How to Select the Right Polymers for Your Modified Release Multiparticulate Capsule

I previously wrote a blog post about polymer selection for modified release tablets. This post will address the same considerations, but for multiparticulate capsules. Many clients come to us with modified release formulations they want to tech transfer or scale-up and take into clinical studies. Just like with tablets, a common problem we see is that the formulation is not robust. The process is challenging to run, and dissolution performance varies from batch to batch or even capsule to capsule. This post will discuss how to select the right polymers (and other best practices), so you can have a robust multiparticulate capsule formulation.

No matter whether you are planning to develop a tablet or capsule, when selecting the right polymers for your modified release dosage form, the best starting point is to decide on the pharmacokinetic profile and then make the strategic formulation decisions about the dosage form (monolithic tablet or multiparticulate capsule) and the release profile (e.g., sustained, delayed, pulsatile) you desire.

In my tablet-focused post, I wrote that a hydrophilic matrix tablet is the best choice for most sustained-release products. There are several things, though, that could sway you to make a multiparticulate capsule instead. A desire to spread the active pharmaceutical ingredient over a larger area of the gastrointestinal tract to avoid local irritation is one. A need for a complex, perhaps biphasic, release profile, or a need to have different release profiles for more than one API could be others.

Regardless of your reason for developing a multiparticulate modified release capsule instead of a matrix tablet, the same desire for a robust formulation arises.

As a starting point, choose your polymer based on the desired release mechanism: pH-dependent for release triggered by location of the dosage form in the GI tract or pH-independent for sustained-release or timed release. For pH-independent designs, try coatings with ammonio methacrylate copolymers or ethylcellulose, aiming for about a 30 µm thick coating. For pH-dependent designs, methacrylic acid copolymers are a good starting point. Include the proper amount of the recommended plasticizer and an anti-adherent.

Make sure that your drug-loaded pellets provide a good substrate for coating before you begin coating trials. Are they smooth and spherical? Do you have a reasonably narrow particle size distribution? A thin seal coat of hypromellose before polymer coating often improves performance reproducibility and polymer adhesion.

I’ve been in the pharmaceutical industry for over 25 years, and for the last 18 I’ve been focused primarily on making modified release dosage forms for clients in the CDMO space. Recently, in collaboration with Chuck Vesey of Colorcon, I delivered a webinar called “How to Select the Right Polymers for Your Modified Release Dosage Form.” As we were preparing our webinar, it was remarkable how many best practices we agreed on.

Modified Release Multiparticulate Capsules

These formulations have a long history since Smith-Kline French pioneered the technology with the introduction of the Dexedrine Spansule (sustained-release dextroamphetamine sulfate) in 1952. Multiparticulate capsules offer a wide range of achievable release profiles for a wide range of API behaviors. They offer a few key advantages over matrix tablets for certain applications. The pellets spread out in the GI tract, leading to more consistent patient-to-patient transit, lower local drug concentrations, and the ability to design distinct populations of pellets with different behaviors (e.g., different active pharmaceutical ingredients (APIs) or release profiles). The technology is well understood, and there are many polymer grades available to help you develop the desired release profile.

Multiparticulate formulations contain the drug within small pellets typically formed by coating a non-pareil (such as a sugar sphere) with the drug and then sealing it with a release-controlling polymer coating. The coated pellets are then loaded into a two-piece hard gelatin (or cellulosic) capsule shell for administration. Once the capsule is taken and travels into the patient’s stomach, the capsule shell dissolves, and the polymer coating forms a barrier that slows the release of the drug. Drug release is obtained by either erosion of the polymer coating (for pH-dependent polymers) or diffusion (predominant for pH-independent polymers).

Polymers for multiparticulate formulations should exhibit the following characteristics:

• Ability to be formulated into a sprayable liquid form (solution or suspension) that has good film-forming characteristics (mechanical strength, adhesion, flexibility, and low tackiness)
• pH-independent release to support robust performance throughout the gastrointestinal tract, or
• pH-dependent release with crisp and predictable pH-dependent solubility
• Availability in multiple grades for flexibility in development

To hear more of our specific polymer recommendations for multiparticulate formulations, watch our recorded webinar “How to Select the Right Polymers for Your Modified Release Tablet or Capsule.”

A Common Problem

If the dissolution release profile of your first formulation is too fast or too slow, the obvious answer is to change the amount of the polymer coating or process parameters such as product temperature or curing conditions to adjust it. If their first formulation is too slow, most formulators will simply reduce the amount of polymer to speed it up. Too fast? They add more or choose a higher molecular weight polymer.

This, by itself, is a bad strategy.

What pain does this cause?

Using too little polymer on your multiparticulate formulation can lead to high variability in dissolution performance.

Using too much polymer in the formulation can lead to poor terminal release, especially for moderately or poorly soluble drugs. Some of the API gets stuck in the pellet and is never released. Too much polymer can also lead to very long processing times and overly large pellets that are difficult to fill consistently into capsules at speed.

All these concerns can create immense headaches during the later stages of development and carry into commercial production.

As a developer, it is our job to create a formulation and process that is robust. That is, when followed, it leads to easy production of a high-quality finished product, time and again. Formulations and processes that are not robust create uncertainty in both product performance and continuity of supply.

What should you do instead?

The optimal amount of rate-controlling polymer for most multiparticulate formulations is to target around 30 µm coating thickness. Ideally, the formulator should target pellets of around 500-1000 µm finished diameter, including the necessary core substrate, drug layer, seal coat, and ~30 µm polymer layer with the appropriate plasticizer and anti-adherent. For example, using 30-35 mesh sugar spheres (~500 µm) as the core, you can add a 260 µm drug layer, 10 µm seal coat, and 30 µm polymer layer, leading to finished pellets of about 800 µm which is a good compromise between easy processing (not too small) and easy encapsulation (not too large). This enables good flow and coating behavior that avoids the tendency of very small particles to agglomerate while allowing reproducible encapsulation via volumetric fill. It also provides additional formulation levers to optimize the processing behavior and dissolution release profile.

What additional levers?

The first is the molecular weight or viscosity grade of the polymer. Different grades of polymer can also be blended to obtain optimal behavior.

The second is the choice of plasticizer. Using a hydrophilic plasticizer like triethyl citrate versus a hydrophobic plasticizer like dibutyl sebacate can influence the dissolution profile.

Third, the addition of a low molecular weight hydrophilic polymer, like hypromellose, can increase diffusion and improve terminal release while keeping the coating thickness from being too thin.

What shouldn’t you do?

Don’t rely on process parameters to adjust dissolution behavior. Don’t change the amount of plasticizer or anti-adherent to adjust dissolution behavior. This is a recipe for variability, frustration, and seemingly endless investigations. By choosing the polymer(s) and other components well, you can create a robust formulation that’s easy to manufacture.

Our webinar goes into more detail about polymer selection and best practices for modified release dosage forms. You can view it here: “How to Select the Right Polymers for Your Modified Release Dosage Form.”

If you have a complicated project, or simply want to learn more, please contact us. We’d love to help.