Dissolution Testing Filtration

Critical in new formulation development and quality control testing during manufacturing, dissolution testing is used to measure active pharmaceutical ingredient (API) release over time. Dissolution testing is required for all solid, oral formulations and utilizes filtration to stop the dissolution process. Depending on the membrane type and format selected, the dissolution testing method and results may be impacted.

Why is filtration important in dissolution testing?

Samples pulled from dissolution baths during testing contain both dissolved and undissolved API. Microporous membranes, such as those used in Millex® syringe filters, separate undissolved from dissolved API, stopping the dissolution process. In addition to capturing API release and stability at the given time point, filtration removes particulates to prepare the sample for downstream testing methods, including HPLC. Samples for dissolution testing are typically filtered using either fritted or membrane filters.

What is the primary difference between frits and membrane filters?

Fritted filters and membrane filters differ by two main criteria: pore size and pore size distribution. Membrane pore sizes in a syringe filter (or membrane filter in a filter holder) are usually between 0.2-1 μm, whereas the pore size of fritted filters is generally between 5–70 μm. Larger pores in fritted filters may allow undissolved API particles to pass through, impacting the quantitation of API and downstream HPLC testing.

Pore size is determined differently for membrane and fritted filters, which leads to differences in their pore size distribution. The pore size reported for membrane filters refers to the largest pore in a membrane filter, while the pore size of fritted filters refers to the average pore size. During filtration, membrane filters retain all particles larger than the pore size listed, while fritted filters may not be able to retain all particles that are larger than the frit pore size, depending on what the actual size is of the largest pore. As the largest pore size of a fritted filter is not reported, the only way to ensure all particles above a certain size threshold are retained is to use a membrane filter.

How is membrane pore size measured?

Due to their small size, the pore size of microporous membranes is typically determined by a bubble point measurement. During this test, the membrane is wetted, either with water or an organic solvent, and placed in a holder, where the wetting liquid is on one side of the membrane and air is on the other. Air is slowly pressurized through the membrane and at a certain pressure the liquid in the membrane pores is displaced, creating a steady stream of bubbles on the liquid side. The pressure at which this displacement occurs is called the bubble point. Bubble point is inversely proportional to membrane pore size, and thus this relationship is used to determine the largest pore size in the membrane filter.

For sterilizing membranes, pore size is also determined by bacterial (0.22 μm) or mycoplasma (0.1 μm) challenge.

How are membrane filters selected for dissolution testing?

There are three key parameters in membrane filter selection for dissolution testing:

  • Chemical compatibility
  • Low levels of extractables
  • Low analyte or API binding

To avoid membrane failure during filtration, the membrane material must be chemically compatible with the solution being filtered. Verify the compatibility of all our Millipore® membranes with our chemical compatibility tables. The presence of extractables in the filtrate or the loss of analytes due to non-specific binding to the membrane, will alter quantitative results obtained in downstream analysis.

Why are hydrophilic PTFE membranes typically used in dissolution testing?

PTFE, or polytetrafluoroethylene, membranes have very broad chemical compatibility, making them ideal for use with a variety of solutions. While native PTFE is hydrophobic, we offer surface-treated, hydrophilic PTFE membranes that allow users to filter aqueous solutions while retaining high chemical compatibility. Our hydrophilic PTFE membranes undergo additional washing steps during membrane coating, resulting in membranes with very low extractable levels. These low extractable levels ensure the filtration device does not add contaminants into the filtrate, which can complicate the downstream HPLC analysis and analyte quantitation. Hydrophilic PTFE membranes also exhibit very low analyte binding, ensuring analyte quantitation, including APIs or other compounds present in the formulation, is not negatively impacted by the analyte binding to the membrane. With the three selection criteria in mind, hydrophilic PTFE membranes offer a universal solution for filtration in dissolution testing.

How is automation used in dissolution testing?

With the rapid pace of the pharmaceutical industry, sample preparation in drug screening and development is often automated. While this advance in technology saves time and resources, standard syringe filters often fail in automated systems due to high back pressure, filter misalignment, or filter jams due to shingling (Figure 1).

The convex, domed housing of our automation-compatible syringe filters prevent shingling in automated systems compared to standard syringe filters.

Figure 1a The convex, domed housing of our automation-compatible syringe filters prevent shingling in automated systems compared to standard syringe filters.

Figure 1b The pressure resistant housing prevents bursting and the Luer-Lok® connection provides precise alignment within automated systems.

Our automation-compatible syringe filters alleviate these issues with:

  • Domed housing to prevent shingling (Figure 1a)
  • Pressure-resistant housing to prevent bursting (Figure 1b)
  • Luer-Lok® connection optimized for precise alignment and fit

Alternatives to manual and automated filtration

While automation can be useful in multisample preparation, the high cost of the required infrastructure limits its application to high-volume industrial applications. Our vacuum-driven Samplicity® filtration device offers a solution for scientists that need to filter more than eight samples daily, but do not meet the threshold for automated sample preparation. Using Millex® Syringe Filters with adaptor funnels, researchers can filter up to eight samples with simultaneously into standard 2 mL HPLC sample vials.

