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Specially designed excipients, improvements in processing capabilities, and a growing understanding of the hot-melt extrusion (HME) process is increasing the use of HME as an approach for enhancing the bioavailability of poorly soluble drugs.
It is well-known that increasing numbers of new drug candidates suffer from poor solubility and, consequently, poor bioavailability. Several methods have been developed to overcome poor solubility, including various solid-dispersion technologies, such as spray drying and hot-melt extrusion (HME) with specially designed polymers. Although the technique is not currently suited for all APIs, excipient producers, extruder manufacturers, and formulators are extending the applicability of HME to a broader range of drug compounds.
HME at work
The goal of dispersion is to bring the API into solution before administration of the drug and reduce its particle or crystallite size in order to increase its wettability after administration, explains Andreas Gryczke, global marketing, new products, Pharma Ingredients and Services at BASF. “The solid glassy solutions formed using HME hold the drug molecularly dispersed in a matrix that can contain additional solubilizing functionality and can produce the solid dispersion using gentle shear conditions and high mixing but without the use of solvents,” he explains.
HME is attractive for many different reasons. One of its most desirable features is its minimal environmental footprint with no use of organic solvents, according to Vivian Bi, technical director for pharmaceutical solubilization and contract services at Ashland Specialty Ingredients. “HME is also a continuous processing method that can impart sufficient mixing, heat, and time to result in homogeneous amorphous solid dispersions for APIs with appropriate chemical properties on a scale ranging from batch sizes of approximately 10 grams to 100’s of kilograms per-hour throughput. HME also has a small footprint and minimal special facility requirements and infrastructure needs, allowing for more flexibility in process siting,” adds Ron Beyerinck, senior research fellow with Bend Research.
There are further benefits of HME that go beyond enhancement of solubility, according to Steven Hamlen, group product manager, MRT with Catalent Pharma Solutions. He cites the elimination of hydrolysis associated with wet agglomeration; the suitability for sustained-/controlled-release or enteric coating; flexibility to develop alternative final dose forms (i.e., tablets, capsules, etc.); high drug loading (up to 90%) for certain molecules to allow for decreased tablet size and/or dosing schedules; potentially more stable final compounds, and in some cases, avoiding the need for cold-chain storage; and taste-masking.
Suitability of HME
To be effective, the API must be thermally stable and have a sufficiently low melting point and/or high solubility in the dispersion polymer of choice. The most important properties of the polymer matrix are its glass-transition temperature (Tg) and melt viscosity, solubilization capacity, stability, and toxicity/regulatory status. Excipients play a critical role in HME, according to Bi. “In addition to their contribution to stability and dissolution performance, excipients affect the processability. An excipient with suitable processability in HME not only can improve product quality, but also reduces time and cost related to manufacturing,” she notes. Gryczke adds that polymers can also play a role in drug release by keeping the drug dissolved in a supersaturated solution, thus avoiding precipitation. Low hygroscopic excipients also alleviate moisture uptake, which can lead to nucleation and crystallization of the API during storage.
Separate plasticizers also can be used to improve processability by lowering the polymer’s Tg and melt viscosity while solubilization agents can prevent the API from crystallizing within the polymer or in the digestive tract, according to Hamlen.
Advances in HME
Recent advances in various aspects of the HME process are increasing its suitability for a greater number of APIs. Beyerinck points to the definition of continuous process trains from the unit operations for dispensing and blending upstream of the extruder to the milling, blending, and manufacture of the final dosage form downstream as key. He also notes that process analytical technology tools are enabling the real-time monitoring necessary for scale-up and manufacturing. For Bi, important innovations include the use of supercritical CO2 improvements in extruder screw designs to achieve better dispersive and/or distributive mixing. Hamlen adds that accelerated screening technologies have been developed for salt screening of the base molecule itself to optimize bioavailability.
The development of excipients that are specifically designed for use with HME technology to enhance solubility, combined with high-throughput screening of these excipients for use with specific APIs, is also noted as important by Hamlen and Beyerinck. In particular, BASF has developed special HME excipient grades, along with easy-to-follow approaches for process characterization, including a special process parameter chart that enables formulators to easily understand and optimize the extrusion process, according to Gryczke.
Limitations remain, however. “In comparison with spray drying, the mixing efficiency of HME is lower, which could impact the content uniformity and quality of the extruded SD [solid dispersion] although by selecting suitable excipient(s) and process parameters, the mixing efficiency can be improved,” says Bi. Drug loading in the matrix can also be a challenge, and HME poses constraints related to the thermal properties of the API, according to Beyerinck, with thermal instability or high melting-point molecules leading to narrow processing and formulation spaces for a compound.
“Excipient choice is a balance across the Tg difference between the API, the excipient itself, and the resulting viscosity limits for processing within the hot melt extruders,” agrees Hamlen. “To address this issue, Catalent has partnered with BASF, academia, and key opinion leaders to integrate polymer selection with hot-melt extrusion design and operating parameters into a comprehensive solution that will represent a significant step forward for the technology application overall.”
Gryczke points to the exploitation of near infrared, terahertz, and other sophisticated tools in downstream processing, which is enabling the monitoring of the homogeneous mixing of drugs in polymers and thus production of robust formulations that meet quality-by-design (QbD) requirements. “The advent and implementation of such new techniques will lead to greater adoption of melt-extrusion technology for future drug development in the pharmaceutical industry,” he asserts.
The key to successful HME, according to Hamlen, however, is to remember that solubility, and thus bioavailability, can be enhanced in four main ways: optimizing the API form itself; optimizing the formulation; optimizing HME processing; and optimizing the dose-delivery form. “Optimization of solubility can require iterations across all four factors, and they are not mutually exclusive in most cases, nor predictable without integrated screening, feasibility, and scale-up trials.”
Investments in HME
Several companies have made investments in HME. For example, Ashland Specialty Ingredients added both non-GMP and GMP extruders and a laboratory extruder for formulation screening at a gram scale, and various rheometers, which are instrumental for understanding the thermal rheology of excipients and formulations. BASF formed a strategic partnership with Catalent in 2012 to merge formulation and excipient expertise to deliver the right solutions. BASF also has a partnership with the extruder manufacturer Thermo Fisher Scientific to ensure that processes and excipients are aligned for optimal results. Catalent expanded its OptiMelt HME GMP capabilities at its sites in Somerset, New Jersey, and Schorndorf, Germany for laboratory, pilot, and commercial scales. Bend Research added an 18-mm Leistritz corotating, twin-screw extruder for both development and cGMP manufacture. Processes are routinely scaled up from the 18-mm extruder to two 27-mm extruders (one non-GMP and the other GMP) to support its customers’ clinical-supply needs from Phase I through Phase III.