Hot-melt extrusion (HME) is an advantageous method for enhancing the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs) — if the formulation is robust and scalable. Partnering early on with an experienced CDMO can help accelerate the development of optimal, scalable, and patient-centric HME products.
Why Hot-Melt Extrusion is the Answer for Many APIs
As high-throughput technologies have been applied in drug discovery to identify API candidates with more targeted activity, many of these lead compounds are high-molecular-weight, complex structures that are typically more hydrophobic or more lipophilic with lower aqueous solubility of the crystalline compound. For many of these APIs, bioavailability is limited by the aqueous solubility of the crystalline compound, and enabling techniques (such as amorphous solid dispersions or ASDs) to improve solubility are needed to formulate a drug product that is efficacious for patients. HME is one avenue by which APIs can be processed to change their inherent physico-chemical properties in an effort to enhance their solubility and ultimately bioavailability.
In the pharmaceutical industry, HME essentially involves feeding a dry mixture of an API and at least one polymer or binder through an extruder — usually a twin-screw extruder (TSE) — to mix them together. Heat is applied to the mixture either by the temperature-controlled barrels or by viscous dissipation from the shear conveyed by the extruder screw elements, resulting in melting or softening of the API and polymer matrix. In some cases, liquid excipients are injected into a port on the extruder to aid with mixing and melting of the API and polymer excipients by reducing the viscosity of the mixture. Melting or dissolution of the crystalline API into the polymer matrix traps the API in a higher-energy or amorphous state compared with the crystalline starting material, forming a single homogeneous phase called an amorphous solid dispersion (ASD).
During this process, the thermal history or properties of the parent API are erased. Most particularly for APIs with high crystal lattice energies that result in low aqueous solubilities, the crystalline property constraints are removed when the amorphous state is formed. In addition, often surfactants are used in HME formulations to improve the ability of the API to interact with its solvent. Both of these factors result in an increase in apparent solubility and hence bioavailability. This can result in achieving an increased drug loading for an ASD formulation and a reduction in the size/number of dosage units required to achieve efficacy, resulting in increased patient compliance.
Spray drying (SD) is another common method for generating ASDs, and both SD and HME have their unique advantages and disadvantages. One significant benefit of HME is the fact that no volatile organic solvents (or associated specialized equipment) are required in the process, which is not the case for SD. As a result, the HME process is simpler, with fewer processing steps, and carries lower associated manufacturing costs. In addition, the equipment for HME is typically more compact compared with an SD unit and thus is advantageous from a manufacturing footprint standpoint. Furthermore, HME is more straightforward from an engineering-first perspective, and thus scaling up is typically more streamlined than in SD, which often requires more development work to move from lab/pilot to larger scale.
Our success can also be attributed to our ability to achieve highly robust process transfers across that network, which is made possible by our commitment to understanding the fundamental principles of formulation and process and their interplay, both at smaller and larger scales.
Polymer Miscibility and Thermal Stability Are Key
A wide range of excipients and polymers can be used for HME processing; however, it is essential to understand the polymer’s miscibility with the active ingredient to determine if it is appropriate for use in an ASD formulation. ASDs are homogeneous one-phase systems, so any polymers used in an HME formulation must have appreciable miscibility with the API. Without specific interactions and substantial miscibility between the API and polymer matrix, the single-phase system has a thermodynamic driving force to phase separate once the melted mixture cools to room temperature, which can result in API recrystallization over time.
In addition, polymers and APIs used in HME formulations must have good thermal stability, given that significant energy is imparted into the API and the polymers during the HME process. Miscibility between the API and polymers again are key, as this results in melting point depression of the API and allows the HME process to be performed at temperatures below the degradation temperatures of the API and the matrix binders.
Overall, a comprehensive understanding of the interplay between the excipients and the API is necessary to ensure the development of optimized HME formulations.
The Importance of Formulation Experience
Although the development and scale-up of HME formulations is often simpler than those involved with SD, formulation and production experience are still invaluable for streamlining the development of HME products.
A successful contract development and manufacturing organization (CDMO) needs to be able to develop HME formulations across a wide range of APIs with varying properties and drug loadings. To accomplish this, scientists with fundamentally sound training in material science, physical chemistry, and formulation sciences are key to design and execute experiments in an efficient manner to identify an optimal formulation to meet the drug product’s quality target product profile (QTPP).
One of the biggest challenges with ASDs is preventing the API from phase separating and recrystallizing over time, thereby losing the solubility enhancement gained by converting the API to an amorphous form. It is not enough to be able to form the ASD easily by melting the API with a polymer; the formulation must be tailored to maintain both physical and chemical stability of the product throughout its shelf life and prevent subsequent recrystallization of the API.
