Oral dosing is the most convenient method of drug delivery, typically correlating with high patient compliance. Yet the limited solubility of many modern drugs frequently translates to low bioavailability, making improved solubility a primary goal of oral dosage formulation development. To rationalize this process, drugs can be categorized into four classes based on solubility and permeability using the biopharmaceutical classification system (BCS). BCS Class II and Class IV drug molecules are defined by low aqueous solubility, a characteristic that can be combated through preparation of an amorphous solid dispersion (ASD). By locking the effective molecule in an amorphous state, ASDs improve bioavailability to provide acceptable in vivo performance. However, since amorphous states are at a higher energy level than in crystal form, and therefore less stable, ASD production requires an enabling technology. Spray drying and hot melt extrusion (HME) are among the most widely applied technologies for producing ASDs, with the latter used successfully to manufacture a wide range of drugs including AbbVie commercial products Kaletra®, Norvir®, Viekira Pak®, Mavyret® and Venclexta.
Spray drying is an established technology used to produce a dry powder from a liquid. In the case of drug manufacturing, it involves dissolving the active pharmaceutical ingredient (API) in a solvent with a polymer(s) before spraying the resulting solution such that droplets form and dry within a specialized spray dryer apparatus. The polymer within the droplets locks the API in an amorphous state after drying, the form of which can be dictated by the design of the spray dryer and through manipulation of various operating parameters.
Despite seeing widespread use within the drug development industry, spray drying suffers from several inherent limitations. Firstly, it often requires a secondary drying step; this can significantly extend drug manufacturing timelines and it has considerable potential to introduce strong electrostatic effects. Secondly, spray drying is a batch process, making it less efficient and more prone to human error than continuous manufacturing. Moreover, spray drying equipment is large and difficult to scale, and in many cases depends heavily on dissolution of the API within a highly volatile solvent.
A further drawback of spray drying is that defining the process is extremely challenging since it is impacted by many different thermodynamic and kinetic factors within the system. Although a mass balance and energy balance would usually be prepared, the sheer number of transformations that occur during spray drying (including phase changes, evaporation, and removal of solvents) makes this difficult. For these reasons, many drug manufacturers instead choose to use hot melt extrusion as a more robust approach to ASD production.
Hot melt extrusion
Unlike spray drying, which requires that the API and the polymer reagent are dissolved together in a solvent, Hot Melt Extrusion instead transforms a powder blend of the two components into an extruded ASD. This is achieved using heat and shear from screws to both melt and mix the API and the polymer, generating an extrudate that can then be converted into granules or pellets for additional downstream processing using standard oral solid dose equipment. Although HME is unsuitable for heat sensitive APIs, it offers a wealth of benefits.
A primary advantage of HME is that it follows a first in-first out methodology, allowing it to operate as a continuous process. This makes it a far more economical and efficient option than spray drying, with fewer processing steps and considerably reduced production time. HME also provides capacity for additional components to be added (e.g. surfactants to further aid bioavailability) and, since it requires no solvents for processing, its use for drug manufacturing greatly reduces environmental and safety concerns.
Another important benefit of HME is that equipment is more compact, meaning the technology is easily scalable from the laboratory to commercial manufacturing. Not only does scalability allow for a rapid development cycle, it also increases confidence that transitioning from small scale drug manufacture for pre-clinical studies to production of larger batches suitable for commercial launch will be successful.
Finally, mass and energy balances are relatively straightforward for HME. Although phase transitions occur, these are typically from solid to glassy (and possibly liquid), and every component that enters the system comes back out without losses being incurred. Moreover, energy can be correlated with melt temperature and motor power/torque during HME to facilitate a comprehensive understanding of the process.
Operational advantages of hot melt extrusion
A CMO with HME capabilities can offer partners in drug development and manufacturing several clear advantages to ensure rapid market entry. For instance, in stark contrast to the various spray drying methodologies available, HME supports a seamless transition from small scale manufacture to drug production at quantities suitable for pre-clinical and clinical trials. Then, during early commercial production, clinical scale equipment can readily be used to produce commercial batches simply by running for a greater length of time.
Due to the continuous nature of the unit operation, HME provides a level of flexibility that spray drying simply cannot achieve. The capacity for continuous manufacturing allows HME to respond dynamically to fluctuating market demands without the need to cycle through multiple batches or to manufacture the drug in excess. Although widely used, these approaches respectively extend timelines (due to requirements for cleaning, line clearances, batch close-out etc) and lead to discarded product.
HME also makes simpler since it uses melt temperature and residence time as critical parameters. Both these attributes are relatively straightforward to measure, making it easy to follow existing fillings as well as allowing adaptability to different equipment or changing scales of production. Finally, residence time can be controlled by screw speed, and melt temperature by screw configuration/barrel temperatures, resulting in a quality product time after time.
Flexible and robust drug manufacturing
HME is widely recognized as a key enabling technology to improve drug solubility and bioavailability, and it can also be used to mask an unpleasant taste, reduce food effects, modulate drug release or to address drug stability issues. To learn more about how AbbVie CMO can help with your drug development efforts, contact us at 1-847-938-8524 or visit www.abbviecontractmfg.com