Automated solutions for this process allow laboratories to benefit from improved accuracy, precision, and productivity.
Filtration plays a key role in sampling for dissolution testing. The selection and use of filters in the workflow can impact data consistency and accuracy.
Why automate dissolution testing?
Dissolution testing can be performed manually or using semi- and fully automated systems. In all cases, it is necessary to comply with specifications outlined in the relevant pharmacopeia.
Automating all or part of the workflow minimizes variables that might otherwise contribute to out-of-specification results. Automation might be involved in:
- Preparation and dispensing of dissolution media
- Introduction of the dosage form
- Preparation of the sample for analysis
- Data collection and analysis
Filtration in sampling
Autosamplers can help maximize data consistency in dissolution testing. As the name suggests, autosamplers automatically draw samples from the dissolution vessel at specified time points. These instruments then prepare samples for injection into analytical instruments, often high-pressure liquid chromatography (HPLC) systems.
Filtration of the sample, either through cannula filters at the tip of sample probes or via in-line syringe-type filters, halts the dissolution process and separates any undissolved API and excipients.
The US Pharmacopeia (USP) General Chapter 11 (2011) specifies that sampling and filtration must occur within ± 2% of the stated time point. For example, a 10 minute timepoint requires pulling and filtering a sample within 12 seconds of the intended time, something that is only reliably achievable through automation.
Filtration enables samples to be stored for analysis, or immediately injected into the analytical instrument without introducing particulates that could block the column frit. Figure 1 describes the sampling workflow.
Fig 1. Schematic of a typical dissolution sampling workflow.
Selection and use of filters
Several factors contribute to the effectiveness of sample filtration and subsequent accuracy and consistency of downstream analyses. Whether using cannula or syringe-type, a filter can vary in its suitability for a given drug formulation and dosage form.
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, the article “Comparison of the Adsorption of Several Drugs to Typical Filter Materials” identified that regenerated cellulose (RC) and glass fiber (GF) have reduced adsorption compared with nylon.
According to a November, 2013 webinar, 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.
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).
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.
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.
Selecting filter materials with broad chemical compatibility, and validating against various media, will simplify 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 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. Specifically, PTFE is a hydrophobic material compatible with organic solvents, strong acids, and alkalis. RC on the other hand is a hydrophilic material, compatible with aqueous solutions and 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.
As stated in a November, 2013 webinar 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.
Where clogging is a risk due to high excipient load, stacked filters containing 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.
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 the API and dissolution media.
Try our Whatman Filter Selector App to find out if you are using the most appropriate filtration solution for your samples. To discuss any challenges you are facing, please contact Cytiva Scientific Support.