Poor solubility of an active pharmaceutical ingredient (API) is a major challenge within pharmaceutical product development and manufacturing, frequently adding costly delays to pipelines. In recent years, the issue has become more pronounced as scientific advances yield increasingly difficult-to-formulate drug compounds. Indeed, estimates suggest that around 40% of marketed drugs and approximately 90% of drugs in development can be characterized as poorly water soluble1. As an effective way of addressing this problem, hot melt extrusion (HME) has become an important enabling processing technology for the pharmaceutical industry. Used to transform poorly soluble drug compounds into an amorphous solid dispersion (ASD) to improve solubility and consequently enhance bioavailability, HME has proven to be a viable option to expedite challenging compounds to market. AbbVie CMO is globally recognized as a pioneer in the pharmaceutical application of HME, offering a customized, regulatory-compliant approach from pilot scale all the way through to commercial supply.
What is Hot Melt Extrusion?
HME is a technology that has been widely applied in the plastics, food, and other industries to manufacture products of various shape and density. In the 1990s, its utility in pharmaceutical manufacturing was cemented with the market launch of Kaletra®, a medication used to treat HIV. Following this success, researchers have repeatedly turned to HME to improve the solubility and bioavailability of various drug compounds.
In essence, Hot Melt Extrusion involves transforming a powder blend of an API and specialized polymeric materials into an ASD that exhibits characteristics distinct from those of the original components. Despite its name, HME does not require extreme heat, but instead simply necessitates the provision of appropriated energy to convert the API/polymer blend into an ASD. AbbVie commercial products manufactured using HME include Kaletra®, Norvir®, Viekira Pak®, Mavyret® and Venclexta®.
How does HME work?
For pharmaceutical applications, HME typically employs co-rotated twin screw extruders. First, solid API and polymer (and potentially other excipients) are drawn into the extruder, then the materials are efficiently mixed and melted to produce a molten matrix before being cooled for further downstream processing such as tableting or encapsulation. By converting the input materials into an ASD, the API dissolution rate is increased by virtue of increased solubility that results from disrupting the crystal lattice. If formulated appropriately, an ASD releases the drug in small particles or nanoparticles during dissolution to increase the dissolution rate further still.
Because HME relies on input energy to form an ASD, it is especially important when working with thermolabile compounds to be cautious with formulation design, paying particular attention to polymer selection and process conditions. Detailed characterization of the API, polymer, and any other potential excipients; informed selection of suitable equipment; and extensive process characterization are all essential to achieve timely delivery on commercial goals. Using a simulation aid approach can also facilitate faster time to market.
What are the benefits of HME?
A major advantage of HME is that it operates as a continuous process, making it extremely economical for drug product manufacturing. It is often preferred to spray drying, the other commonly used enabling technology for producing ASDs, since HME involves fewer processing steps and can significantly reduce production time. Moreover, unlike spray drying, milled extrudates provide an improved wettability without agglomeration, which helps to achieve a better dissolution. HME is also a mature and robust technology, enabling the production of a quality drug product while being readily adaptable to fluctuating demand. A further benefit of HME is that it requires no solvents for processing, greatly reducing potential safety concerns. It can also be used to manufacture numerous dosage forms - including tablets, capsules, multi-layer tablets, and controlled and modified release dosing - as well as having the ability to add taste-masking.
Because the HME process consists of multiple unit operations, scale up can be problematic without a thorough understanding of formulation and process. AbbVie has demonstrated streamlined transition from small scale drug manufacturing for pre-clinical studies to production of larger batches suitable for commercial launch, thereby supporting a rapid development cycle for multiple on-marketed products.
Unrivaled HME expertise
AbbVie CMO has HME expertise dating back more than 20 years and has proven time and again the value of this powerful technology for enabling poorly soluble compounds. With extrusion capabilities ranging from the smallest lab scale to the largest pharmaceutical extruders in the world – situated at multiple facilities across Europe and North America – we leverage unrivaled expertise in formulation optimization, scale up, and manufacturing to ensure commercial success.
Whether you wish to improve the solubility of your drug product to enhance bioavailability, or you plan to mask an unpleasant taste, deter drug abuse, modulate drug release, or address drug stability issues, HME can be used to deliver on these objectives and more. To discuss extrusion applications or to learn how AbbVie CMO can help with your drug development and manufacturing efforts, contact us at 1-847-938-8524 or visit www.abbviecontractmfg.com
1.) Pharmaceutical applications of cyclodextrins: basic science and product development, Loftsson T and Brewster ME, J Pharm Pharmacol. 2010 Nov; 62(11):1607-21