Learn more about how the Samplicity® filtration device can simplify your sample preparation.

Filtration products recommended for dissolution testing

Millex® syringe filters for 1 – 10 mL samples
 

Product Description Membrane Type Pore Size Diameter Pack Size Product Number
Millex®-LG syringe filters Hydrophilic PTFE 0.2 μm 13 mm 100 SLLGX13NL
100 SLLGH13NL
100 SLLGC13NL
1000 SLLGX13NK
1000 SLLGH13NK
Millex®-LCR syringe filters Hydrophilic PTFE 0.45 μm 13 mm 100 SLCRX13NL
100 SLCRX13TL
1000 SLCRX13NK
1000 SLCR013NK
Millex®-LH syringe filters Hydrophilic PTFE 0.45 μm 13 mm 100 SLLHC13NL
Millex®-GV syringe filters Hydrophilic PVDF 0.22 μm 13 mm 100 SLGVX13TL
100 SLGVX13NL
1000 SLGVX13NK
Millex®-HV syringe filters Hydrophilic PVDF 0.45 μm 13 mm 100 SLHVX13TL
100 SLHVX13NL
1000 SLHVX13NK
Millex®-GN syringe filters Nylon 0.2 μm 13 mm 100 SLGNX13TL
100 SLGNX13NL
1000 SLGNX13NK
Millex®-HN syringe filters Nylon 0.45 μm 13 mm 100 SLHNX13TL
100 SLHNX13NL
1000 SLHNX13NK


Millex® syringe filters for 10 – 100 mL samples
 

Product Description Membrane Type Pore Size Diameter Pack Size Product Number
Millex®-AP syringe filters Glass fiber 20 μm 25 mm 50 SLAP02550
Millex®-LG syringe filters Hydrophilic PTFE 0.2 μm 33 mm 50 SLLG033NS
250 SLLG033NB
1000 SLLG033NK
Millex®-LCR syringe filters Hydrophilic PTFE 0.45 μm 33 mm 50 SLCR033NS
250 SLCR033NB
1000 SLCR033NK
Millex®-GV syringe filters Hydrophilic PVDF 0.22 μm 33 mm 50 SLGV033NS
250 SLGV033NB
1000 SLGV033NK
Millex®-HV syringe filters Hydrophilic PVDF 0.45 μm 33 mm 50 SLHV033NS
250 SLHV033NB
1000 SLHV033NK
Millex®-GN syringe filters Nylon 0.2 μm 33 mm 50 SLGN033NS
250 SLGN033NB
1000 SLGN033NK
Millex®-HN syringe filters Nylon 0.45 μm 33 mm 50 SLHN033NS
250 SLHN033NB
1000 SLHN033NK


Automation-compatible Millex® syringe filters for 10 – 100 mL samples
 

Product Description Membrane Type Pore Size Pack Size Product Number
AC Millex® syringe filters Glass fiber 1 μm 200 (8 x 25) SLPBDZ5NZ
1000 SLPBDZ5NK
Hydrophilic PTFE 0.2 μm 200 (8 x 25) SLLGDZ5NZ
1000 SLLGDZ5NK
Hydrophilic PTFE 0.45 μm 200 (8 x 25) SLCRDZ5NZ
1000 SLCRDZ5NK
Hydrophilic PTFE, with glass fiber pre-filter 0.45 μm 200 (8 x 25) SLCRBZ5NZ
1000 SLCRBZ5NK
Hydrophilic PVDF 0.45 μm 200 (8 x 25) SLHVDZ5NZ
1000 SLHVDZ5NK
Nylon 0.2 μm 200 (8 x 25) SLGNDZ5NZ
1000 SLGNDZ5NK
Nylon 0.45 μm 200 (8 x 25) SLHNDZ5NZ
1000 SLHNDZ5NK


Millex® syringe filters for Samplicity® G2 system
 

Product Description Membrane Type Pore Size Pack Size Product Number
Millex® syringe filters for Samplicity® G2 system Hydrophilic PTFE 0.2 μm 250 SAMP2LGNB
1000 SAMP2LGNK
Hydrophilic PTFE 0.45 μm 250 SAMP2LCRB
1000 SAMP2LCRK
Hydrophilic PVDF 0.22 μm 250 SAMP2GVNB
1000 SAMP2GVNK
Hydrophilic PVDF 0.45 μm 250 SAMP2HVNB
1000 SAMP2HVNK
Nylon 0.2 μm 250 SAMP2GNNB
1000 SAMP2GNNK
Nylon 0.45 μm 250 SAMP2HNNB
1000 SAMP2HNNK


Samplicity® G2 filtration system & accessories
 

Product Description Pack Size Product Number
Samplicity® Filtration System Tube 1 SAMTUBING
Samplicity® Vial Trays 2 SAMVIALTR
Samplicity® Waste Trays 5 SAMWASTTR
Samplicity® G2 Lid 1 SAMP2LID
Samplicity® G2 System, Bold Blue 1 SAMP2SYSB
Samplicity® G2 System, Glossy Green 1 SAMP2SYSG