	Hot-melt extrusion (HME) is a well-known process within industry, being used since the 1930s, and more recently has found prominence in the pharma industry within the application of enhancing the bioavailability of APIs. As the industry is witnessing a surge in the number of poorly soluble drug molecules entering the development pipeline, techniques to improve solubility will inevitably continue to experience growth.

	To learn more about HME, its advantages, limitations, and recent advances, 

spoke with Michael Dennis, director of technical operations, science and technology, and Bill Huang, senior principal research scientist, formulation sciences, both from AbbVie.

Can you give a brief overview of HME and how it can aid in solubility/bioavailability enhancement?

Historically, HME was used to convert raw materials into a homogenous solid with a particular shape. In pharmaceuticals, it also enables dissolution of APIs into a polymer to form a matrix known as an amorphous solid dispersion (ASDs). ASDs achieve higher apparent solubility and faster dissolution for enhanced absorption of poorly soluble compounds (BCS Class II and IV).

	In an ASD, solute molecules are dispersed molecularly randomly within the amorphous carrier. This allows for a drastic significant increase in the apparent solubility and dissolution rate achieving high bioavailability and better human pharmacokinetic/pharmacodynamic performance. A rationally formulated ASD generates drug-rich amorphous nanodroplets that maximize the surface area of the compound for improved absorption when contacting the dissolution medium as the carrier dissolves.

	While this technology is gaining significant traction in the pharmaceutical industry, especially in the oncology therapeutic area, it is key for anyone developing in this area to have a solid understanding of HME or to partner with someone with a strong and long tenure in understanding its nuances to ensure timely entry into the market.

What are the advantages afforded by HME over other available technologies/solutions aimed at enhancing solubility/bioavilability?

A major advantage is that it does not use organic solvents. This significantly reduces or minimizes both environmental and safety concerns. In spray drying, an alternative method for manufacturing ASDs, for instance, organic solvents are required to dissolve the polymer and drug and then the solvents are removed during spray drying and a subsequent product drying step.  

	Other benefits of HME when comparing to other techniques, such as spray-drying, is that it offers shorter cycle times, a smaller footprint, and lower capital costs, which all add to its efficiency. Moreover, it is inherently a continuous unit operation, allowing fast development and scalability. HME is well placed to serve as an effective anchor for an integrated continuous manufacturing line, whether that means sequencing a continuous blender to the extruder or sizing and compressing unit operations downstream.

	A well-developed ASD formulation and HME process is robust and well controlled, enabling the production of consistent product quality both intra- and inter-batch. Furthermore, HME provides an option to formulate drug products for molecules which have zero or limited solubility in organic solvents. 

Are there specific limitations of HME that should be considered?

Since HME depends on melting the polymer and drug, thermally sensitive API molecules and potentially some polymers may not be suitable. Additionally, as a result of the inherent characteristics of BCS Class II and IV API molecules, it is challenging to attain high drug loading in many cases. Further, the choice of pharmaceutical grade polymers and surfactants that are suitable for HME is still very limited.

Could you highlight the most recent advances in HME?

Absolutely, there are numerous efforts being made by industry to advance HME. For example, the understanding of fundamental aspects of formulation and drug release has been dramatically improved in recent years, which is aiding HME product and process design and development. We have also seen industry embrace the rigorous application of physicochemical characterization tools that are helping in the understanding of the impact of physical and thermal properties of materials (constituent components as well as drug-polymer and drug-surfactant interactions) on HME processing and product characteristics. We are also seeing a surge in the use of one-dimensional and three-dimensional computational models to optimize HME processes, which is a result of computational power increases and more efficient algorithms for discrete element models and computational fluid dynamics.  Through this improved understanding, it is becoming easier to develop robust formulations and processes with reduced development time and costs.

	Various custom in-house modeling tools have been developed by companies, enabling scientists to select the appropriate polymers, surfactants, and drug concentration, which is supporting faster and more efficient drug development. Additionally, in recent years, there have been significant research efforts made by excipient suppliers to advance HME through the development of new polymer systems (e.g., hypromellose acetate succinate and graft polymers).

	In addition to HME processes being applied to traditional solid oral drug products, they are also now being used in the formulation of biodegradable implantable products, such as poly lactic acid- and poly glycolic acid-based implants.

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Experts from AbbVie discuss the advantages and limitations of HME for enhancing bioavailability of poorly soluble APIs.

Considering Hot-Melt Extrusion

	Seal integrity is crucial. A good seal ensures “product efficacy, shelf-life stability, and microbial sterility,” says Jeff Morrow-Lucas, director of Engineering at Leak Detection Associates. Non-destructive leak detection technologies include vacuum decay, airborne ultrasound, helium trace, high voltage, and laser-based headspace analysis. Selecting the right technology depends on the product, package, and sensitivity requirements. Morrow-Lucas notes it’s important to understand what the equipment is protecting against and advises verifying that desired pass/fail limits can be delivered by the model chosen. He also recommends selecting flexible equipment that works across today’s and tomorrow’s packaging formats. 

	Recent equipment innovations in seal integrity testing include PTI’s updated VeriPac tester, a vacuum-based unit that combines the ability to locate smaller leaks and shorten test cycle time with several in-demand features, such as non-subjective results, qualitative data analytics, and data trending. FLEX test chambers accommodate multiple flexible package sizes (1).

	Another recent introduction from PTI, the semi-automatic Seal-Scan airborne ultrasound tester, delivers an in-depth profile of seal quality and works with any material combination regardless of color, transparency, print, surface finish, or porosity (2). For online applications, the Seal-Sensor airborne ultrasound tester identifies seal defects in less than one second and locates flaws that a human inspector cannot see. The unit passes or fails each pouch and also captures quantitative, traceable data (3). 