Another challenge is to ensure that any HME formulation developed in the laboratory is practically scalable for commercial production. In many cases, customers come to AbbVie Contract Manufacturing because the formulation and/or processes they have established do not scale well. In these cases, additional work is needed to thoroughly understand the API’s inherent physical properties and how these interplay with the excipient components in the HME formulation. Formulation adjustments are often needed to achieve dosage form performance of the ASD while also ensuring robust process manufacturing performance upon scale-up to commercial scale. As a result, projects become more time and cost intensive.
The best approach to HME development if a pharma company lacks appropriate in-house capabilities is to contact a highly experienced CDMO like AbbVie as early as possible in the development process. By identifying a robust, tailored formulation from the outset, it is possible to accelerate development, thereby reducing the time to clinic and the market. AbbVie has industry-leading experience in successfully transferring HME processes from the small to large scale and are aware of the critical knowledge needed to ensure that a robust process will successfully transfer to commercial scale and will provide consistent, high-quality product from batch to batch.
Welcoming a Toolbox of Solutions
Indeed, a CDMO that can successfully support HME process development has a toolbox of technologies and solutions that can be leveraged for different types of APIs. Two important tools include extrusion modeling capability and a network of extruders at different scales.
With these two capabilities, it is possible for a CDMO to execute experimental studies and obtain a great deal of information about the extrusion design space for an HME formulation without wasting large quantities of API. The information gained at small scale provides critical inputs into determining appropriate parameters at larger scale, depending on the scale-up strategy employed (volumetric, heat transfer, specific mechanical energy, shear rate). Similarly, studies that provide an understanding of the impact of process parameters and screw design on shear forces and energy input contribute to determination of a robust design space that can be maintained regardless of the production scale.
Having a large number of extruders with varying capacities (and non-potent/potent capabilities) located at multiple sites around the world also affords significant flexibility for a CDMO’s customers. They have the ability to scale their processes within the network as well as move between different sites to meet evolving supply needs for different markets.
The Criticality of Robust Analytical Methods
It is essential with HME processes — like all processes designed to produce ASDs — to develop robust analytical methods (e.g., dissolution, crystallinity) to measure ASD performance over time.
This is another area in which the benefits of partnering with a CDMO like AbbVie Contract Manufacturing that has extensive experience developing HME processes for many different types of APIs are very apparent. The knowledge gained from working on a variety of projects enables the rapid development of truly robust analytical methods that can be properly validated and transferred as needed.
Development and Commercialization Experience
AbbVie/Abbott have been developing and commercializing HME products for nearly 15 years. We have worked with hundreds of different products that leverage HME (which includes five of our own that have been commercialized), including ASDs with a wide range of drug loading capacities from lower than 10% to as high as 60%. We believe that we have worked on more HME projects than anyone else and truly have the expertise and experience needed to create optimal ASDs using HME for even the most complex APIs and challenging formulations.
Based on that experience, AbbVie has extensive knowledge on polymer excipients that can both achieve a robust dosage form from a product performance and stability perspective as well as from an extrusion process standpoint. We also have unique characterization techniques and analytical tools that allow us to be even more effective at API characterization and polymer selection. Our team also collaborates with academic researchers at the forefront of understanding ASDs and how they perform, not only in the sold state, but once placed in solution.
In addition, AbbVie has a large number of extruders in our network — more than 10 — and some of the largest-capacity extruders owned by CDMOs. Our small-scale extruders have similar if not the same operating principles as our commercial equipment, allowing effective scale-down/up modeling. The network is also global, so we provide significant flexibility for customers looking to grow their product into new markets.
Our success can also be attributed to our ability to achieve highly robust process transfers across that network, which is made possible by our commitment to understanding the fundamental principles of formulation and process and their interplay, both at smaller and larger scales. We look at drug candidates and work to identify the best dosage forms that will be most effective at achieving the efficacy needed, taking into consideration physicochemical properties, including solubility and bioavailability, along with patient concerns, such as pill burden.
Indeed, AbbVie is a pioneer in the HME space and has the expertise to create formulations that are truly robust and patient-centric and can be readily commercialized. We work closely with our customers and have open and transparent communication to facilitate product and process development. That includes a willingness to have difficult but honest conversations about projects transferred in from other CDMOs that need to be fixed.
Developments for the Future
Even though HME is a mature technology, extensive research continues, including innovation in the excipient space to address the changing needs of novel APIs. HME is also being explored for 3D printing of personalized dosage forms, such as in a hospital or on the battlefield where on-demand manufacture of a dose for a particular patient is needed. AbbVie has been investigating small-scale 3D printing potentially to accelerate drug discovery and early-stage product development.
