The Myths and Reality of Hot Melt Extrusion

Advances in combinatorial chemistry and high-throughput screening in drug discovery have delivered APIs with various innovative therapeutic mechanisms. However, newly discovered APIs also tend to be more lipophilic, and exhibit higher melting points and molecular weights, resulting in limitations for solubility and bioavailability.  In the small molecule pipeline, approximately 64 percent of new molecular entities are practically insoluble, with an additional 10-15 percent having other solubility challenges. Poor solubility limits drugs’ bioavailability and pharmacological potential, as poorly soluble APIs are more likely to fail during drug development. Several technologies can improve the solubility of drug substances, including physical and chemical modifications, salt formation, co-crystallization, complexation, particle size reduction, lipid base formulations, and amorphous solid dispersions. In this article, we focus on the latter.

Amorphous solid dispersions and hot melt extrusion
 

Amorphous solid dispersions break the solubility-limiting crystal lattice of drug substances and disperse the amorphous API into a carrier matrix. Solvent-based or fusion methods can be used to make amorphous solid dispersions, with hot melt extrusion (HME) being a popular fusion method that has gained significant traction in pharma applications because of its ability to enable continuous manufacturing. HME with twin screw extrusion (TSE) brings several benefits, including being a continuous, versatile, and efficient self-wiping small mass mixer amenable to PAT. The process parameters are well controlled and easily scalable from R&D to commercial scale equipment. Once process parameters are established at a given equipment scale, batch size is a time factor; hence, batch sizes could be flexibly scaled up or down by running the process for a longer or shorter time, keeping all process parameters constant. A pharmaceutical material can be processed at ambient or elevated temperature, depending on the purpose of use. Extruders have heating and cooling mechanisms, which provide heat transfer, temperature control zones, and good temperature control along the length of the machine.

Integrating the TSE/HME process with other upstream and downstream semi-continuous unit operations, such as continuous blenders, mills, and tablet presses, would establish a fully end-to-end continuous manufacturing process. TSE has a small footprint and requires relatively less investment to maintain the space, or to put containment features around it. As a solvent-free process, it also brings environmental and sustainability benefits. 

Oral dosage form development and HME myths
 

Although HME has been recognized as a valuable technique for oral dosage form development, several myths have historically discouraged manufacturers from taking full advantage of the technology. Here are some examples of the myths versus facts:

Only certain molecules are suitable for HME

Myth: Molecules with a high melting point are poor HME candidates because the processing temperature needs to be higher than the API melting point. Molecules that degrade at their melting point or are susceptible to recrystallization are also unsuitable.

Fact: With a good understanding of formulation and processes, HME can be applied to various materials. Molecules with a high melting point (even as high as 270 ^oC), those that degrade at their melting point, and molecules prone to recrystallization can all be processed with HME. 

High API requirements and costs

Myth: HME requires a large quantity of API and is expensive. 

Fact: Feasibility studies using small API amounts (mg scale) can be performed to determine if HME is suitable for a particular molecule. As HME is a continuous process, it is also cost-effective compared to batch process technologies because of better utilization of materials and energy. 

Complex scale-up and quality concerns

Myth: HME is too complex for standard applications and challenging to scale. The high process temperatures also raise concerns regarding increased impurity levels during scale-up. 

Fact: Carefully selecting processing conditions and excipients can aid scale-up and prevent API degradation. The continuous HME process also helps to facilitate scale-up. 

The myths surrounding HME often leave it overlooked in oral dosage form development, with many companies failing to benefit from this technology. However, these myths can be effectively debunked by conducting pre-formulation studies and understanding extrusion process parameters. 

HME versus spray drying
 

Both HME and spray drying are widely used techniques for preparing amorphous solid dispersion intermediates for poorly soluble/permeable developability classification system (DCS) class IIb and class IV new chemical entities (NCEs). Spray drying relies on dissolving the API and the polymer carrier in a common solvent, followed by spray atomization, drying, and collecting the product. 

There are some key areas where HME offers benefits and advantages over spray drying, including in manufacturing unit operations and product cost. Typically, spray drying requires more unit operations to manufacture the amorphous intermediate product and downstream operations to develop oral solid dosage forms. Spray-dried powders typically have residual solvents that are much higher than the safety threshold (such as those set by ICH guidelines). They may also require secondary drying to remove residual solvents to acceptable limits for human consumption. This secondary drying adds additional capital, operational costs, and time to the manufacturing process, reducing the efficiency and flexibility of the production.

Furthermore, spray-dried powders are typically fine particles with low bulk density. This prevents the direct use of spray-dried powders in downstream oral solid manufacturing processes such as tablet compression and encapsulation – adding yet another step of powder densification through the roller compaction process. 

On the other hand, HME has advantages over downstream operation. The amorphous extruded intermediate is prepared through a solvent-free melt mixing process and does not require drying. 

The characteristics of extruded and spray-dried particles also vary significantly in terms of physical and morphological attributes, and molecular uniformity and distribution. The HME process is designed to create uniform mixing, thanks to the distributive and dispersive mixing elements arranged along the extruder length in a screw design. The extrudate consists of a homogeneous melt of a molecularly dispersed API in the polymeric matrix. After milling the extrudate, the particles are dense and non-porous, with a uniform distribution of the formulation components. 

Compare this to spray drying, which generates droplets with a large distribution of different sizes during atomization. These sprayed droplets experience varying drying kinetics, which could lead to the formation of concentration gradients within a single particle. Depending on the chemical affinity and solubility of both the polymer and API in the process solvent, as well as the diffusion coefficient, variations in droplet size and drying kinetic may result in particles with API-rich surfaces and a core with lower API concentration. This “non-uniformity” could be exacerbated during secondary drying when the product is exposed to heat for an extended period. 

HME particles, however, exhibit dense and more uniform surface morphology with less variability in drug release – both in vitro and in vivo. In contrast, spray-dried amorphous solid dispersions typically exhibit “raisin-like” morphology with porous structure and non-uniform surface topology. These concentration gradients, coupled with the porous structure of the spray-dried powders, are a major root cause of high variability in drug release and in vivo bioavailability associated with spray-dried formulations. 

In conclusion
 

Developing oral dosage forms presents significant challenges, particularly when dealing with poorly soluble drug substances. However, a variety of advanced technologies are available to enhance drug solubility and bioavailability. Among these, solvent-based and fusion-based techniques have proven effective in producing amorphous solid dispersions (ASDs). Notably, hot-melt extrusion (HME)—a widely recognized fusion-based approach—has gained prominence for its ability to overcome key formulation challenges. HME enables the production of ASDs that significantly enhance the solubility and dissolution rates of poorly soluble drugs, while also facilitating continuous manufacturing, an essential aspect of modern pharmaceutical production.

Both HME and spray drying are well-established technologies for manufacturing ASDs, each with its own advantages. While spray drying is a widely used solvent-based method with proven success, HME offers distinct benefits, particularly in terms of certain material quality attributes, cost efficiency, and environmental sustainability. Its solvent-free nature reduces the need for solvent recovery systems, minimizes environmental impact, and enhances process robustness, making it an attractive choice for certain formulations and manufacturing environments.