	Lighthouse Instruments supplies laser-based headspace analysis technology for the KHS Series inspection system from Bosch. It performs 100% container/closure integrity (CCI) inspection on vials, cartridges, and ampules and detects leaks by identifying changes in headspace gas composition or total headspace pressure. The company also offers FMS benchtop test systems as well as the Pulsar Headspace CCI Inspection Lease System for online applications (4).

	CMP PHARM.MA combines high-voltage leak detection with visual inspection and labeling in its RS1-LAB/RS2-LAB machines, capable of handling 200 or 400 ampules, vials, or cartridges/min, respectively. Machines are equipped with four leak-test stations and a rotation system to support 360-degree surface inspection. Systems check for particles, correct fill level, leaks, and other flaws (5).

	Although X-ray inspection typically checks for product contaminants, the Integrity-Checktoolsbuilt into the Safeline X34 system from Mettler Toledo can identify products trapped in the seal of a blister pack or other format (6). “Historically, vision systems were utilized to perform this inspection,” says Sarrina Crowley, marketing communications manager at Mettler Toledo, North America, Product Inspection. However opaque packaging can be challenging for vision technology. Because opacity doesn’t affect X-ray performance, it “can detect product in seals in most scenarios,” she reports. 

	For induction seals on containers, cooled thermal imaging technology can check seal quality through the closed cap. The Countec Coglix InspecSeal TI-200 machine, represented in North America by Key International, inspects for damaged, inverted, incomplete, or missing seals; over- or under-heating; and loose or crooked caps and generates real-time data and statistics. The system is compatible with glass or high-density polyethylene (HDPE) containers from 20–200 mm in diameter and 50–300 mm in height and HDPE, polypropylene, or child-resistant caps (7).

	1. PTI-Package Technology & Inspection, “Transformative Shifts in Vacuum Decay Leak Testing,” Brochure, October 2018. 

	2. PTI-Package Technology & Inspection, “Seal Quality Testing and Seal Analysis,” Brochure, 2019. 

	3. PTI-Package Technology & Inspection, “Immediate Seal Check and Seal Verification,” Brochure, 2018. 

	4. Lighthouse Instruments, “Bosch KHS for CCI,” 

www.lighthouseinstruments.com/lighthouse-instruments-bosch-khs-series

	5. CMP Pharm.Ma, “CMP Pharma Inspection,” Brochure, 2018. 

	6. Mettler Toledo Product Inspection, “Mettler Toledo’s New Safeline X34 X-ray Inspection System Quickly and Reliably Performs Component Presence Verification and Contamination Inspection in Pharmaceutical Products,” Press Release, March 25, 2019. 

	7. Coglix Co., “InspectSeal Sealing Inspection System,” Brochure, undated. 

New testing equipment for seal integrity of pharmaceutical packaging improves accuracy and flexibility.

Checking Seal Integrity

	Twin-screw extruders (TSE) are used in multiple pharmaceutical manufacturing processes, including the extrusion of drug-loaded implants and hot-melt extrusion (HME) of amorphous solid-dispersions for improving bioavailability of oral solid-dosage formulations. The Leistritz Pharmaceutical-Nutraceutical Extrusion Seminar (June 12–13, 2019) offered demonstrations of operating equipment and presentations on best practices from extrusion experts. Philippe David, general manager at Sciences Computers Consultants, spoke about using computer simulation to model the extruder, which enables initial evaluation without using samples. Simulation is being used in HME development today, notes David, pointing to a research paper to be published in the August 2019 issue of the 

European Journal of Pharmaceutics and Biopharmaceutics 

titled “Holistic QbD Approach for Hot-Melt Extrusion Process Design Space Evaluation: Linking Materials Science, Experimentation and Process Modeling” (1).  

spoke with David about the benefits and limitations of simulation in pharmaceutical extrusion. 

What are the benefits of using numerical simulation in pharmaceutical twin-screw extrusion?

Simulation is a powerful tool to schedule the best trials to perform. Even at an early stage of the processability evaluation (without any real samples), it is worth trying to see what could happen in term of the quality-by-design (QbD) operational domain. The bad news is that, in general, the physics of the HME process is by far too complex to be fully modelled. The good news is that even with raw or approximate data, it is worth running virtual trials to evaluate the trends. These trends obviously need to be confirmed by real tests [with material], but the required quantity of material needed has dramatically been reduced. 

What do pharma developers need to understand about TSE simulation?

Mechanistic [extrusion experts] understand the relation between torque, flow rate, RPM, residence time, shear rate, etc. These relations are generic and valid in the polymer world as well as in the pharma world. Pharmaceutical process people are specialists in degradability, solubility, etc. These two cultures need to share and fill the gap to design the mechanical-to-pharma bridge and understand the root causes. 

How does your software for pharma extrusion differ from your original software for polymer extrusion?

Ludovic software, designed as a general-purpose TSE simulation, is valid for plastic as well as pharma, but the Ludovic Pharma Edition (introduced in 2018) incorporates pharma-specific considerations. These include material characteristics defined as a function of temperature (rather than a constant value), a specific design of experiment adjusted to the QbD style, and several temperature-related outputs meaningful for pharma. 

Eur. J. Pharmaceutics and Biopharmaceutics 

online DOI:10.1016/j.ejpb.2019.05.021 (Aug. 2019).

A presentation at the Leistritz Pharmaceutical-Nutraceutical Extrusion Seminar explained how simulation tools benefit the development process.

Equipment and Processing Report-06-19-2019

Considering Hot-Melt Extrusion

Checking Seal Integrity

Simulating the Pharma Twin-Screw Extrusion Process