Discovering Selection of Membranes and Devices for Dissolution Testing

[Abstract] Drug dissolution testing requires filtration. The filtration membrane may impact the performance of the post-dissolution test method. Different manufacturing techniques affect both the membrane pore size and range. Here we discuss these differences, compare the manufacturing techniques used for frit formats with syringe filter formats. Finally, we address the impact of chemical compatibilities on analysis and quantitation.

Why is filtration important for dissolution testing?

As we know, the goal of the dissolution test is to determine the amount of active pharmaceutical ingredient (API) that is dissolved at a particular time when the samples are withdrawn. When a sample is pulled from a dissolution bath, it contains both dissolved and undissolved API. Since filtration using a microporous membrane separates the dissolved API from undissolved API, filtration is actually the key sample prep that is needed for successful dissolution testing.

How are the membranes manufactured?

Different membranes are manufactured using different techniques. Membranes such as PVDF, or polyvinylidene fluoride, nylon and PES, or polyether sulfone, are manufactured by a technique known as solvent casting. In this process, a polymer solution is brought in contact with a nonsolvent, thereby precipitating the polymer in the form of a membrane. Some membranes, like the mixed cellulose ester or MCE, are manufactured by the air casting technique. Therein, a polymer solution is brought in contact with air, which acts as a nonsolvent. Polytetrafluoroethylene (PTFE) membranes are manufactured by expansion of a PTFE film under heat and pressure. Thus, different membranes are manufactured by different techniques, which affect their pore size and morphology, and thereby their filtration performance.

How is the membrane pore size measured?

Pores of a typical microporous membrane are very small. They are either 0.2 micron or 0.45 μm, so we can’t measure them with a ruler or a micrometer screw gauge. The most commonly used technique for measuring pore size of the membrane is bubble point, wherein a membrane is wetted with a liquid. It’s either water or an organic solvent depending on the type of membrane.

For example, a hydrophilic membrane will be wetted with water and a hydrophobic membrane will be wetted with organic solvent and then it will be held in a holder. On one side of the membrane, there is the wetting liquid and on the other side of the membrane there is air, which is slowly pressurized. When a certain pressure is reached, air displaces liquid filled inside the pores of the membrane, thereby creating a steady stream of bubbles on the liquid side. This pressure is called the bubble point of a membrane.

Bubble point is inversely proportional to pore size of the membrane and thus pore size can be determined based on bubble point. In case of sterilizing grades of membranes, like the 0.22-μm or a 0.1-μm membrane, pore size is also determined by bacterial challenge or mycoplasma challenge. B. diminuta is a bacterial strain commonly used for measuring the pore size of 0.22-μm membranes, whereas mycoplasma is used for measuring pore size of 0.1-μm membranes.

What is the main difference between frits and syringe filters?

There are two main differences. The first is the pore size. The typical pore sizes for a membrane filter or a syringe filter is usually 0.2 μm, 0.45 μm, or 1 μm, whereas the pore size of a frits filter is generally 5–70 μm, which means that the frits have a much larger pore size than the syringe filter or the membrane filter.

Implications of this large pore size are that frits may allow for undissolved API particles to pass through them and into the filtrate, which can impact the quantitation of API. The particles that pass into the filtrate can also affect HPLC chromatography downstream, which is commonly used following dissolution testing.

The second difference is the pore size distribution. As I mentioned, typical membrane pore size is measured using bubble point, which provides information about the largest pore in a membrane. Meanwhile, the frits are rated by their average pore size. What that means from an application standpoint is that a membrane of pore size of 0.45 μm can retain particles that are larger than 0.45 μm in size. Meanwhile, a frit with a 10-μm pore size can have pores that are larger than 10 μm, thus it may not be able to retain all the particles that are larger than the pore size of the frit.

Why are PTFE membranes often the membranes of choice when developing dissolution test methods?

There are three important parameters for selecting a membrane for a dissolution test. The first one is chemical compatibility, the second is a low extractable, and the third is the low analyte binding or API binding. When we think about the chemical compatibility, the hydrophilic PTFE membrane that MilliporeSigma offers has the broadest chemical compatibility of membranes available on the market.

Typically, PTFE membranes have broad chemical compatibility. At MilliporeSigma, we treat this hydrophobic membrane to make it hydrophilic, which allows this membrane to be used for direct filtration of aqueous solutions and at the same time retains its high chemical compatibility. This particular hydrophilic PTFE membrane also has very low levels of extractables as measured by HPLC UV or even by LCMS.

As we all know, most commonly, the downstream analytical technique used after a dissolution test is HPLC, and hence these low levels of extractables ensure that these devices do not add any contaminants into the filtered sample, which can complicate the downstream HPLC analysis and quantitation.

Finally, the hydrophilic PTFE membrane also has the lowest amount of analyte binding, especially for low molecular-based APIs and any related impurities. This low binding ensures that the quantitation of the analytes—meaning API or any other compounds that may be present in the formulation—is not negatively impacted by the analyte binding to the membrane.