Pharmaceutical Melt Extrusion – Most Frequently Asked Questions

As more knowledge on melt extrusion is developed and discovered by pharmaceutical scientists worldwide, people who are new to the arena are faced with similar questions. In our Melt Extrusion-FAQ page, we will address and comment on some of the most frequently asked questions.

Our solutions span the pharmaceutical process from formulation to manufacturing. Visit us at www.thermoscientific.com/mc_pharma or contact us at info.mc.us@thermofisher.com for more information.

The melt extrusion process is becoming more established in the pharmaceutical industry due to its ability to improve the limited bioavailability of “challenging” drugs during the formulation stage. Furthermore, the melt extrusion process is operated in continuous mode and can be equipped with online analytical monitoring, saving cost in the production of drug dosage forms.

In just a few minutes, a sample can be obtained from raw materials. This sample can either be the final dosage form or at least a granular form that can be further processed into tablets or any other required form. All this can be done without using solvents. Modern melt-extrusion formulation approaches show that the process is also suitable for heat sensitive molecules as well as for shear sensitive molecules.

FAQ 2: How can I ensure the content uniformity of my active pharmaceutical ingredient?

The most important tools for ensuring content uniformity are feeders. The commonly used method is split-feeding which means that each component is fed by a separate gravimetrical feeder. These modern feeders can control the feeding by measuring the loss in weight continuously over time. The feeders can be calibrated for the material you are going to feed. During this process, the feeder learns about the flowing characteristics of the material.

Did you know that you can not only feed solids, but also liquids and pasty substances into the extruder? The feeding site in the extruder can be chosen depending on your formulation needs. For labile substances, feeding at a very late stage of the extruder is possible by e.g. side feeding.

In case you are not using the split-feeding method, content uniformity relies more on the blending quality of the pre-blend you are working with. The extruder compensates smaller variations in concentration by using different decelerating processes for the material.

Thermo Scientific extruders have excellent mixing properties due to their co-rotating, twin-screw principle. The material is not only homogeneously distributed in the extruder but components such as your active ingredients are also dispersed at a microscopic scale.

We offer the full range of feeders that allow the use of any kind of method and to feed any kind of material into the extruder.

FAQ 3: How can I apply Cremophor* as a plastisizer even though it is in a paste form?

Substances like Cremophor® have a melting point close to ambient conditions. A pasty form can be fed with a gravimetric liquid feeding station which is equipped with controlled heaters to transform the material into liquid form and feed it into the extruder in liquid form.

For material which is in a pasty form but cannot be melted by gentle heating so called ram-feeders are available to bring the pasty material into the extruder. Such feeders work normally in a volumetric mode, meaning that they bring a defined volume over time into the extruder.

The purpose of the up-scaling process is to transfer the manufacturing of your formulation from a small-scale to a large-scale device. Process as well as formulation aspects have to be taken into consideration. Due to this, there is no general recommendation possible, each up-scaling process has to be worked out depending on formulation. The Thermo Scientific HAAKE MiniLab micro-compounder is designed to ensure an easy up-scaling.

During up-scaling, it is important to keep key parameters such as viscosity, energy input etc. in mind and also look for formulation parameters like dissolution behavior and impurity profile of your formulation. Depending on the chosen excipient and the chemical characteristics, the process parameters can play a major role or minor role in the formation of a solid solution. This is especially important for up-scaling from HAAKE MiniLab to Thermo Scientific Pharma 16 HME Hot Melt Extruder since the HAAKE Minilab is equipped with conical screws and the Pharma 16 HME with parallel screws.

We offer custom services to speed up your process and ensure the quality of your formulations.

FAQ 5: I have bubbles in my extrudate. Do they matter and where do they come from?

We assume here that the target was not to obtain a foam by adding foaming agents to the formulation and so the answer to the first question is: Yes, bubbles matter, because they can lead to a different mechanical characteristics of the extrudate as well as bubbles could mean the result of an non-optimized process as it will be discussed below.

Where do they come from? This can have different causes.

• With feeding in materials, air was pulled in and could not leave in the feeding zone. This can happen with micronized materials especially if the material tends to stick. Also if liquids are fed in and some gases are dissolved in the liquid these gases could be released in the extruder. As long as oxygen or other gases does not mean a harm to the formulations ingredients, this is no problem and can be overcome by optimization of feeding zone and/or by opening the venting port.
  
• If a component of the formulation is hygroscopic and it is fed non-conditioned (i.e. dry air) or in pre-dried condition, this absorbed moisture can be released at temperatures above boiling point as vapor which form the bubbles in the extrudate then. Since liquids like e.g. water acts as plasticizer they can be a problem if included uncontrolled or not-considered in the formulation. If a substance in your formulation would be unstable in humid condition this moisture would mean a problem. The problem can be avoided by opening the venting port to remove the water steam and by using dry products. In general it is important to not expose hygroscopic components to high moisture.
  
• Bubbles could mean a degradation of one or more components. If decomposition occurs by unfavorable process conditions you need to optimize your process. With the melt extrusion process it is possible to have very gentle conditions which allows to handle even heat-sensitive substances. If decomposition of a component is caused by chemical incompatibility or by a chemical reaction with another component you need to optimize the formulation.

Please feel free to contact Thermo Fisher if you find bubbles in your extrudate. We will help you in solving this problem.

FAQ 6: How can an API be stabilized in the amorphous state for the complete shelf-life period of a drug?

Many drug molecules are not stable in the amorphous state because they tend to re-crystallize or they chemically decompose over time or react with other ingredients. Therefore the amorphous state is not recommended at all. Developing a solid dispersion, the amorphous suspension where drug and polymer both are amorphous but are in two different phase is not preferable. Amorphous systems are meta-stable and are underlying a permanent change. Stability over shelf-life of the formulation would have to be defined as what change is acceptable over the desired time.

Preferable would be to stay with the drug-in-polymer concentration below the saturation concentration to obtain a molecular dispersed system, where the drug can be stabilized by formation of e.g. hydrogen bonds between polymer and drug. Such glassy solid solutions can be long-term stable if they are treated with factors like moisture. A solid solution is a thermodynamic stable system but it has to be recognized that the true solubility of a drug in polymer is also limited.

The other option to obtain a stable solid dispersion is to leave the drug in a crystalline state, but generate very small crystals to have an improvement in solubility of the drug by a dramatic increased specific surface. Which method is working better has to be determined for each drug separately.

FAQ 7: Is the material already well mixed right after it is put into the extruder?

Actually, the extruder is an excellent mixer. The material will be inside the extruder distributed and the material also will be dispersed. The mixing conditions inside the extruder make it more independent from the particle size of the fed-in materials. But the mixing may take a moment inside the extruder so it will have to pass two or more zones, also depending on the chosen screw configuration and the temperature (for softening or meting components).

By the way: Theoretically a pre-blend can segregate after leaving the feeder falling down the way to the extruder if the particle size as an example is different of the components. Inside the extruder this will be homogenized again, so that this means for the practice no issue.

FAQ 8: How do you control the constant feeding from the Hopper?

To ensure a constant feeding rate, a few pre-requisites have to be ensured:

• Good flowing characteristics of the material which need to be fed.
• Homogenous particle size if fed as pre-blend

Feeders can be operated in a volumetric mode and in a gravimetric mode. Thermo Fisher is recommending the gravimetric mode. In the volumetric mode the feeder speed will be kept constant but a real constant material flow is only achieved with excellent flowing characteristics of the material that do not change over time. In the gravimetric mode the feeder is permanently monitoring the loss in weight over time and can adjust the feeder speed permanently to ensure a constant mass flow.