Fusion Method in Solid Dispersion Systems-Hot Melt Extrusion

Recently, Hot Melt Extrusion (HME) technology has gained significant traction and evolved into a viable solution for routine pharmaceutical manufacturing. This method operates by blending active pharmaceutical ingredients (APIs) with excipients in a molten state under tightly controlled conditions of pressure, temperature, screw speed, and screw configuration. The primary objective is to disperse the API within the excipients in various states (molecular or particulate), thereby enhancing the solubility and bioavailability of poorly water-soluble drugs.

1. Principles of Hot Melt Extrusion

The HME process involves mixing the raw materials (API and excipients, typically polymers) and feeding them into an extruder. Inside the extruder, the materials are heated to a molten or semi-molten state. Under the action of rotating screws, the materials are homogeneously blended and forced through a die of a specific shape. Upon exiting the die, the product is rapidly cooled and solidified, retaining the desired shape.

Key stages of the HME process:

1. Material Blending: API and excipients (usually polymers) are mixed into a homogeneous powder blend. This stage is critical to ensure uniformity in the final product.
2. Feeding into the Extruder: The blended materials are introduced into the extruder via a hopper.
3. Heating and Melting/Softening: Inside the extruder, precise temperature control heats the materials, causing the polymer and API to melt or soften, allowing for thorough blending.
4. Mixing and Transport: Rotating screws inside the extruder ensure consistent mixing and transport the molten mixture toward the die. The screw design significantly affects the efficiency and homogeneity of mixing.
5. Extrusion through the Die: The molten mixture is forced through a die, which determines the final product’s shape (e.g., strands, sheets, pellets).
6. Cooling and Solidification: The extruded product is rapidly cooled using air or water to solidify and retain its shape.
7. Post-Extrusion Processing: The solidified product can undergo further processing, such as cutting into pellets, grinding into powder, or film coating.

Key stages of the Hot Melt Extrusion process

Factors Influencing HME process:

Some important parameters related to equipment and process:

- Screw Design: The screw configuration is tailored to optimize mixing and dispersion. Different screws can be used for different materials and applications. Single screws are suited for low-viscosity materials, while twin screws offer superior mixing for high-viscosity materials.


Single-Screw	Twin-Screw

- Temperature: Materials must be heated above their glass transition temperature (Tg) to enable proper melting. Excessive temperatures can degrade APIs or polymers, while insufficient heat may result in incomplete extrusion.
- Pressure: Pressure generated by the screws ensures material is adequately forced through the die, influencing extrusion speed and product shape.
- Screw Speed: Screw speed controls the residence time of materials in the extruder. High speeds may reduce mixing efficiency, while low speeds may lead to incomplete melting or clogging.
- Feed Rate: The material feed rate affects residence time and mixing efficiency within the extruder.

2. Applications of Hot Melt Extrusion

Commercial products utilizing HME:

Trade name	Chemical name	Company	Year of Approval
Incivek	Telaprevir	Vertex	2011
Kalydeco	Ivacaflor	Vertex	2012
Zelboraf	Vemurafenib	Roche	2012
Venclexta	Venetoclax	AbbVie	2016
Vosevi	Sofosbuvir/Velpatasvir/Voxilaprevir	Gilead	2017
Symdeko	Ivacaftor/Tezacaftor	Vertex	2018
Ubrelvy	Ubrogepant	AbbVie	2019
Tukysa	Tucatinib	Seagen	2020
Rybelsus	Semaglutide	Novo Nordisk	2020

3. Advantages and Limitations of Hot Melt Extrusion

Advantages	Description
No Solvents Required	Reduces the risk of API degradation . Avoids residual organic solvents. Aligning with green manufacturing practices.
Uniform Dispersion	Ensures even distribution of API within the molten mixture, enhancing dosage uniformity.
No compression required	Compressible components are not required.
Enhanced Bioavailability	Improving the solubility and bioavailability of poorly water-soluble drugs is one of the most common reasons for using HMEs..
Controlled Drug Release	The ability to mix the drug with a polymer of specific solubility allows for the adjustment of drug release (slow, controlled, sustained).
Reduced Manufacturing Steps	Integration of mixing, melting, and cooling into a single process.
Continuous Operation	Traditional HME is a continuous-mode technique. It can be monitored and controlled using Process Analytical Technology (PAT). Many advanced methods such as near-infrared (NIR) spectroscopy or thermal sensors have been developed and adapted to suit the specific requirements of the HME process.
Scope of application	Many dosage forms can be prepared by the HME method such as: granules, pellets, tablets, capsules, implants and can be provided through many routes of administration: oral, transdermal, subcutaneous.

Limitations	Description
Thermal Sensitivity	HME is only suitable for heat-stable drugs and polymers. The high temperatures during extrusion can cause degradation of some drugs or polymers.
Viscosity Requirements	The drug-polymer mixture must have the appropriate viscosity to be extrudable. Some drugs or polymers with high viscosity may cause difficulties during extrusion.
Compatibility Issues	Not all drugs and polymers are compatible with each other. Some drugs may interact with polymers, resulting in reduced effectiveness or side effects.
Solvent Issues	HME uses less solvent than other methods such as spray drying, but may still require a small amount of solvent during mixture preparation.
Phase Separation	Phase separation during extrusion can compromise stability and performance.
Crystallization	APIs may recrystallize during storage, reducing solubility and bioavailability.
High Cost of Equipment	HME equipment is typically more expensive than other manufacturing technologies.